BRIEFING BOOK FOR THE MARCH 13, 2003 ODAC

MEETING REGARDING ACCELERATED APPROVAL

CLINICAL PHASE 4 COMMITMENTS

nda 21-029 TEMODARÒ (temozolomide)
SCHERING-PLOUGH CORPORATION

 

 

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

 

 

BRIEFING BOOK FOR THE MARCH 13, 2003 ODAC

MEETING REGARDING ACCELERATED APPROVAL

CLINICAL PHASE 4 COMMITMENTS

nda 21-029 TEMODARÒ (temozolomide)
SCHERING-PLOUGH CORPORATION

 

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

TABLE OF CONTENTS

I. GENERAL INFORMATION 1

A. Drug Name 1

B. Indication 1

C. Accelerated Approval Date 1

D. Outline of the Summary Basis of Approval 1

II. DESCRIPTION OF COMMITMENTS INCLUDING TITLES OF INDIVIDUAL STUDIES 3

III. INFORMATION CONCERNING THE COMMITMENT STUDY 4

A. Essentials of the Study Design 4

1. Summary of the Study Sites (Geography, Number) 4

2. Patient Population (Eligibility/Exclusion Criteria) 4

3. Endpoints 5

4. Treatment Schema 5

5. Efficacy and Safety Monitoring 6

6. Statistical Design 7

B. Date of Initiation 10

C. Accrual 10

D. Estimated Timelines for Study Completion 10

E. Estimated Timelines for Submission of Study Results 11

IV. OTHER ISSUES 11

A. Difficulties encountered in conduct/accrual/completion of trial 11

1. Changes in Medical Practice 11

2. Natural History of the Disease 11

3. Safety Considerations 12

4. Timelines 12

B. Other Applicant Concerns 13

Attachment 1 14

Attachment 2 16

Attachment 3 18

Attachment 4 20

 

Briefing book for the March 13, 2003 ODAC meeting regarding accelerated approval clinical phase 4 commitments
NDA 21-029 TEMODAR® (temozolomide)
Schering-Plough corporation

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

 

 

I. GENERAL INFORMATION:

A. Drug Name: TEMODAR® (temozolomide)

B. Indication: For the treatment of adult patients with refractory anaplastic astrocytoma (AA), i.e., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine.

C. Accelerated Approval Date: August 11, 1999

D. Outline of the Summary Basis of Approval:

The TEMODAR® clinical development program for malignant gliomas focused on GBM and AA from 1993 to 1998. The New Drug Application (NDA) for temozolomide capsules for the treatment of recurrent malignant GBM (glioblastoma multiforme) and AA was submitted to the FDA on August 12, 1998.

During the NDA review process, the FDA agreed that there was no standard of care for relapsed AA in recurrent disease, and agreed to review the AA indication under the accelerated approval regulations with a phase Phase IV 4 commitment to confirm clinical benefit in an AA population in a randomized controlled study to be approved by the Agency.

The clinical section of the AA accelerated approval NDA was based upon a multicenter 32 institution open-label Phase 2 study of temozolomide in the treatment of adult patients with AA at first relapse (Study C/I94-123). The primary efficacy endpoint of this study was Progression progression-free survival (PFS) at six months. Secondary efficacy endpoints were overall survival, objective response and HQL (Health-related Quality of Life). An analysis of event free survival was also included in the NDA.

The FDA clinical review for accelerated approval of temozolomide in AA was completed January 29, 1999. According to FDA analysis of the results of the study C/I94-123 (ITT population n=162), the response rate was 5% CR and 28% PR; median PFS was 6.18 months; PFS at 6 months was 51% (95% CI 43-59%); median OS was 13.59 6 months; and survival rate at 6 months was 75% (95% CI 68-82%); the safety profile was acceptable.

In AA patients who were refractory to both a nitrosourea and procarbazine, the FDA analysis was indicated that the overall response rate (CR + PR) was 22% with 9% complete response and the median duration of all response was 50 weeks (16-114 week range) with median duration of complete response of 64 weeks (range 52 to 114 weeks); the median PFS was 4.4 months and median OS was 15.9 months.

