ODAC Briefing Document

 

Application #

N021673

Drug Name

 

Medical Reviewer

 

Medical Team Leader

 

Statistician

Martin H. Cohen, M.D.

 

John R. Johnson,M.D.

 

Rajeshwari Sridhara, Ph.D.

 

Documents reviewed

EDR Document: 2456412 Location: \\CDSESUB1\N21673\N_000\2004-03-29

\\CDSESUB1\N21673\N_000\2004-08-02

\\CDSESUB1\N21673\N_000\2004-08-05

\\CDSESUB1\N21673\N_000\2004-10-06

 

 

 

 

 


 

Table of Contents

 

Executive Summary......................................................................................... 1

I.††††††††† Recommendations.................................................................................................. 1

A.††††††† Recommendation on Approvability................................................................. 1

B.†††††††† Recommendation on Phase 4 Studies and/or Risk Management Steps............. 1

II.††††††† Summary of Clinical Findings................................................................................ 1

A.††††††† Brief Overview of Clinical Program................................................................ 1

B.†††††††† Efficacy......................................................................................................... 1

C.††††††† Safety............................................................................................................ 2

D.††††††† Dosing........................................................................................................... 2

E.†††††††† Special Populations........................................................................................ 2

Clinical Review................................................................................................ 3

I.††††††††† Introduction and Background................................................................................ 3

A.††††††† Drug Established and Proposed Trade Name, Drug Class, Sponsorís Proposed Indication(s), Dose, Regimens, Age Groups.................................................................................. 3

B.†††††††† State of Armamentarium for Indication(s)....................................................... 4

C.††††††† Important Milestones in Product Development................................................ 5

D.††††††† Other Relevant Information.......................................................................... 14

E.†††††††† Important Issues with Pharmacologically Related Agents............................... 14

II.††††††† Clinically Relevant Findings From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews 15

III.†††††† Human Pharmacokinetics and Pharmacodynamics............................................ 15

A.††††††† Pharmacokinetics......................................................................................... 15

B.†††††††† Pharmacodynamics...................................................................................... 16

IV.†††††† Description of Clinical Data and Sources........................................................... 16

A.††††††† Overall Data................................................................................................ 16

B.†††††††† Table Listing the Clinical Trials..................................................................... 16

C.††††††† Postmarketing Experience............................................................................ 16

D.††††††† Literature Review........................................................................................ 16

V.††††††† Clinical Review Methods..................................................................................... 16

A.††††††† How the Review was Conducted................................................................. 16

B.†††††††† Overview of Materials Consulted in Review................................................. 17

C.††††††† Overview of Methods Used to Evaluate Data Quality and Integrity............... 17

D.††††††† Were Trials Conducted in Accordance with Accepted Ethical Standards...... 17

E.†††††††† Evaluation of Financial Disclosure................................................................. 17

VI.†††††† Integrated Review of Efficacy............................................................................. 17

A.††††††† Brief Statement of Conclusions..................................................................... 17

B.†††††††† General Approach to Review of the Efficacy of the Drug.............................. 18

C.††††††† Detailed Review of Trials by Indication......................................................... 18

D.††††††† Efficacy Conclusions.................................................................................... 35

VII.†††† Integrated Review of Safety................................................................................ 38

A.††††††† Brief Statement of Conclusions..................................................................... 39

B.†††††††† Description of Patient Exposure Per Sponsor............................................... 39

C.††††††† Methods and Specific Findings of Safety Review.......................................... 40

D.††††††† Adequacy of Safety Testing......................................................................... 54

E.†††††††† Summary of Critical Safety Findings and Limitations of Data......................... 54

VIII.††† Dosing, Regimen, and Administration Issues..................................................... 54

IX.†††††† Use in Special Populations................................................................................... 54

A.††††††† Evaluation of Sponsorís Gender Effects Analyses and Adequacy of Investigation†††††††††† 55

B.†††††††† Evaluation of Evidence for Age, Race, or Ethnicity Effects on Safety or Efficacy 55

C.††††††† Evaluation of Pediatric Program................................................................... 55

D.††††††† Comments on Data Available or Needed in Other Populations...................... 55

X.††††††† Conclusions and Recommendations.................................................................... 56

A.††††††† Conclusions................................................................................................. 56

B.†††††††† Recommendations....................................................................................... 56

C.††††††† Binding phase 4 commitments...................................................................... 56

XI.†††††† Appendix 1- Inspection Results........................................................................... 57

XII.†††† Appendix 2 - Basic protocol elements................................................................. 62

 


Table of Tables

 

Table 1: FDA approved drugs for pediatric ALL and AML. 5

Table 2: Regulatory review.. 7

Table 3: Clofarabine studies. 14

Table 4: Submitted clinical trials (pediatric patients only) 16

Table 5: Participating sites. 21

Table 6: Enrollment by site. 22

Table 7: Reasons for discontinuation. 23

Table 8: Demographics and Karnofsky Performance Status. 23

Table 9: Prior Induction Therapies. 24

Table 10: Best response - ITT population. 24

Table 11: CLO-222 FDA Responder Summary. 25

Table 12: CLO-222 Reasons for Discontinuation. 26

Table 13: CLO 222 Patients receiving a transplant 26

Table 14: CLO-222 Non-responding patients who received a transplant 27

Table 15: CLO-222 Survival (weeks) 27

Table 16: Pediatric AML patients benefiting from clofarabine + transplant treatment 28

Table 17: CLO-212 Patient Enrollment by Site. 29

Table 18: Reason for Discontinuation. 30

Table 19: CLO-212 Demographics and Performance Status. 31

Table 20:Prior Regimens. 31

Table 21:Prior Transplants. 32

Table 22: Objective Responses. 32

Table 23: CLO-212 FDA Response Summary. 33

Table 24: CLO 212 Survival (weeks) 34

Table 25: CLO-212 Responder reasons for discontinuation. 34

Table 26: CLO 212 Bone Marrow or Stem Cell Transplant 35

Table 27: Median Total Exposure to Clofarabine by Cycle. 39

Table 28: Concurrent Conditions at Baseline. 40

Table 29: Adverse Events Summary. 41

Table 30: AE's in > 5% of Pediatric Patients by CTC Toxicity Grade. 42

Table 31: Adverse Events in Pediatric Patients by Maximum CTC Grade. 45

Table 32: SAE's in 2 or More Pediatric Patients Overall by NCI CTC Grade. 50

Table 33: Hepato-biliary toxicities. 52

 


Table of Figures

 

 

..... Figure 1: Clofarabine structural formula. 3


Clinical and Statistical Review for NDA 21-673

††††††††† Executive Summary

 

††††††††† I.†††††† Recommendations

 

A.††††††† Recommendation on Approvability

 

††††††††††††††† Awaits ODAC discussion and advice.

 

B.                 Recommendation on Phase 4 Studies and/or Risk Management Steps

†††††††††††††††

††††††††††††††† Awaits ODAC discussion and advice.

 

†††††††††††††††

††††††††† II.††††† Summary of Clinical Findings

 

A.††††††† Brief Overview of Clinical Program

 

††††††††††††††† Two Phase II pivotal studies have been conducted by ILEX in pediatric patients with

refractory or relapsed ALL (CLO-212) or refractory or relapsed AML (CLO-222), in which clofarabine was used as a single agent.

 

In addition phase I/II pediatric and adult clofarabine studies conducted at The University of Texas MD Anderson Cancer Center (MDACC) were submitted.

 

B.                 Efficacy

 

In pediatric AML there was 1 CRp (2.9%) and 8 PR's among 35 treated patients. Twelve of 35 AML patients went on to transplant including the CRp patient, 6 PR's, 3 not-evaluable patients and 2 treatment failures. The usual definition of efficacy is long duration complete responses or prolonged overall survival. In trial CLO-222 there were no CRís, only one CRp (2.9%) and 8 PRís. The CRp patient and 6 of the PRís went on to have a transplant. Long duration responses and prolonged survival were confined to patients who received a transplant. Four clofarabine plus transplant patients had longer time to progression (TTP) with that treatment then they had with the therapy that immediately preceded clofarabine. Three of these 4 patients also had longer TTP with clofarabine plus transplant then they had with their preceding transplant.

