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 CR’s, only one CRp (2.9%) and 8 PR’s. The CRp patient and 6 of the PR’s 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 CR’s (12.2%), 4 CRp’s (8.2%) and 5 PR’s 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 of longer 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 patient’s 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 – 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, Sponsor’s Proposed Indication(s), Dose, Regimens, Age Groups
Established Name: Clofarabine
(Cl-F-Ara-A)
Proprietary Name: CLOLARÔ
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
Proposed Label: 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 patient’s body surface area (BSA), calculated using the actual
height and weight before the start of each cycle.
B.
State of Armamentarium
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
|
|
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 (Fludara®)
and cladribine (Leustatin®). 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)—both of which were used in Phase I
studies and toxicology dose-ranging studies. For ILEX’s 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
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
FDA-Sponsor Discussion
An End-of-Phase 2 meeting
was held on
Designation on
preNDA package was
submitted to the Division on
· 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):
|
DATE |
meeting,
Submission, action |
indication,
protocol, issues |
agreements
or fda recommendations |
|
|
Pre-IND meeting |
·
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 |
|
|
Receipt of |
Protocol
No. CLO-221: A Phase II,
open-label study of Clofarexin 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 |
|
|
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. |
|
|
Written Request for
Pediatric studies |
|
Phase 1 and Phase 2 studies
in refractory or relapsed pediatric
hematologic malignancies and solid tumors |
|
|
Telecon: Sponsor-FDA |
Clarification
of pediatric protocols |
Sponsor:
studies were not exploratory but registration studies FDA:
request an end-of-Phase 2 meeting |
|
|
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 ³ 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- After
discussion, the following bullet was added: Two
randomized trials in leukemia are strongly recommended. |
|
|
sponsor
request that comments be included as part of the official meeting minutes. |
In
response to the Division’s 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. |
|
|
Request for Fast Track
Designation |
For
the treatment of pediatric primary refractory or relapsed ALL |
|
|
addendum written by FDA |
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. |
|
|
Granted Fast Track
Designation |
Clofarabine
for the treatment of pediatric primary refractory
or relapsed ALL |
|
|
|
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/or CRp[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).
|
|
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 5’-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
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 the clinical investigators who
participated in Protocol 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
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 CR’s, only one CRp (2.9%) and 8 PR’s. The CRp patient and 6 of the PR’s 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 CR’s (12.2%), 4 CRp’s (8.2%) and 5 PR’s 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 of longer 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
Amendment 1,
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
Amendment 2,
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 “End of Phase II” 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 monitor’s approval
prior to implementing prophylactic use of colony stimulating factor.
· Added a patient assent form to the Informed Consent Document for
patients ³7 years
old to sign.
· Revised the response crit eria for PR to aid in the stratification
of patient response.
Amendment 4,
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
Amendment 5, 01 May
2003
Ten patients
were enrolled and treated under this amendment as of the
· 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,
No patients
were enrolled and treated under Amendment 6 prior to the
· 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 ³70 rather
than ³50, 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 ³7 years
old according to the local IRB/IEC and institutional requirements.
Table 5 lists the principal investigators and the corresponding participating institutions.
Site Investigator Name & Address
001 Edythe Albano, MD The Children’s Hospital
1056 East 19th Avenue, B115 Denver, Colorado
80218
002 Arnold Altman, MD
003 Victor M Aquino, MD The
004 Paul S Gaynon, MD Children’s Hospital Los
Angeles 4650 Sunset Boulevard MS#54
005 Stuart Goldman, MD Children’s Memorial
Hospital 2300 Children’s 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 Children’s Hospital
and Health Center 3020 Children’s 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 Children’s
Hospital One Children’s Place St Louis, Missouri 63110
011 Susan Rheingold, MD The Children’s
Hospital of Philadelphia 34th Street and Civic Center
Boulevard 4300 Wood Building Philadelphia, Pennsylvania 19104
012 Arthur Kim Ritchey, MD Pediatric
Hematology/Oncology Children’s 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
015 Kimo C Stine, MD
016 Timothy C Griffin, MD Cook Children’s
Research Hematology Laboratory
017 N/A Site number was assigned, however the
investigator was not registered and did not participate
in this study.
018 Violet Shen, MD Children’s Hospital of
Orange County Pediatric Subspecialty Faculty, Inc.
455
019 Susan M Blaney, MD
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,
Other
Participants
Independent
Response Review Panel Address
Craig Alan
Hurwitz Maine Children’s Cancer Program 100 US Route One-Unit 107
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
Independent
Pathologist Address
Mark P
Burton, MD Department of Pathology, MTLP
Lackland Air
Force
Table 6 indicates enrollment by site.
|
Site |
Investigator |
Institution |
N
=36* |
% |
|
001 |
Edythe Albano, MD |
Children's Hospital at |
1 |
2.8 |
|
002 |
|
|
1 |
2.8 |
|
004 |
Paul Gaynon, MD |
Children's |
1 |
2.8 |
|
006 |
Sima |
MD |
6 |
16.7 |
|
007 |
Richard Kadota, MD |
Children's |
1 |
2.8 |
|
009 |
Lori Luchtman-Jones, MD |
|
2 |
5.6 |
|
010 |
|
St. Jude Children's |
7 |
19.4 |
|
011 |
Susan Rheingold, MD |
The Children's |
4 |
11.1 |
|
012 |
A. |
Children's |
1 |
2.8 |
|
014 |
Peter Steinherz, MD |
|
9 |
25.0 |
|
015 |
|
|
1 |
2.8 |
|
019 |
Susan Blaney, MD |
|
1 |
2.8 |
|
023 |
Robert Arceci, MD |
Johns Hopkins, |
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