The Oncology Oncologic Drugs Advisory Committee (ODAC) in its 1/12/1999 meeting unanimously agreed (12-Yes, 0-No) that:

In eEarly February 1999, the sponsor submitted a Protocol protocol Concept concept Sheet sheet (PCS) for a proposed post-approval study in newly diagnosed AA patients to be conducted by the cooperative group Radiation Therapy Oncology Therapy Group (RTOG). At that time the proposal was for a two-arm study comparing radiation with BCNU to radiation with BCNU followed by temozolomide. There was no need for a Phase 1 safety program prior to this Phase 3 study.

On February 12, 1999, the FDA issued an approvableapprovable letter for TEMODAR® for the indication "treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients at first relapse with disease progression on a nitrosourea and procarbazine drug regimen".

The PCS of the RTOG study in newly diagnosed AA patients (Study 98-13) was reviewed by the FDA and initial comments were communicated to Schering Corporation on March 5, 1999. The protocol was revised in collaboration with RTOG to incorporate the FDA comments and was re-submitted to the Agency on June 24, 1999. The revised protocol included a third arm to study the doublet of BCNU/temozolomide. This revised protocol required a Phase 1-safety assessment of the doublet and the FDA required submission of the safety data prior to initiating the study with the BCNU/temozolomide combination. Additional FDA comments were received on July 8, July 30 and August 3, 1999.

On August 11, 1999, FDA approved TEMODAR® capsules under 21 CFR §314 Subpart H for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine.

The FDA approval was based on a surrogate endpoint (response rate) with a post-approval commitment to conduct a study entitled :entitled: "A phase Phase I/III1/3 randomized study of radiation therapy and temozolomide versus radiation therapy and BCNU versus radiation therapy and temozolomide and BCNU for anaplastic astrocytoma". The commitment further stipulated that safety data from a phase Phase I 1 segment of the study would be submitted to the FDA with agreement that initiation of the combination arm (BCNU/temozolomide) would be contingent on FDA approval to proceed. Furthermore, Schering Corporation committed to completing the two monotherapy arms of the study in the event that the combination arm was stopped for any reason.

Two GBM studies were submitted in the original NDA. The first study, C/I94-091, compared temozolomide (112 patients) to procarbazine (113 patients). The primary endpoint of this study was progression free survivalfree survival (PFS) with overall survival (OS) as a secondary endpoint.secondary endpoint. PFS at 6 months was 21% (95% CI 13-29%) for temozolomide versus 9% (95% CI 4-15%) for procarbazine (p=0.016 )0.016). Median overall survival in this study showed a trend favoring temozolomide (7.34 vs 5.82 months; p=0.067).

The second study (C/I94-122) was a single arm study of 138 GBM patients inpatients in which 6-month PFS was reported as 19%.

The GBM claim from the August 12, 1998 NDA was determined not to be eligible for standard or accelerated approval.

.

 

II. DESCRIPTION OF COMMITMENTS INCLUDING TITLES OF INDIVIDUAL STUDIES:

1. A phase Phase I/III1/3 randomized study of radiation therapy and temozolomide versus radiation therapy and BCNU versus radiation therapy and temozolomide and BCNU for anaplastic astrocytoma.

1.1. In addition, SPRI Schering-Plough Research Institute (SPRI) will provide Phase I/II1/2 safety data of the above study to support the dosing schedule in the combination arm of the trial, and agree that initiation of the combination arm will be contingent on FDA approval to proceed.

1.2. Furthermore, SPRI committed to completing the two monotherapy arms of the trial in the event that the combination arm is stopped for any reason.

[Reference FDA Fax dated January 25, 2001 (attachment Attachment #1) and FDAand FDA letter dated August 30, 2001 (attachment Attachment #2)]

2. Other TEMODAR® Commitments: On January 25, 2001, the FDA issued a Pediatric Written Request and SPRI submitted the required studies on September 12, 2002. As a result of this, pediatric exclusivity was granted on November 12, 2002 and this commitment is now completed.