 

In Pediatric ALL there were 6 CRís (12.2%), 4 CRpís (8.2%) and 5 PRís among 49 treated patients. Eight ALL patients went on to transplant including 2 CR's,2 CRp's, 2 PR's, 1 not-evaluable patient and 1 treatment failure The usual definition of efficacy is long duration complete responses or prolonged overall survival. In study CLO-212 among the 6 CR patients 3 had ongoing responses at the time of data cutoff and 3 had relapsed. Using the criteria oflonger TTP with clofarabine + transplant than to immediate prior therapy 2 of 6 CR patients, 3 of 4 CRp patients and 0 of 5 PR patients demonstrated benefit. With further follow-up benefit may be demonstrated in 3 additional CR patients and 1 PR patient.

 

C.††††††† Safety

 

The toxicity profile of clofarabine was as expected for a heavily pretreated acute leukemia pediatric patient population.The principal toxicities were nausea and vomiting, hematologic toxicity, fever and febrile neutropenia, hepatobiliary toxicity, infections and renal toxicity. Clofarabine can produce systemic inflammatory response syndrome/ capillary leak syndrome (SIRS), manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, and multi-organ failure. Cardiac toxicity most often manifest as left ventricular systolic dysfunction with accompanying tachycardia may also occur. With attentive patient care, however, the drug was tolerable.

 

D.                Dosing

†††††††††††††††

The recommended clofarabine pediatric dose and schedule is 52 mg/m2 administered by intravenous infusion (IVI) over 1 to 2 hours daily for 5 consecutive days. Treatment cycles are repeated every 2 to 6 weeks following recovery or return to baseline organ function. The dosage is based on the patientís body surface area (BSA), calculated using the actual height and weight before the start of each cycle.

 

E.                 Special Populations

 

Pediatrics -

 

The studies were performed in pediatric patients

 

Elderly -

 

††††††††††† No clofarabine data is available for elderly patients.

 

††††††††††† Renal or Hepatic Impairment -

 

The major route of clofarabine elimination is renal clearance. Clofarabine is likely not metabolized by the CYP450 enzyme system,

†††††††††††††††

Gender -

 

††††††††††† Results appeared comparable for males and females

 

Ethnicity -

 

††††††††††† There was no significant effect of race/ethnicity on either efficacy or safety results.

 

Pregnancy Ė Category D

 

Pregnancy studies have not been done in humans. Female patients with

childbearing potential must have a negative serum pregnancy test before starting each cycle of clofarabine therapy. Men and women with reproductive potential must use an effective contraceptive method while taking the drug. If a patient becomes pregnant while taking clofarabine, she should be apprised of the potential hazard to the fetus. Because

impairment of fertility is unknown, reproductive planning should be discussed with the patient, as appropriate.

 

††††††††† Clinical Review

 

††††††††† I.†††††† Introduction and Background

 

A.††††††† Drug Established and Proposed Trade Name, Drug Class, Sponsorís Proposed Indication(s), Dose, Regimens, Age Groups

 

Established Name:†††† Clofarabine (Cl-F-Ara-A)

Proprietary Name:†††† CLOLAR

Applicant:†††††††††††††††††† Ilex Products Inc

Drug Class:††††††††††††††† Antimetabolite: Second-generation purine nucleoside analogue

 

The chemical structure of clofarabine is 2-chloro-2'-fluoro-deoxy-9-b-arabinofuranosyladenine. The molecular formula is C10H11ClFN5O3. The molecular weight is 303.68.

CLOLAR (1 mg/mL) is supplied in a 20 mL, single-use vial. The 20 mL vial contains 20 mg clofarabine dissolved in 20 mL of 0.9% sodium chloride injection, United States Pharmacopeia (USP). The pH range of the solution is 4.5 to 7.5. The solution is clear and practically colorless, and free from foreign matter. The structural formula (Figure 1) follows:

 

 

 

 

 

 

Figure 1: Clofarabine structural formula

 

 

††††††††††† Indication:

 

Current: None

 

Proposed: Clofarabine is indicated for the treatment of pediatric patients 1 to 21 years old with refractory or relapsed acute leukemias.

 

††††††††††† Dosage and Administration

 

††††††††††††††† Current Label:None

 

ProposedLabel: The recommended clofarabine pediatric dose and schedule is 52 mg/m2 administered IV over 1 to 2 hours daily for 5 consecutive days. Treatment cycles are repeated every 2 to 6 weeks following recovery or return to baseline organ function. The dosage is based on the patientís body surface area (BSA), calculated using the actual height and weight before the start of each cycle.

 

B.     State of Armamentarium for Indication(s)

 

Drugs approved by the FDA for the treatment of pediatric ALL and AML are listed in Table 1.

†††††††††††

 

 

 

 

 

 

 

 

††††††††††† Table 1: FDA approved drugs for pediatric ALL and AML

 

Drug

Approved for Pediatric Acute Leukemias

ALL

AML

Asparaginase

X

 

Corticosteroids

††††† Dexamethasone

†††† Prednisolone

†††† Prednisone

 

X

X

X

 

X

 

X

Cyclophosphamide

X

X

Cytarabine

X

X

Daunorubicin

X

 

Doxorubicin

X

X

Mercaptopurine

X

 

Methotrexate

X

 

Teniposide

X

 

Thioguanine

 

X

Tretinoin

 

X

Promyelocytic

Vincristine

X

X

 

C.     Important Milestones in Product Development

 

††††††††††† Clofarabine was originally synthesized at the †††††††††††††††† as a hybrid

molecule to incorporate the favorable properties of both fludarabine (Fludaraģ) and cladribine (Leustatinģ). It is a nucleoside pro-drug that must be metabolized to its triphosphate conjugate by deoxycytidine kinase within tumor cells before activity occurs. Compared to other purine nucleoside analogues, it has greater affinity for the activating phosphorylating enzyme deoxycytidine kinase. It is differentiated from other purine nucleoside analogues by incorporating 2 halogen atoms (fluorine and chlorine) within its chemical structure.

 

Clofarabine was first investigated at The University of Texas M.D. Anderson Cancer Center (MDACC); IND 43,275 filed in 1993. The original route of synthesis produced Lot BK-I-48 (June 1993) that was used in preclinical, toxicology, pharmacology, and the early Phase I dose-escalation study. This lot was synthesized at_____________. However, the API manufacturer changed to __________and 2 more lots were synthesized, Lot GB-3-63-1 (November 1999) and Lot GB-3-77-1 (December 1999)óboth of which were used in Phase I studies and toxicology dose-ranging studies. For ILEXís pivotal Phase II studies (CLO-212 and CLO-222), the API manufacturer was ___and the drug product manufacturer was ___.The lot numbers used in CLO-212 were CTM-02059, ICJ001, CTM-02081, N12008F, CO3E015.

 

The lot numbers used in CLO-222 were CTM-02059, ICJ001, and CO3E015.

In March 2001, ILEX acquired licensing rights from________, which previously licensed rights from MDACC and a new IND was filed by ILEX on 07 November 2001 (IND 63,641).

 

The ILEX IND used API lots manufactured by both _______________and later on ___lots manufactured by ASI, but eventually transitioned to lots made only at____. In March 2002, ILEX assumed responsibility for the MDACC IND (43,275).

 

Clofarabine was granted Orphan Drug Designation for ALL on 07 February 2002 and Orphan Drug Designation for AML on 14 March 2002. The ILEX pre-IND meeting was held on 30 August 2001 and the ILEX IND (63,641) was opened on 07 December 2001. The MDACC studies were transferred to the ILEX IND 11 April 2002.

 

FDA-Sponsor Discussion

 

An End-of-Phase 2 meeting was held on 29 April 2002. ILEX requested Fast Track

Designation on 08 May 2003, which was approved by the Division on 08 July 2003. A

preNDA package was submitted to the Division on 15 July 2003. On 13 August 2003, ILEX and the Division had a preNDA teleconference, as a result of which the following decisions were made:

The phase 2 study design (CLO-212 and CLO-222) was determined to be acceptable.

Proportion of responding patients who have a successful transplant was ††††††† determined to be an important issue.

The COG Response Criteria could be acceptable after review by the Division.

CR/CRp/PR can be considered a clinical benefit, depending on response duration,††† survival, toxicity, and results achievable with other therapy. For transplant patients,clinical benefit depends upon the success of transplant after treatment with clofarabine.

The rolling NDA submission was determined to be acceptable.

The analysis plan was determined to be acceptable.