III. INFORMATION CONCERNING THE COMMITMENT STUDY:

A. Essentials of the Study Design

  1. Summary of the Study Sites (Geography, Number).
  2. There are 103 RTOG investigative sites (US and Canada) and additional sites as part of the Intergroup network participating in this study which is identified as RTOG 98-13. See Attachment 1 3 for the geographic location of sites.

    The initial phase Phase 1 safety study was conducted at the sites listed in Attachment 24.

  3. Patient Population (Eligibility/Exclusion Criteria)

The Radiation Therapy Oncology Group (RTOG) Protocol 98-13 has been reviewed by the FDA on several times occasions and in response to FDA guidance, has been amended three times. The date(s) entered between parentheses next to section headings refer to the dates of the protocol amendment.

Eligibility Criteria (8/17/01)

Exclusion Criteria (8/17/01, 2/18/02)

  1. Endpoints (8/15/02)

 

  1. Treatment Schema (8/15/02)
  2.  

     

    S

    T

    R

    A

    T

    I

    F

    Y

     

    Age

    1. <50

    2. >50

    R

    A

    N

    D

    O

    M

    I

    Z

    E

     

     

    Arm 1: Radiation Therapy:59.4: 59.4 Gy (1.8 Gy x 33 fractions, 5 days a week x 6 weeks) plus Temozolomide 200 mg/m2 daily on days 1-5 of the first week of radiotherapy. Repeat Temozolomide every 28 days for a total of 12 cycles.

    KPS

    1. 60-80

    2. 90-100

     

     

     

    Arm 2: Radiation: Radiation Therapy: 59.4 Gy (1.8 Gy x 33 fractions, 5 days a week x 6 weeks) plus BCNU (80 mg/m2) on days 1, 2 and 3 of the first week of radiotherapy and on days 56, 57, and 58, then every eight weeks for four cycles for a total of six cycles (maximum BCNU dose 1440 mg/m2).

    Surgery

    1. Biopsy only

    2. Resection

    The following 2 arms have been closed:

    Pilot#1, Arm 4, 15 patients: Radiation Therapy: 59.4 (1.8 Gy x 33 fractions, 5 days a week x 6 weeks6 weeks) plus BCNU 200 mg/ m2 on day 1 of radiotherapy and Temozolomide 150 mg/m2 on days 1-5 of the first week of radiotherapy. Repeat every six weeks for a total of six cycles (maximum BCNU dose 1200 mg/m2). (closed 3/15/01)

    Pilot#2, Arm 5, 14 patients: Radiation Therapy: 59.4 (1.8 Gy x 33 fractions, 5 days a week x 6 weeks) plus BCNU 150 mg/m2 on day 5 of radiotherapy and Temozolomide 150 mg/m2 on days 1-5 of the first week of radiotherapy. Repeat every eight weeks for a total of six cycles; BCNU will be given on day 5 of Temozolomide in these cycles. (maximum BCNU dose 900 mg/m2). (closed 5/2/02)

  3. Efficacy and Safety Monitoring
  4. In accordance with the protocol, the case report form is designed to capture data related to study efficacy endpoints (survival, time to progression) and relevant safety information. Patients are monitored for progression and survival every three months from study start for one year, then every 6 months for 2 years and thereafter annually.

    The dates of death, recurrence or progression are completed in the case report forms.

    Toxicities are captured monthly using the Common Toxicity Criteria (CTC) 2.0, and for each toxicity, severity grade and attribution is captured. For each toxicity ≥ grade 3, a date of onset, a description and treatment given is also captured.

    The table below depicts the toxicities observed in the Phase 1 safety assessment of the BCNU/temozolomide doublet arms (arms 4 and 5 from the above schema).

     

     

     

     

    Pilot #1, Arm 4 (n=15)

    Grades

    Pilot #2, Arm 5 (n=12)

    Grades

     

    1

    2

    3

    4

    5

    1

    2

    3

    4

    5

    Auditory/Hearing

    0

    1

    0

    0

    0

    0

    0

    0

    0

    0

    Blood/Bone Marrow

    3

    3

    1

    5

    0

    3

    1

    2

    3

    0

    Thrombocytopenia

    2

    3

    4

    2

    0

    1

    2

    6

    0

    0

    Cardiovascular (General)

    0

    0

    0

    0

    1*

    0

    0

    0

    0

    0

    Constitutional Symptoms

    5

    4

    0

    0

    0

    1

    1

    0

    0

    0

    Dermatology/Skin

    4

    4

    1*

    0

    0

    3

    1

    0

    0

    0

    Gastrointestinal

    5

    4

    0

    0

    0

    4

    1

    0

    0

    0

    Hepatic

    4

    1

    0

    0

    0

    1

    0

    0

    0

    0

    Infection/Febrile Neutropenia

    0

    0

    3

    2

    0

    0

    0

    0

    0

    0

    Metabolic/Laboratory

    3

    1

    1

    0

    0

    2

    1

    0

    0

    0

    Musculoskeletal

    0

    1

    0

    0

    0

    0

    0

    0

    0

    0

    Neurology

    1

    2

    2*

    0

    0

    1

    0

    0

    0

    0

    Ocular/Visual

    1

    1

    0

    0

    0

    0

    0

    0

    0

    0

    Pain

    1

    1

    0

    0

    0

    1

    1

    0

    0

    0

    Pulmonary

    1

    3

    1*

    0

    0

    1

    1

    0

    0

    0

    Renal/Genitourinary

    4

    0

    0

    0

    0

    0

    0

    0

    0

    0

    Maximum Toxicity per Patient

    0

    5

    3

    5

    1

    3

    1

    4

    3

    0

    Maximum Non-Hema Tox per Patient

    1

    6

    4

    2

    1

    5

    3

    0

    0

    0

     

    *Case number

    Arm

    Toxicity

    Grade

    Most recent cycle of chemotherapy

    Days from Start of RT

    3

    Pilot #1, Arm 4

    Pulmonary: Dyspnea

    3

    1

    28

    7

    Pilot #1, Arm 4

    Dermatology: rash/desquamation

    3

    2

    45

    13

    Pilot #1, Arm 4

    Neurology: confusion

    3

    6

    259

    14

    Pilot #1, Arm 4

    Cardiovascular (General): thrombosis/embolism

    5

    2

    Unk

    15

    Pilot #1, Arm 4

    Neurology: vertigo

    3

    6

    199

    As per the second annual report by the RTOG, which was submitted to the FDA on Julyon July 11, 2002, there have been no IND safety reports issued by SPRI.

    There were 8 deaths reported during the first year of the study. Seven deaths were attributed to disease. One death was a pulmonary embolism.

  5. Statistical Design

The primary endpoint of RTOG 98-13 is survival. The standard arm is radiotherapy (RT) plus BCNU. The experimental arm is RT and temozolomide. Assuming that the Median Survival Time (MST) for RT+BCNU is 36 months and the RT and temozolomide arm has a MST of 54 months, then a sample size of 216 evaluable patients per arm will provide overall statistical power of 90% with a one-sided significance level of 0.05. Since it is expected that 5% of the patients will be ineligible, then a total of 454 randomized patients will be required. The primary analysis method will be Kaplan-Meier with a stratified log rank test.

According to Scott et al.59 and Curran et al.9 [superscript numbers indicate references in the protocol] the recursive partitioning analysis (RPA) classes are prognostically important. Based upon eligibility criteria, patients may be in RPA classes I-IV which have decreasing estimated MST from 58.6 to 11.1. The distribution of patients by RPA class will affect the expected number of deaths during the study. It is assumed that 67% of the patients will be in class I, 25% in class III, and 8% in classes II and IV combined. If the percentage of RPA class II patients in the study sample is substantially higher than 25%, then the MST will be lower than 36 months, or if the percentage of RPA class I patients is higher than 75%, then the MST will be higher than 36 months. In either case the sample size may need to be adjusted. (8/17/01, 2/18/02)