The ALL approach was determined to be acceptable for AML.

 

A summary of the regulatory history of clofarbine, provided by Robert White, Jr., M.D. follows (Table 2):

†††††††††††

 

 

 

 

 

 

††††††††††† Table 2: Regulatory review

DATE

 

meeting, Submission, action

indication, protocol, issues

agreements or fda recommendations

August 30, 2001

Pre-IND meeting

U.S. registration strategy

         Adult salvage ALL: Two Phase II studies

         20% CR + CRp

Standard battery of GLO in vitro genotoxicity tests performed concurrently with Phase II trial

Randomized, controlled studies for approval; for Phase II studies: high rate of durable CRs

Phase III protocol requested

November 11, 2001

Receipt of IND

Protocol No. CLO-221: A Phase II, open-label study of Clofarexin adult patients

with refractory or relapsed acute myelogenous leukemia (AML).

 

To demonstrate an overall response (OR) rate > 30% in

salvage therapy adults with refractory or relapsed AML.

 

         The pre-clinical dcvelopment does not support further Phase II development; additional toxicology and genetic toxicology studies should be ongoing

         There was cardiac toxicity seen in the rat study

         A phase 2 trial is unlikely to be adequate to support accelerated approval for an indication of acute leukemia

January 28th 2002

 

Receipt of new pediatric protocols

CLO-212

a phase 2 open label study of Clofarex in children with refractory or relapsed acute lymphoblastic leukemia (ALL)

 

Indications: For the induction of remission in patients less than are equal to 21 years of age with ALL who had failed to achieve remission following two or more different regimens

 

CLO-222

a phase 2 open label study of Clofarex in children with refractory or relapsed acute myelogenous leukemia (AML)

 

Indications: For the induction of remission in patients less than are equal to 21 years of age with AML who had failed to achieve remission following two or more different regimens

The expansion of the protocol to a larger number of patients with intent to register a marketing claim should be discussed with the FDA prior to the enrollment of patients. Issues to be resolved would include entry criteria, endpoints, stratification, and statistical analysis.

This ALL protocol could form one component of a program in pediatric oncology that may be used to qualify for an Exclusivity extension in response to a Written Request from the FDA should the sponsor be interested in qualifying for an exclusivity extension.

 

This protocol may be sufficient to fulfill the requirements of the Pediatric Rule if an adult indication is sought for AML.

March 3, 2002

Written Request for Pediatric studies

 

Phase 1 and Phase 2 studies in refractory or relapsed pediatric hematologic malignancies and solid tumors

March 21, 2002

Telecon: Sponsor-FDA

Clarification of pediatric protocols

Sponsor: studies were not exploratory but registration studies

FDA: request an end-of-Phase 2 meeting

April 29, 2002

End-of-Phase 1 meeting

Pediatric Acute Lymphoblastic Leukemia

 

Pediatric Acute Myelogenous Leukemia

 

 

 

 

ILEX contends that treatment with a single agent (CLOFAREX) administered to

Pediatric patients with refractory/ relapsed ALL and AML and demonstrating a ≥ 30% overall response rate is clinically significant in this refractory patient population. Do you concur?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Do you concur that the study design of our Phase II pediatric ALL (CLO-212) and/or AML pediatric (CLO-222) protocol as a single pivotal trial (multi-center) would be sufficient for registration approval of CLOFAREX for treatment of pediatric salvage ALL?

 

 

 

 

Advice to the Sponsor: The FDA views the planned Phase 2 study as exploratory. Plans for a randomized Phase 3 trial should be made. Please be advised that the Agency strongly recommends two Phase 3 trials to support an application. (2 pediatric or 1 adult/1 pediatric, all in leukemia).

 

Response by the FDA:

No, not if the Sponsor is asking whether this endpoint and magnitude demonstrated in the proposed single arm trials would be adequate for registration. Although Phase 2 trials may be the next step in the development of this drug, and an overwhelmingly positive result

(extremely high rate of durable complete response) in single arm trials might be considered

for registration in these diseases, randomized controlled studies are generally required for approval because the clinical relevance of the observed magnitude of response and duration is best evaluated in the presence of a comparator arm. Historical comparisons are fraught with difficulty and conclusions drawn from such comparisons are not generally valid.

 

(See answers to #7 and #8 above.) Complete response rate observed in a properly designed randomized trial might be accepted as the basis for accelerated approval. The

biological rationale to support the clinical significance of a CRp associated with the proposed chemotherapy combination is not evident, and it would not be considered a valid component of the CR-endpoint. (See Oncologic Drug Advisory Committee discussion of the Mylotarg NDA- March 17, 2000)

 

After discussion, the following bullet was added:

Two randomized trials in leukemia are strongly recommended.

May 6, 2002

sponsor request that comments be included as part of the official meeting minutes.

 

In response to the Divisionís preference for 2 randomized Phase 3 trials to support

registration of Clofarex in the pediatric population, with either 2 pediatric trials OR one trial in adults and the second trial in children, ILEX ontends that it will be difficult to enroll

patients due to the limited number of patients available for the AML and ALL indications.

 

As presented by ILEX, we anticipate great difficulty in gaining consensus from the medical community as to an agreement defining the comparator arm for a randomized Phase 3 pediatric study with Clofarex and to complete these trials in a reasonable time frame.

 

The Division gave ILEX approval to initiate the Phase 2 pediatric protocols.

 

May 9, 2003

 

Request for Fast Track Designation

For the treatment of pediatric primary refractory or relapsed ALL

 

May 23, 2003

 

addendum written by FDA 10/13/03

Request for elimination of the solid tumor component from Pediatric Written Request

Rationale: absence of evidence of activity of clofarabine in pediatric solid tumors and therefore no scientific or ethical basis for performing a formal study.

 

FDA agreed

There was no endpoint stated for the Phase 2 component.

The endpoint of complete remission rate for hematologic malignancies was added.

July 8, 2003

Granted Fast Track Designation

Clofarabine for the treatment of pediatric primary

refractory or relapsed ALL

 

August 13, 2003

Pre-NDA meeting

Pediatric Refractory or Relapsed ALL

Nonrandomized, open-label, Phase 2 study of clofarabine in pediatric patients with refractory or relapsed ALL Primary endpoint: CR and/orCRp[1])

 

Supportive: CLO-222[2] and ID99-383[3]

 

Sponsor contends that the design of the Phase II pediatric ALL study (CLO-212) is sufficient for registration approval of clofarabine for treatment of relapsed or refractory pediatric patients with ALL.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The sponsor asked whether 40 patients from CLO-212 would be sufficient to

file an NDA.

 

 

The sponsor asked whether it would be acceptable to submit the data on the first 40 patients, and then submit data on any additional patients at a later date.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The sponsor asked whether the Division would accept a post-marketing commitment to

conduct a Phase 2 study in a similar population of patients.

 

 

ILEX contends that treatment with a single agent (clofarabine) administered to

Pediatric patients with relapsed or refractory ALL demonstrating a > 15% overall response rate (CR + CRp) is clinically significant in this heavily pretreated and refractory population.

 

The Sponsor contends that a 1 to 3 month remission is considered durable and a clinical benefit in this population of patients (refractory or in second or subsequent relapse).

 

The Sponsor contends that a CR or CRp is a clinical benefit, especially for patients who are enabled to undergo a bone marrow, stem cell, or umbilical cord transplant.

 

The Sponsor contends that a PR (>5% to <25% blasts) is of clinical benefit in this group of children, allowing selected patients to receive a bone marrow, stem cell, or umbilical cord transplant.

 

The Sponsor contends that the ID99-383 pediatric ALL efficacy data will be supportive of the registration application by demonstrating additional clinical activity in pediatric leukemia.

 

The Sponsor contends that CRF's for only those patients who died or discontinued from the study be supplied.

 

The Sponsor asked what the age cut-off was for pediatric studies and gave the following

Scenario: Suppose a patient is diagnosed at age 17, then relapses at age 18 or 19. Would that patient be treated on the adult protocol and can the data from this patient be included in the pediatric patient dataset?

 

The design is acceptable

 

The number of patients studied is relatively small and the CR rate is relatively low.

 

The Sponsor was encouraged to increase the size of the study to gain experience.

 

It was strongly suggested that the Sponsor continue to accrue patients regardless of whether you submit the NDA as proposed.