Initially, fifteen patients were accrued to the RT+temozolomide+BCNU arm and the specified number of dose limiting toxicities was not exceeded (≥ 2 patients with grade ≥ 3 pulmonary toxicity or ≥ 5 patients with grade ≥ 4 thrombocytopenia or neutropenia). However, a sufficient number of patients had dose reductions resulting in protocol changes, notably a reduction in the BCNU dose from 200mg/m2 to 150mg/m2. In addition, the eligibility criteria were also changed (patients with oligodendrogial/astrocytic tumors are eligible if the oligodendrogial component is less than 25%; pre-study liver and renal function limits added; eligible DLCO increased from ≥ 60% to ≥ 70%).

An additional 14 patients were accrued to assess further the combination of the RT+temozolomide+BCNU. The dose of temozolomide was 150 mg/m2 p.o. daily on days 1-5 with BCNU 150 mg/m2 i.v. on day 5. Accrual was suspended for 3 months to assess safety. Based on the high proportion of dose reductions seen and the toxicities encountered, the outcome of this safety assessment was that the phase 3 component of this study will consist only of Arms 1 and 2 (see Treatment Schema).

An additional 454 patients are to be randomized to these two treatment arms discussed in Section 13.2 of the protocol.

Patients are to be randomized according to a permuted block design, balancing by institution within strata. The randomization is stratified by age (<50 vs >50), KPS (60-80 vs. 90-100), and prior surgery (resection vs. biopsy). These stratification factors ensure balance by RPA classes as well.

Interim Analyses of Endpoints (8/15/02)

Three interim analyses of the primary study endpoint (survival) are scheduled as per the following table:

Cumulative Events

Significance Level

63

0.0041

126

0.0158

188

0.0285

If a significance level is smaller than the H0 values, then the null hypothesis will be rejected. These significance levels were calculated to ensure an overall significance level of 0.05. There will be two stochastic analyses: at 50% accrual and 75% accrual. If the stochastic analysis indicates less than 15% power to observe the alternative hypothesis, then the study will be recommended to be closed. The results of these interim analyses will only be reported in a blinded fashion to the RTOG Data Monitoring Committee (DMC). A report with recommendations will be given to the study chairman. Any problems or recommendations identified by the DMC, not results, will be reported to the Brain Committee, which is responsible for this study and, if necessary, the RTOG Executive Committee, so that corrective action can be taken.

 

Analysis for Reporting the Initial Treatment Results (8/15/02)

This analysis is planned at the point where all patients have been followed for a minimum of 36 months, or a maximum of 251 deaths have occurred. The anticipated components of this analysis are:

a) tabulation of all cases entered, and any excluded from the analysis with reasonswith reasons for the exclusion;

b) reporting institutional accrual;

c) distribution of important prognostic baseline variables by treatment arms;

d) observed results with respect to the endpoints described in (need correct reference)

Survival (8/15/02)

Survival is the primary endpoint. RT+BCNU will be compared to RT+temozolomide. A significance level of 0.0405 (one-sided) will be used, adjusting for prior analyses. Analyses within RPA classes, or other prognostic groups, may be performed if there are sufficient numbers of patients.

Tumor Progression (8/15/02)

Time to tumor progression will be evaluated. Subgroup analyses within RPA classes, or other prognostic groups, selecting the best treatment, may be performed if there are sufficient numbers of patients.

Toxicity

Overall toxicity will be compared across treatments. The comparison will be performed using the Pearson chi-square test.

Molecular Analyses

Pathologic samples will be analyzed for chromosomes 1p and 19q and CDKN2A. The distribution of the outcome of molecular analyses will be examined by treatment arm to identify any imbalance. If there is no imbalance then the treatment arms will be collapsed and survival and time to tumor progression will be compared by the groups identified by Cairncross et al. These groups will also be correlated with other pretreatment characteristics.

B. Date of Initiation

Following protocol review and approval within RTOG and NCI, the phase Phase 1 component of the study was initiated 16 June 2000June 16, 2000. Enrollment was suspended on 15 March 2001March 15, 2001 for evaluation of the safety profile of the combination arm in this cohort. This evaluation was completed by RTOG in June 2001 and it was decided that additional safety data for the combination of BCNU/temozolomide was needed before commencing the phase Phase 3 study. An additional cohort of 15 patients was added to the phase Phase 1 plan. The phase Phase 1 study re-opened on August 17, 2001 and closed to enrollment on January 25, 2002.

The safety results from the two cohorts of phase Phase 1 did not support starting phase Phase 3 portion of the study with the combination arm. Consequently, the third arm (BCNU/temozolomide doublet) was dropped, the amended protocol submitted to the FDA on October 8, 2002 and the phase Phase 3 study was submitted to IRBs beginning on 16 October 2002.October 16, 2002. The Phase III portion of the study was initiated in January, 2003.

C. Accrual

The study completed accrual to initial cohort of the phase Phase 1 study (15 patients) on March 15, 2001 and the second cohort completed enrollment (14 patients) on January 25, 2002 whereupon enrollment was suspended. Following review of the safety data and the decision to drop the doublet arm, enrollment was opened to the Phase 3 portion of the study on January 10, 2003.

As of 30 January 2003January 30, 2003, 5 patients have been accrued in the Phase 3 study. The total accrual is targeted to be 454 patients. The patient accrual was originally projected to be 12 cases per month based upon accrual rates to study RTOG 94-04. At this rate, it will take approximately 38 months to reach the required total accrual of 454 cases. Several initiatives are being taken to increase the accrual rate in order to decrease the time needed to achieve the target study size.

D. Estimated Timelines for Study Completion

At the time the phase Phase 3 study was designed, the anticipated patient accrual was 12 patients per month for 38 months. Based on the study status as of January 2003 the last patient would be enrolled in December 2006. If the accrual rate can be at least doubled through current initiatives, it is estimated that the last patient would be enrolled by the end of 2004. The primary endpoint of the study is survival and the presumed median survival time for the treated AA patient population is 36 months.

 

If the target of last patient enrollment by the end of 2004 is achieved, and the event rate occurs as predicted, an analysis of survival could be available by late 2007.

E. Estimated Timelines for Submission of Study Results

The final study protocol has scheduled interim analyses based on a prespecified number of events which may allow study results to be shared with the Agency in advanced of June 2007.

A report of the survival analysis, assuming the current initiatives to achieve accelerated enrollment are successful, may be available by late 2007.

 

IV. OTHER ISSUES:

A. Difficulties encountered in conduct/accrual/completion of trial

  1. Changes in Medical Practice
  2. Temozolomide is approved for patients with relapsed anaplastic astrocytoma (AA). There is no standard chemotherapy for the treatment of patients with newly diagnosed AA. However, from a survey of how temozolomide is being used in clinical practice in the United States, it appears that there is about equal use in recurrent AA and newly diagnosed AA. While it is impossible to precisely predict the effect of current clinical practice for AA on enrollment in the current RTOG study, the significant and growing use of temozolomide in first line treatment of AA may well be an impediment to accrual to this trial.

     

  3. Natural History of the Disease
  4.  

    Patients diagnosed with anaplastic astrocytoma have a median survival of approximately 36 months. As a consequence, any randomized survival study in this population can be projected to require at least 3 years (and longer if temozolomide extends survival) after completion of enrollment to reach maturity. The current RTOG study with its targeted enrollment of 454 patients into two arms will be the largest randomized comparative study ever conducted for first line anaplastic astrocytoma. Given these circumstances, the original target of initiating and completing first a Phase 1-safety evaluation and then a phase III study within 7 years was ambitious at the outset. Furthermore, the necessity for a more extensive than envisaged safety evaluation of the combination of temozolomide and BCNU, and the resulting time required in this evaluation, make the June, 2007 deadline even more ambitious.