 

If the proposed NDA is approved, it will likely be accelerated approval under subpart H. This requires confirmatory studies. It must be credible that the confirmatory studies will be completed in an acceptable time frame. This means that the protocols for confirmatory studies should be submitted prior to submission of the NDA. If there is concern that the studies will have difficulty accruing patients or that approval will interfere with completion of the confirmatory studies, the studies should have completed accrual or accrued a substantial portion of the patients, prior to approval

under subpart H.

 

a commitment to a specific number of patients generally cannot be made, but encouraged the sponsor to continue accruing patients.

 

The Division discouraged this approach and stated that in general, it is acceptable to submit additional safety data (i.e., 120-day safety update), but not efficacy data. The Division explained that in the rolling review process, the sponsor must submit complete sections of the NDA. The sponsor has the option of submitting additional information as an amendment, but if the information is substantial and is submitted within 3 months of the due date, it may extend the review clock by 3 months.

 

The Division further explained that 40 patients may not be enough if the drug has a low response rate, however, 40 patients may be enough if the drug has a high response rate.

This will be an ongoing discussion and should be addressed again in the future when more data is available.

 

The Division explained that the type of confirmatory study that may be appropriate has not been assessed at this stage, however, the Division encouraged the sponsor to submit any proposed post-marketing commitment protocols with the NDA for review. The Division reminded the sponsor that the NDA is not restricted to Subpart H accelerated approval, because there may be enough data to receive full approval.

 

The Oncology Division does not commit to a particular response rate in advance. This will be a review issue. There are many other factors to consider, such as response duration, toxicity and results that can be achieved with other therapy.

 

An important aspect will be the proportion of responding patients that have a successful

transplant.

 

This will be a review issue.

 

For transplant patients, it depends on the success of the transplant after treatment with Clofarabine. For non-transplant patients, it depends on response duration, survival, toxicity and results achievable with other therapy.

 

Same answer as above

 

 

 

 

 

 

This will be a review issue.The Division noted that only 9 patients were treated with the regimen proposed for marketing and none of these had a CR. In patients treated at

other doses, there was disagreement between the independent review board and the investigator regarding CR status.

Documentation of Refractory/ relapse history should be provided for each patient.

The Division asked the Sponsor to submit for each patient the prior treatment regimens received (including dates)

and the response and response duration status after each regimen. The date of most recent relapse or documentation of refractoriness should be provided for each patient.

For transplanted patients the date of transplant and results of transplant should be submitted.

 

The Division added that a complete electronic database on all patients is submitted.

Otherwise, CRFs on all patients should be submitted. We need complete information on each patient. There are relatively few patients in this NDA.

 

The Division said that this is a review issue and would have to be addressed on a case-by-case basis.

 

 

 

 

 

Overview of Clinical Studies

 

MDACC conducted 2 Phase I studies and 2 Phase II studies with clofarabine in patients with leukemias and solid tumors. In addition, ILEX has conducted a total of 5 clinical studies with clofarabine in patients with leukemias and solid tumors as well as an emergency expanded access program. Table 3 provides a chronology of the clofarabine studies including the ongoing emergency expanded access patient treatment program (EEAP).

 

††††††††††† Table 3: Clofarabine studies

 

Date

Patient

 

Protocol

Sponsor

Initiated

Population

Disease Description

DM93-036

MDACC

Feb 1999

Adult

Solid and Hematologic Malignancies

DM99-225

MDACC

Sep 1999

Adult

CLL Refractory to Fludarabine/Alkylators

ID99-383

MDACC

Aug 2000

Pediatric

Hematologic Malignancies

ID00-038

MDACC

May 2001

Adult

Acute Leukemia and MDS, Refractory/ Relapsed

CLO-221

ILEX

Nov 2001

Adult

AML

CLO-212

ILEX

Apr 2002

Pediatric

ALL

CLO-222

ILEX

Jan 2002

Pediatric

AML

CLO-151

ILEX

May 2002

Adult

Solid Tumors

CLO-141

ILEX

June 2002

Adult

Clofarabine in Combination with Ara-C in AML, ALL, High-Risk MDS; or CML Blast Phase as First or Second Line Therapy

Expanded

Access

ILEX

Jan 2002

Adult/Pediatric

AML and ALL

 

D.††††††† Other Relevant Information

†††††††††††††††

Clofarabine inhibits DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action on ribonucleotide reductase, and by terminating DNA

chain elongation and inhibiting repair through incorporation into the DNA chain by

competitive inhibition of DNA polymerases. The affinity of clofarabine triphosphate for

these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In

preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by

incorporation into the DNA chain during the repair process. Clofarabine 5í-triphosphate

also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-

apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to

programmed cell death.

 

E.†††††††† Important Issues with Pharmacologically Related Agents

 

The nucleoside analogs are among the most widely used class of drugs for treating acute leukemias. Cytosine nucleoside analogs include cytarabine (ara-C), the most active drug in treating AML, gemcitabine which has broad antitumor activity including hematologic malignancies, and 5-azacytidine and decitabine which have activity in myelodysplastic syndrome. Guanosine analogs, including 6-mercaptopurine and 6-thioguanine, have antitumor activity in ALL. Deoxyadenosine nucleoside analogs, including fludarabine, cladribine and deoxycorfomycin, have activity against several hematologic malignancies.

 

††††††††† II.††††† Clinically Relevant Findings From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews

 

A.     Clinical Pharmacology and Biopharmaceutics

 

See appropriate review.

 

B.     Statistics

 

See statistical review.

 

C.     Chemistry

 

See chemistry review.

 

D.    Animal Pharmacology and Toxicology

 

See pharmacology review.

 

††††††††† III.††† Human Pharmacokinetics and Pharmacodynamics

 

A.                 Pharmacokinetics

 

The population pharmacokinetics of clofarabine were studied in 40 pediatric patients ages 2 to 19 years old (21 males/19 females) with relapsed or refractory ALL or AML given

multiple doses. Clofarabine pharmacokinetics were weight-dependent, although intravenous infusion (IVI) of 52 mg/m2 produced equivalent exposure across a wide range of weights. Clofarabine pharmacokinetics were best described by a 2-compartment model with a systemic clearance of 32.8 L/h (27% between-subject variability) in a 40 kg pediatric patient.

 

Clofarabine had a beta-half-life of 6.4 hours in a 40 kg person having a WBC count of 10 x 103/mL. Clofarabine was 47% bound to plasma proteins, predominantly to albumin, and had a volume of distribution at steady-state in a 40 kg person having a WBC count of 10 x 103/mL of 210 L (72% between-subject variability). Based on noncompartmental analysis, systemic clearance and volume of distribution at steady-state were estimated to be 28.8 L/h/m2 and 172 L/m2, respectively. As WBC count was depleted, clofarabine AUC decreased and Cmax increased, although the change was likely not clinically significant. No apparent difference in pharmacokinetics was observed between patients with ALL and AML or between males and females.

 

Hepatic and Renal Impairment: The effects of significant renal or hepatic insufficiency on the disposition of clofarabine have not been assessed.

 

Special Populations: The studies were performed in pediatric patients. No clofarabine data is available for elderly patients. Results appeared comparable for males and females.

†††††††††††

B.                 Pharmacodynamics

 

††††††††††††††† No pharmacodynamic data was reviewed.

 

††††††††† IV.†††† Description of Clinical Data and Sources

 

A.                 Overall Data

 

††††††††††††††† EDR submission of March 29, 2004

 

B.                 Table Listing the Clinical Trials

††††††††††† Table 4: Submitted clinical trials (pediatric patients only)

Data Source

ALL

n

AML

n

ALL/AML

n

Total

67

46

113

CLO-212

49

 

49

CLO-222

 

35

35

ID99-383 (MDACC)

17

8

25

DM 93-036/CLO-221/CLO-141

1

3

4

 

 

C.                 Postmarketing Experience

 

††††††††††††††† None

 

D.††††††† Literature Review

 

Manuscripts and abstracts relating to the submitted clinical trials. Manuscripts related to the role of stem cell transplantation in the management of acute pediatric leukemias.

 

††††††††† V.††††† Clinical Review Methods

 

A.††††††† How the Review was Conducted

 

The efficacy review is based primarily on data submitted as SAS transport files for the two pivotal pediatric AML (CLO-222) and ALL (CLO-212) studies. Bone marrow aspirates/biopsy were provided in the Aspirate database, hematology analysis in the ANL_Hema database, hematology in the HEMA database and AE's in the adverse event dataset.
 

B.††††††† Overview of Materials Consulted in Review

 

††††††††††† See above.

 

C.††††††† Overview of Methods Used to Evaluate Data Quality and Integrity

 

DSI on-site audit was used to audit sponsor's data quality, integrity and analysis.

 

D.††††††† Were Trials Conducted in Accordance with Accepted Ethical Standards

 

Yes.

 

E.†††††††† Evaluation of Financial Disclosure

 

The sponsor has submitted certification that they have not entered into any financial arrangement with any of theclinical investigators who participated inProtocol CLO-212 "A Phase II, Open-Label Study of Clofarabine in Pediatric Patients with Refractory or Relapsed Acute Lymphoblastic Leukemia" or Protocol CLO-222 " A Phase II, Open-Label Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Myelogenous Leukemia" . This certification was signed on 3/29/04 by Mike Bernstein, MPH, Senior Director Regulatory Affairs and Safety.

 

††††††††† VI.†††† Integrated Review of Efficacy

 

A.                 Brief Statement of Conclusions

 

In pediatric AML there was 1 CRp (2.9%) and 8 PR's among 35 treated patients. Twelve of 35 AML patients went on to transplant including the CRp patient, 6 PR's, 3 not-evaluable patients and 2 treatment failures. The usual definition of efficacy is long duration complete responses or prolonged overall survival. In trial CLO-222 there were no CRís, only one CRp (2.9%) and 8 PRís. The CRp patient and 6 of the PRís went on to have a transplant. Long duration responses and prolonged survival were confined to patients who received a transplant. Four clofarabine plus transplant patients had response durations to that treatment exceeding those of immediate prior therapy. Three of these 4 patients also had longer TTP with clofarabine plus transplant then they had with their preceding transplant.

 

In Pediatric ALL there were 6 CRís (12.2%), 4 CRpís (8.2%) and 5 PRís among 49 treated patients. Eight ALL patients went on to transplant including 2 CR's,2 CRp's, 2 PR's, 1 not-evaluable patient and 1 treatment failure The usual definition of efficacy is long duration complete responses or prolonged overall survival. In study CLO-212 among the 6 CR patients 3 had ongoing responses at the time of data cutoff and 3 had relapsed. Using the criteria oflonger TTP with clofarabine + transplant than to immediate prior therapy 2 of 6 CR patients, 3 of 4 CRp patients and 0 of 5 PR patients demonstrated benefit. With further follow-up benefit may be demonstrated in 3 additional CR patients and 1 PR patient.

 

B.††††††† General Approach to Review of the Efficacy of the Drug

 

Individual patient data provided by the sponsor were analyzed to confirm sponsor's reported results and analyses.†††††††††††

 

C.††††††† Detailed Review of Trials by Indication

 

The efficacy review is based primarily on two multicenter trials, one for pediatric ALL and one for pediatric AML

 

Protocol Review

 

The initial version of the phase 2 study designs was approved by Ilex on 24 January 2002. There were 6 amendments. Basic protocol elements for studies 212 and 222 are provided in the Appendix.

 

Amendment 1, 05 March 2002

No patients were enrolled and treated under the original protocol or Amendment 1. This amendment included administrative changes to improve the clarity and consistency of the document such as previous clinical data, treatment regimen, number of patients required to enroll, updated cycle definition to reflect the current practice at MDACC, and any references to the study being performed in Europe, as well as the following specific changes:

The decision was made to treat all patients at 52 mg/m2/day for a maximum of 12 cycles, thus all references to Induction and Post- induction phases of treatment were deleted. The rationale for selecting the 52 mg/m2/day dose was added and the timing for subsequent cycles was revised.

The decision was made to limit enrollment to 40 patients, thus all references to a patient population >40 were deleted.

A decision was made to broaden the inclusion criteria to allow patients in first or subsequent relapse as there are fewer treatment options for pediatric AML patients. Other aspects of the entry criteria were modified for clarification and to reflect recent data and current practice.

Inclusion laboratory values were revised based on toxicity seen in an ongoing MDACC study and to allow for greater flexibility in enrolling patients.

The incidence of pediatric AML was updated for 2002, as was information regarding pediatric and adult exposure to clofarabine and timing for repeat cycles to reflect the current practice at MDACC.

The decision was made to confine this study to the US, thus all references to European sites and regulatory requirements were deleted.

 

 

 

Amendment 2, 01 April 2002

Three patients were enrolled and treated under Amendment 2. This amendment included administrative changes for clarification and consistency, as well as substantive changes. The substantive changes are itemized below:

Cardiac and renal toxicities information was added to "possible Risks/Discomfort" section in response to a request from the FDA.

A requirement was added to specify that patients with acute promyelocytic leukemia (M3) be treated with at least 2 prior regimens before being considered for this study.

A clarification was made that both male and female patients were required to use barrier contraception.

A 25% dose reduction was added in the event a patient experienced a second occurrence of a grade 3 event.

 

Amendment 3, 08 May 2002

Sixteen patients were enrolled, but only 15 were treated under Amendment 3. This amendment consisted of administrative changes for clarification and consistency, as well as substantive changes, many of them at the request of the FDA following the ďEnd of Phase IIĒ Meeting (29 April 2002), and investigator comments that arose from the Investigator's Meeting (05 April 2002). The substantive changes are itemized below:

Per FDA request, the significance level was changed from 0.04 to 0.02, which resulted in a change in the power from 94 to 79%, and a change in the confidence level from between 16 to 44% to between 25 to 55%.

Per FDA request, a requirement was added that cardiac assessments be performed every 4 cycles of treatment.

Per FDA request, more pharmacokinetic samples were added to provide more reliable pharmacokinetic parameter estimates.

The targeted remission rate was revised from 30 to 40%.

Safety and pharmacokinetic data were updated to reflect the first completed clinical study, DM93-036.

Per FDA request, patients experiencing an NCI CTC grade 2 neurologic or cardiac event were to have their clofarabine dose level re-evaluated by the medical monitor.

A statement was added to obtain the medical monitorís approval prior to implementing prophylactic use of colony stimulating factor.

Added a patient assent form to the Informed Consent Document for patients 7 years old to sign.

Revised the response crit eria for PR to aid in the stratification of patient response.

 

Amendment 4, 18 July 2002

Two patients were enrolled and treated under Amendment 4; however 1 of these patients

(001-0021) had been previously enrolled under Amendment 3, but was not treated. This amendment consisted of administrative changes to reflect the decision to include Europe, thus changes were made throughout the protocol and appendices to be compliant with European regulatory requirements. However, no European patients were enrolled in this study.

 

Amendment 5, 01 May 2003

Ten patients were enrolled and treated under this amendment as of the 21 November 2003 data cutoff date. Amendment 5 consisted of administrative changes for clarification and consistency, as well as substantive changes. The substantive changes are itemized below:

Changes were made throughout the protocol and appendices to reflect the name change from CLOFAREX to clofarabine.

Information regarding HIPAA was added to the protocol and the informed consent documents.

The stopping rule was voided to continue enrollment to 40 patients to collect further response and safety data.

 

Amendment 6, 10 October 2003

No patients were enrolled and treated under Amendment 6 prior to the 21 November 2003 data cutoff. This amendment consisted of administrative changes for clarification and consistency, as well as substantive changes, and patients enrolling in the ongoing study are subject to the terms of this amendment. The substantive changes are itemized below:

Upon review of all SAEs reported in the CLO-212 and CLO-222 studies, it appears that patients with poor Karnofsky Performance Status (KPS) are at an increased risk of developing hypotension and capillary leak syndrome, which may be attributed to sepsis. Thus, in order to minimize the possibility of these occurrences and more importantly, to reduce the risk to patients, entry criteria were changed to include a KPS of 70 rather

than 50, patients with known or suspected fungal infections or febrile neutropenia at study entry were to be excluded.

Cardiac assessments were increased for all patients with either ECHO or MUGA to be performed prior to every cycle. In select patients, cardiac assessments will be performed on Days 1, 3, and 5 of all cycles and will be reviewed by a pediatric cardiologist.

A requirement was added that patients who undergo peripheral blood stem cell transplant or bone marrow transplant post-clofarabine treatment be followed for 120 days post-transplant in an effort to gather safety and efficacy data on clofarabine in this subpopulation.