     

  5. Safety Considerations
  6. As noted, the need to conduct sequential safety assessments of the BCNU and temozolomide arms (Pilot #1, Arm 4, and Pilot #2, Arm 5), resulted in RTOG extending the phase Phase 1 segment of this study until January 2002. The outcome of this assessment led to the decision to discontinue one of the planned arms of the phase Phase 3 portion (BCNU/temozolomide plus radiation therapy) of the current study.

     

  7. Timelines

As a result of the review the phase Phase 1 safety data before allowing initiation of phase Phase 3 (consistent with FDA guidance on the phase IV 4 commitment), the phase Phase 3 portion of this study was initiated in October, 2002.


The below table summarizes the key milestones.

Initiation first Phase 1 study

16 June 2000June 16, 2000

Completion of Accrual

March 14, 2001

Safety data sent to FDA

July 27, 2001

Initiation 2nd Phase 1 study

August 17, 2001

Completion of Accrual

25 January 2002January 25, 2002

Safety data sent to FDA

11 July 2002July 11, 2002

Revised Phase 3 protocol to FDA

October 8, 2002

Initiation of phase Phase 3

16 October 2002October 16, 2002

First Patient enrolled in Phase 3

January 10, 2003

 

Initiatives are being taken to increase accrual to the Phase 3 study to about twice the original estimates. Accordingly, it is estimated that the last patient could be enrolled by the end of 2004.of 2004. If the target of last patient enrollment by the end of 2004 is achieved, an analysis of survivalof issurvival is anticipated by Novemberby November of 2007. It would be possible to issue a summary report on survival by the end of 2007. The RTOG protocol has scheduled interim analysis, which may allow study results to be shared with the Agency prior to June of 2007.

B. Other Applicant Concerns

Alternative Approaches

The sponsor would like to explore with the Agency possible alternative means to meet the post-approval commitment (confirmation of clinical benefit), foremost among them submission of the results of an EORTC randomized study in first line GBM comparing radiotherapy with temozolomide to radiotherapy alone.

 

Attachment 1

JAN 200f

MA" JUE NM

DIVISION OF ONCOLOGY DRUG

PRODUCTS

Center for Dmg Evaluation and Research, HFD-150

Woodmont Office Complex - Two

1451 RockvWc Pike,. RackviUc, AM 20852

TO: Mary Jane NehOng Fronu Sean Bradley

Fa= 908-740-2243 Fs= 310-827-4590

Phww. 908-740-6713 Phom 301-594-5750

pages, Including cwor shoot: 2 Datei January 26, 2001

Ro: NDA 21-209, Post appmvW commentB

13 Urgent [3 par Review Oplonge Comment 0 Please Reply 0 Please Recycle

THIS DOCUMENT IS INTENDED ONLY FOR THE USE OF THE PAKTY TO WHOM rr IS ADDRESSED AND MAY

CONTAN INFORMATION THAT IS'PRIVILECED. CONFIDENTIAL AND PROTECTED FROM DISCLOSURE

UNDER APPLICABLE LAW. Ifyou are not the addressee, or a person authorized to doiivcr the docwnent to the addressee,

you am hereby notified ftt any mview, disclosam. disscmination or other action based on the content of the communication

is not authorized. If you have received this documetit in error, please immediately notify us by telophone and return it to us

at the above addmss by mail.

0 Cominents-

Please refer to your January 16, 2001 submission regarding your drug product TemodarOD

(temozolomide) C4psulcs.

Per your reques4 here am the post approval comments, which were included with the August II, 1999

approval letter for Tomodar Capsides.

Schering will conduct a study according to the following protocol:

"A phase VIH randomized study of radiation therapy and temozolomide versus radiation therapy

and BCNU versus mdiadon therapy and temozolomide and BCNU for miaplasfic astrocytotna!'.

The stagstical muslysis plon for this study will be performed according to your submission dated

July 19,1999.