Patients who achieved a response and did not go on to transplant or who discontinued for reasons other than disease relapse or treatment failure were to be followed until disease relapse, the initiation of alternative therapy, or death, whichever occurred first. All SAEs and drug-related AEs were to be followed until resolution, initiation of alternative treatment, or patient death.

A statement clarifying that no deletions or major deviations were to be made to the sample ICD/PIS or patient assent document without prior approval from ILEX, and the patient assent document had to be signed by patients 7 years old according to the local IRB/IEC and institutional requirements.

 

Table 5 lists the principal investigators and the corresponding participating institutions.

†††††††††††

†††††††††††

††††††††††† Table 5: Participating sites

Site††††† Investigator Name & Address††

001 ††††† Edythe Albano, MD The Childrenís Hospital 1056 East 19th Avenue, B115 Denver, ††††††† Colorado 80218

002 ††††† Arnold Altman, MD Connecticut Childrenís Medical Center 282 Washington Street †††††††† Hartford, Connecticut 06106

003 ††††† Victor M Aquino, MD The University of Texas Southwestern Medical Center 5323 †††††††† Harry Hines Boulevard Dallas, Texas 75390

004 ††††† Paul S Gaynon, MD Childrenís Hospital Los Angeles 4650 Sunset Boulevard MS#54 †††††† Los Angeles, California 90027

005 ††††† Stuart Goldman, MD Childrenís Memorial Hospital 2300 Childrenís Plaza, Box #30 †††††††† Chicago, Illinois 60614

006 ††††† Sima C Jeha, MD Replaced by Michael Rytting MD The University of Texas MD †††††††††† Anderson Cancer Center 1515 Holcombe Boulevard Box 87 Houston, Texas 77030

007 ††††† Richard P Kadota, MD Childrenís Hospital and Health Center 3020 Childrenís Way, MC ††††††††††† 5035 San Diego, California 92123

008 ††††† N/A Site number was assigned, however the investigator was not registered and did not †† participate in this study.

009 ††††† Lori Luchtman-Jones, MD Washington University School of Medicine St Louis ††† Childrenís Hospital One Childrenís Place St Louis, Missouri 63110

010 ††††† Bassem Razzouk, MD St Jude Childrenís Research Hospital 332 North Lauderdale Street

††††††††††† Memphis, Tennessee 38105

011 ††††† Susan Rheingold, MD The Childrenís Hospital of Philadelphia 34th Street and Civic †††††††† Center Boulevard 4300 Wood Building Philadelphia, Pennsylvania 19104

012 ††††† Arthur Kim Ritchey, MD Pediatric Hematology/Oncology Childrenís Hospital of Pittsburgh 3705 Fifth Avenue Pittsburgh, Pennsylvania 15213

013 ††††† N/A Site number was assigned, however the investigator was not registered and did not †† participate in this study.

014 ††††† Peter Steinherz, MD Memorial Sloan Kettering Cancer Center 1275 York Avenue

††††††††††† New York, New York 10021

015 ††††† Kimo C Stine, MD Arkansas Childrenís Hospital 800 Marshall Street Little Rock, ††††††††††† Arkansas 72202

016 ††††† Timothy C Griffin, MD Cook Childrenís Medical Center Hematology/Oncology &

††††††††††† Research Hematology Laboratory 901 Seventh Avenue, Fort Worth, Texas 76104

017 ††††† N/A Site number was assigned, however the investigator was not registered and did not †† participate in this study.

018 ††††† Violet Shen, MD Childrenís Hospital of Orange County Pediatric Subspecialty Faculty, ††† Inc. 455 South Main Street Orange, California 92868

019 ††††† Susan M Blaney, MD Texas Childrenís Hospital 6621 Fannin Street, MC 3-3320

††††††††††† Houston, Texas 77030

020 ††††† N/A Site number was assigned, however the investigator was not registered and did not †† participate in this study.

021 ††††† N/A Site number was assigned, however the investigator was not registered and did not †† participate in this study.

022 ††††† Bruce Gordon, MD Pediatric Hematology/Oncology & Bone Marrow Transplantation ††††† Program University of Nebraska Medical Center Omaha, Nebraska 68198-2168

023 ††††† Robert J Arceci, MD, PhD Sidney Kimmel Comprehensive Cancer Center at Johns

††††††††††† Hopkins1650 Orleans Street, Room 2M51 Baltimore, Maryland 21231

 

 

Other Participants

Independent Response Review Panel Address

Craig Alan Hurwitz Maine Childrenís Cancer Program 100 US Route One-Unit 107

Scarborough, Maine 04074-9308

Nita Louise Seibel, MD Children's National Medical Center Dept of Pediatric Hematology/ Oncology 111 Michigan Avenue NW, Suite 4293 Washington, DC 20010

Marta Kligerman Rozans, MD, PhD Department of Pediatrics Tulane Medical School SL37

1430 Tulane Avenue New Orleans, Louisiana 70112

 

Independent Pathologist Address

Mark P Burton, MD Department of Pathology, MTLP

Wilford Hall Medical Center

2200 Berquist Drive, Suite 1

Lackland Air Force Base, Texas 78236

 

††††††††††† Table 6 indicates enrollment by site.

††††††††††† Table 6: Enrollment by site

Site

Investigator

Institution

N =36*

%

001

Edythe Albano, MD

Children's Hospital at Denver

1

2.8

002

Arnold Altman, MD

Connecticut Children's Medical Center

1

2.8

004

Paul Gaynon, MD

Children's Hospital of Los Angeles

1

2.8

006

Sima Jeha, MD

MD Anderson Cancer Center

6

16.7

007

Richard Kadota, MD

Children's Hospital of San Diego

1

2.8

009

Lori Luchtman-Jones, MD

Washington University Medical Center

2

5.6

010

Bassem Razzouk, MD

St. Jude Children's Research Hospital

7

19.4

011

Susan Rheingold, MD

The Children's Hospital of Philadelphia

4

11.1

012

A. Kim Ritchey, MD

Children's Hospital of Pittsburgh

1

2.8

014

Peter Steinherz, MD

Memorial Sloan-Kettering Cancer Center

9

25.0

015

Kimo Stine, MD

Arkansas Children's Hospital

1

2.8

019

Susan Blaney, MD

Texas Children's Cancer Center

1

2.8

023

Robert Arceci, MD

Johns Hopkins, Baltimore, MD

1

2.8

*One patient 014-0006 was enrolled but not treated. One patient was initially enrolled as 001-0012 but not treated at the time due to elevated AST; the patient later re-enrolled as Patient 001-0021.

 

Reasons for discontinuation of therapy are listed in Table 7. The two most common reasons were failure to achieve response and patient scheduled to receive a transplant.

†††††††††††

 

 

 

 

Table 7: Reasons for discontinuation

††††††††††† Termination Reason

N=35

%

Investigator decision

2

5.7

Refused further treatment

1

2.9

AE

2

5.7

Failure to achieve response after 2 cycles

13

37.1

Disease Progression

2

5.7

Transplant

9

25.7

Death from AE

5

14.3

Not available

1

2.9

 

††††††††††† The median age of the 35 treated patients was 12 years. See Table 8 for patient ††††††††† demographics and Karnofsky performance status.

††††††††††† Table 8: Demographics and Karnofsky Performance Status

Variable

N=35 (%)

Age Category

††† 0 to 2

††† >2 to < 12

†† >12 to < 16

†† >16 to 22

 

2 (5.7)

16 (45.7)

7 (20.0)

10 (28.6)

Sex

†† Female

†† Male††

 

13 (37.1)

22 (62.9)

Ethnicity

†† Hispanic

†† Caucasian

†† Black

†† Asian

†† Other

 

7 (20.0)

19 (54.3)

3 (8.6)

3 (8.6)

3 (8.6)

Karnofsky Performance Status

†† 100

†† 90

†† 80

†† 70

†† 60

 

 

14 (40.0)

9 (25.7)

8 (22.9)

3 (8.6)

1 (2.9)

†††††††††††

Each of the patients had received at least 1 prior induction therapy. Most of the patients (18/35 [51%]) had received at least 3 prior induction therapies before study entry (Table 9).

†††††††††††

††††††††††† Table 9: Prior Induction Therapies

 

ITT Patients (N=35)

Number of Prior Induction Regimens

n

%

1

5

14.3

2

12

34.3

3

8

22.9

4

4

11.4

5

6

17.1

 

 

A total of 18/35 (51%) patients received at least 1 transplant before study entry: 13/35 (37%) received 1 prior transplant and 5/35 (14%) received 2 prior transplants

 

††††††††††† Table 10 indicates best response, judged by the Independent Review panel, and confirmed†††††† by FDA review.

††††††††††† Table 10: Best response - ITT population

Response Category

N=35

%

Complete Remission (CR)

0

0.0

Complete Remission-Absence of Total Platelet Recovery (CRp)

1

2.9

Partial Remission (PR)

8

22.9

Treatment Failure

19

54.3

Not Evaluable*

7

20.0

††††††††††††††††††††††† * 2 patients had early death; 1 patient stopped treatment after 2 doses; 1 patient †††††††††††††††††††††† ††††††††††† stopped treatment after 4 doses; 1 patient was enrolled but not treated

 

Table 11 indicates the FDA reviewer's response summary. This table includes disease history including time to relapse from prior therapies. The asterisk indicates the number of months on the treatment immediately preceding entry into the clofarabine study. As indicated 3 of the responders had a prior stem cell transplant. Only one patient had a confirmed response (second marrow > 21 days after the initial response was demonstrated). Response duration (days) and time from initiation of clofarabine treatment to disease progression (TTP) or death are also indicated. Response duration and TTP, for patients with CR, CRp or PR, was censored at the date of the last bone marrow evaluation

†††††††††††


Table 11: CLO-222 FDA Responder Summary

Patient

014-0003

006-0013

009-0018

014-0002

014-0019

014-0027

015-0017

006-0036

014-0031

Time to first relapse (mo)

3

2

4*

26

10*

1

8

14

1

Time to 2nd relapse (mo)

12

1

-

27

-

3*

2*

16

1*

Time to 3rd or later relapse (mo)

3, 9*

2, 1*

-

7,2,9*

-

-

-

1,1*

-

Stem cell transplant (Y or N)

Y

N

N

Y

Y

N

N

Y (2)

N

Stem cell transplant response duration (mo)

5

-

-

6

6

-

-

12,16

-

Clofarabine response

CRp

PR

PR

PR

PR

PR

PR

PR

PR

Clofarabine response confirmed Y or N

Y

N

N

N

N

N

N

N

Y

Clofar response duration (d)**

519+

12

34

141

44+

14

410+

82+

53+

Clofarabine TTP or death (d)**

547+

54

67

161

78+

49

465+

130+

93+

Post-clofarabine SCT (Y or N)

Y

N

N

Y

Y

N

Y

Y

Y

Current status (Alive or Dead)

A

D

D

D

D

A

A

A

A

Post-clofarabine OS (w)

93.6+

7.7

24.3

30.3

39.0

29.0+

67.9+

16.4+

24.9+

* response duration for treatment immediately preceding clofarabine treatment

** censored at the time of last bone marrow evaluation


Reasons for discontinuation of clofarabine treatment for treatment responders are summarized in Table 12..

Table 12: CLO-222 Reasons for Discontinuation

 

Pt ID

 

IRRP

Response

 

Alive at

Last Follow Up

 

Reason for Discontinuation

Progressive

Disease

AE

Transplant

006-0013

PR

N

 

Y

 

009-0018

PR

N

Y

 

 

014-0002

PR

N

 

 

Y

014-0003

CRp

Y

 

 

Y

014-0019

PR

N

 

 

Y

014-0027

PR

Y

 

 

Y

015-0017

PR

Y

 

 

Y

006-0036

PR

Y

 

 

Y

014-0031

PR

Y

 

 

Y

Clofarabine treated patients who underwent a transplant are listed in Table 13. As indicated in the table, transplants were performed in 5 patients who had not responded to clofarabine based on independent committee review (3 patients non-evaluable, 2 patients treatment failures).

Table 13: CLO 222 Patients receiving a transplant

 

 

Survival from

Start of Clofarabine (w)

(30APR04 Cutoff)

Site-Patient

Number

# of Courses of

Clofarabine

Clofarabine Response

(IRRP)

006-0014

2

NE

75.3+

006-0036

3

PR

16.4+

010-0020

2

TF

28.7

010-0022

1

NE

24.4

010-0023

1

TF

20.6+

014-0002

2

PR

30.3

014-0003

5

CRp

93.6+

014-0019

2

PR

39.0

014-0027

4

PR

29.0+

014-0031

2

PR

24.9+

014-0034

4

NE

23.3+

015-0017

1

PR

67.9+

 

†††††††††††

†††††††††††††††

 

 

††††††††††† Patients who were treatment failures or who were non-evaluable and nevertheless, ††††††† received a transplant are summarized in Table 14.

†††††††††††

††††††††††† Table 14: CLO-222 Non-responding patients who received a transplant

Patient

010-0020

0010-0023

006-0014^

010-0022

014-0034^

Time to first relapse (mo)

4

2

13*

13*

4

Time to 2nd relapse (mo)

1

1

-

NE

19

Time to 3rd or later relapse (mo)

1,1,1*

1, 1*

-

 

14*

Stem cell transplant (Y or N)

N

Y

N

Y

Y

Stem cell transplant response duration (mo)

-

7

-

5

11

Clofarabine response

TF

TF

NE

NE

NE

Clofarabine TTP or death (d)

109

55+

107+

ND

137+

Post-clofarabine SCT (Y or N)

Y

Y

Y

Y

Y

Current status (Alive or Dead)

D

A

A

D

A

Post-clofarabine OS (w)

28.7

20.6+

75.3+

24.4

 

††††††††††† ^ Not eligible for enrollment. 20% marrow blasts (010-0022) and 12% blasts†††††††††††† (014-0034) at entry; ND=no data;

††††††††††† NE=non-evaluable; TF=treatment failure

 

††††††††††† Survival data for patients enrolled in CLO-222 is summarized in Table 15.

††††††††††† Table 15: CLO-222 Survival (weeks)

Response Category

N

Kaplan-

Meier

Median

Lower

Limit of

95% CI

Upper

Limit of

95% CI

Minimum

Maximum

%

Censored

CRp

1

.

.

.

93.6

93.6

100.0

PR

8

30.3

24.3

.

7.7

67.9

50.0

Treatment Failure/Not Evaluable

26

12.4

5.4

22.1

1.6

84.9

15.4

Overall Remission(CR+CRp)

1

.

.

.

93.6

93.6

100.0

Remission(CR+CRp+PR)

9

24.3

24.3

.

7.7

93.6

55.6

All Patients

35

21.0

7.7

30.3

1.6

93.6

25.7

 

Patients benefiting from clofarabine treatment, using the criteria of longer TTP to clofarabine + transplant compared to the therapy immediately preceding clofarabine, are listed in Table 16.

 

 

 

††††††††††† Table 16: Pediatric AML patients benefiting from clofarabine + transplant ††††††† treatment

Patient

014-0003

015-0017

006-0036

014-0031

TTP for treatment immediately preceding entry into CLO-222 (mo)

9

2

1

1

Prior Stem cell transplant (Y or N)

Y

N

Y (2)

N

Post-transplant response duration (mo)

5

-

12, 16

-

Number of courses of clofarabine

5

1

3

2

Clofarabine response

CRp

PR

PR

PR

Clofarabine TTP (d)

519+

465+

130+

93+

Post-clofarabine SCT (Y or N)

Y

Y

Y

Y

Current status (Alive or Dead)

A

A

A

A

Post-clofarabine OS (w)

93.6+

67.9+

16.4+

24.9+

 

Efficacy conclusions

 

The patient population studied is a difficult population to evaluate. Patients had failed several prior treatment regimens and had often failed one or more bone marrow or stem cell transplants. In this multiply resistant population it is difficult to demonstrate efficacy. Further, depending upon availability of a donor and other clinical considerations, stem cell transplant is an important modality of treatment. Transplants are often performed before blood count recovery from treatment and before additional cycles of treatment can be administered.

 

The usual definition of efficacy is long duration complete responses or prolonged survival. In trial CLO-222 there were no CRís, only one CRp and 8 PRís. The CRp patient and 6 of the PRís went on to have a transplant. Long duration responses and prolonged survival were confined to patients who received a transplant. Thus patient 014-0003 had a TTP of 74+ weeks after starting clofarabine and an OS of 93.6+ weeks. This patient had had a stem cell transplant prior to starting clofarabine with a post-transplant response duration of 5 months and an overall response duration of 9 months. The clofarabine plus transplant TTP has already exceeded that of prior treatment, including transplant, and the remission is ongoing.

 

Patients 006-0036 and 014-0031 also seemed to benefit from clofarabine plus transplant. The former patient had received 2 transplants prior to enrollment in CLO-222 and had also failed two consecutive post-transplant regimens administered prior to clofarabine treatment. The TTP following the second transplant was 16 months. Thus if benefit was determined based on the two most recently failed chemotherapy regimens then the patient benefited from clofarabine + transplant treatment. If it is based on the remission duration achieved after prior transplant it is too early to tell.

 

Similarly patient 015-0017 has an ongoing TTP with clofarabine plus transplant treatment that currently just exceeds his prior therapy TTP.

 

††††††††††† Pediatric ALL (CLO-212)

 

STUDY PATIENTS

 

This report summarizes the data for the 49 patients enrolled and treated. Data cutoff for this report is 30 April 2004.

 

Eighteen study sites participated in CLO-212; however, only 14 sites enrolled patients into the study (Table 17). One (patient 005-0001) of the 50 patients enrolled in the study did not receive study drug and was not included in the efficacy or safety analyses.

††††††††††† Table 17: CLO-212 Patient Enrollment by Site

 

 

 

N=50

Site

Investigator

Institution

n

%

001

Edythe Albano, MD

Children's Hospital at Denver

2

4.0

002

Arnold Altman, MD

Connecticut Children's Medical Center

1

2.0

004

Paul Gaynon, MD

Children's Hospital of Los Angeles

7

14.0

005

Stewart Goldman, MD

Children's Memorial Hospital, Chicago

2

4.0

006

Sima Jeha, MD

MD Anderson Cancer Center

3

6.0

007

Richard Kadota, MD

Children's Hospital of San Diego

5

10.0

009

Lori Luchtman-Jones, MD

Washington University Medical Center

4

8.0

010

Bassem Razzouk, MD

St. Jude Children's Research Hospital

5

10.0

011

Susan Rheingold, MD

The Children's Hospital of Philadelphia

2

4.0

012

A. Kim Ritchey, MD

Children's Hospital of Pittsburgh

2

4.0

014

Peter Steinherz, MD

Memorial Sloan-Kettering Cancer Center

9

18.0

016

Timothy Griffin, MD

Cook Children's Hematology & Oncology

Center, Fort Worth Tx

2

4.0

018

Violet Shen, MD

Children's Hospital of Orange County CA

3

6.0

019

Susan Blaney, MD

Texas Children's Cancer Center, Houston

3

6.0

 

††††††††††† Patient Disposition

 

Table 18 summarizes the reasons for discontinuation for the 49 patients who received study drug. A total of 20/49 (41%) patients discontinued because of failure to respond after 2 cycles of treatment and 9/49 (18%) discontinued due to disease progression. Of the 3 patients who were discontinued by the investigator, 2 were to receive a transplant. Therefore a total of 6 (12%) patients were discontinued to receive transplant.

†††††††††††

†††††††††††

††††††††††† Table 18: Reason for Discontinuation†††††††††

 

ITT Patients (N=49)

Termination Reason

n

%

Investigator Decision

3

6.1

Refused Further Treatment

3

6.1

Adverse Event or Treatment Toxicity

1

2.0

Failure to Achieve Response after 2 Courses

20

40.8

Disease Progression

9

18.4

Patient Scheduled to Receive Transplant

4

8.2

Death:

 

 

†† Malignant Disease

1

2.0

†† Adverse Event

3

6.1

†† Other

3

6.1

Not Available

2

4.1

 

Protocol Deviations

 

Multiple patients received steroid treatment per investigator decision. The protocol excluded steroid treatment. As these patients likely had received steroids multiple times in the past the FDA disregarded this protocol deviation.

 

††††††††††† Demographic and Other Baseline Characteristics

 

Patient demographics and performance status are recorded in Table 19.

 

 

 

 

 

 

 

 

 

 

 

 

††††††††††† Table 19: CLO-212 Demographics and Performance Status

Variable

 

ITT Patients (N=49)

Age (years):

Mean

12.18

 

Median

12

 

Minimum

1

 

Maximum

20

Age Category

0 to <2

3 (6.1%)

 

>2 to <12

22 (44.9%)

 

>12to<16

11 (22.4%)

 

>16 to <22

13 (26.5%)

Sex:

Female

20 (40.8%)

 

Male

29 (59.2%)

Ethnicity:

Caucasian

20 (40.8%)

 

Hispanic

20 (40.8%)

 

Other

3 (6.1%)

 

Black

6 (12.2%)

Karnofsky Grade

n

%

100

15

30.6

90

12

24.5

80

7

14.3

70

8

16.3

60

4

8.2

50

2

4.1

Not assessed

1

2.0

 

ALL Subtype

 

A subtype analysis showed that 20/49 (41%) patients had subtype Ll and 12/49 (25%) had subtype L2. The subtype was not known for 17/49 (35%) patients. Analysis showed that 32/49 (65%) patients had a pre-B cell phenotype; 9/49 (18%) had B cell; 5/49 (10%) had T cell/pre-T cell; and 3 (6%) were unknown.

 

Each of the patients had received at least 2 prior regimens. The median number of prior regimens (Table 20) was 3 (range: 2 to 6).

Table 20: Prior Regimens

Number of

ITT Patients (N=49)

Prior Regimens

n

%

2

17

34.7

3

17

34.7

4

12

24.5

5

1

2.0

6

2

4.1

 

Prior transplants are shown in Table 21.†††††††††††

††††††††††† Table 21: Prior Transplants

 

ITT Patients (N=49)

Number of Prior Transplants

n

%

0

34

69.4

1

13

26.5

2

2

4.1

 

 

Efficacy Evaluation

 

All responses are per IRRP determination and have been confirmed by the FDA. Table 22 summarizes the best objective response rates.

 

Table 22: Objective Responses

Response Category

N=49

n

%

Complete Remission (CR)

6

12.2

Complete Remission Without Total Platelet Recovery (CRp)

4

8.2

Partial Remission (PR)

5

10.2

Treatment Failure

26

53.1

Not Evaluable

8

16.3

Overall Remission (CR + CRp)*

10

20.4

CR+CRp+PR

15

30.6

*95% Confidence Interval for Independent Panel Response Rate of Overall Remission (CR + CRp): (0.10, 0.34)

 

 

Table 23 indicates the FDA reviewer's response summary. This table includes disease history including time to relapse from prior therapies. The single asterisk indicates the number of months on the treatment immediately preceding entry into the clofarabine study. As indicated 3 of the responders had a prior stem cell transplant. Only one clofarabine treated patient had a confirmed response (second marrow > 21 days after the initial response was demonstrated). Response duration (days) and time from initiation of clofarabine treatment to disease progression or death are also indicated. Response duration and TTP, for patients with CR, CRp or PR, was censored at the date of the last bone marrow evaluation.

 


Table 23: CLO-212 FDA Response Summary

Patient

007-0018

014-0030

006-

0047

018-0036

009-

0045

014-

0049

009-0024

009-0028

012-0014

014-0040

010-

0042

004-0025

006-0003

006-

0004

014-0007

Time to 1st relapse mo)

22

86

1

30

53

53

2

25

31

3

50

11

19

8

28

Time to 2nd relapse (mo)

2

35

3

10

48*

31

4*

25*

1

3

4*

6

1

4*

1

Time to 3rd or later relapse (mo)

1*

18*

1, 1*

2, 31*

-

68*

-

-

1, 1, 2, 1*

1*

-

2, 1*

1, 1*

-

8*

Stem cell transplant (Yes or No)

N

Y (2)

N

Y (2)

N

N

Y

Y

N

N

N

Y

N

Y

Y

Stem cell transplant resp dur (mo)

-

27, 10

-

6, 29

-

-

2

20

-

-

-

4

-

2

3

Clofarabine response

CR

CR

CR

CR

CR

CR

CRp

CRp

CRp

CRp

PR

PR

PR

PR

PR

Clofar response confirmed (Y or N)

N

Y

N

Y

Y

Y

Y