In addition, as agreed upon in your letter dated August 2, 1999, you will provide the Phase 1/11

safety data to support the dosing schedule in the combination arm of the trial and agree that

initiation of the combination arin wila be contingeat on FDA approval to proceed. Furthennore,

NDA 21-029 Page 2 Januaiy 25, 2001

 

YOu COmmitted to completing the two mcinOthOrOPY ams of the trial in the event that the

c-ombinafion arm is stopped for any remn.

Final stWy reports should be submitted to ENS NDA as a supplemental application. For

tidministrative purposes, all submissions relating to this Phase 4 commitmont must be clearly

designated "SubPart H Phme 4 Commitments.-

 

If You have any questions regarding this trammission, please contact me at 301-594-5750.

Sean Bradley, R.Ph.

Gg-ulatory Pr-oject M4&gcr

 

Attachment 1 (cont)

 

 

Attachment 2

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

 

Food and brug Administration

Rockville, MD 20857

 

 

4

NDA-21-029

MARy jAi,@E t4[vjRiNG

Schering Corporation

2000 Galloping Hill Road

Kenilworth, NJ 07033 99

Attention: Mary Jane Nehring

Senior Director

Matketed Products Support

Dear Ms. Nehring:

We refer to your new dnig apphcation (NDA) submitted under section 505(b) of the Federal

Food, Drug, and Cosmetic Act for Temodar (temozolomide) capsules.

We have received your submission dated May 9, 2001, mgarding the following postmarketing

study commitrnents.

I . A commitment for a Phase I/11 randomized study of radiation therapy and

temozolomide versus radiation therapy aiid BCNU versus radiation therapy and

temozolomide and BCNU for anaplastic astrocytoma. The statistical analysis

plan for this study will be performed according to firm's submission dated July

19, 1999.

STATUS: gtudy ongoing; scheduled cotnpletion is June 30, 2007.

2. A commitment to, provide the Phase 1/11 safety data to support the dosing

schedule in the combination arm of the trial aiid agree that initiation of the

combination arm will be contingent on FDA approval to proceed. Furthermore,

the Firm conu-nits to completing the two monotherapy arms of the trial in the

event that the combination arm is stopped for any reason.

STATUS: Study ongoing; scheduled completion is June 30, 200 1.

3 . Pediatric - 120 day committnent

STATUS: FDA issued Pediatric Written Request January 25, 2001. Applicant

requested revision on April 27, 200 1; "granted" letter issued August 24, 200 1.

 

 

NDA 21-029

Page 2

Two studies ongoing (I93-125 and CCGA09701); scheduled completion is June

29, 2001.

If you have any questions, call S.ean Bradley, Project Manager, at (301) 594-5750.

Sincerely, Isl

---------------------

(Seeappe?, Richard Pazdur

8/30/01 04:31:01 PM

Ricbard Pazdur, M.D.

Director

Division of Oncology Drug Products

Office of Drug Evaluation I

Center for Drug Evaluation and Research

 

Attachment 2 (cont)

 

Attachment 13: Geographic location of sites (Study 98-13)

Group Name

City

State/Country

Kansas City CCOP

Kansas City

MO

Virginia Mason Medical Center

Seattle

WA

West Michigan Cancer Center CCOP

Kalamazoo

MI

Metro-MN CCOP

Minneapolis

MN

Cancer Research for the Ozarks

Springfield

MO

Mt. Sinai Comprehensive Cancer Center CCOP

Miami

FL

Mayo Clinic

Rochester

MN

Oncology Institute of Greater Lafayette

Lafayette

LA

The Wendt Regional Cancer Center of the Finley Hospital

Dubuque

IA

Yakima Valley Memorial Hosp

Yakima

WA

Providence Cancer Therapy Center

Anchorage

AK

Sutter Health Western Division Cancer Research Group

Greenbrae

CA

Peninsula Hospital & Medical Center

Burlingame

CA

University of Rochester

Rochester

NY

Finger Lakes Radiation Oncology PC

Clifton Springs

NY

University of Kentucky Hospital

Lexington

KY

Southeast Cancer Control Consortium, Inc. CCOP

Winston-Salem

NC

Thomas Jefferson University Hospital

Philadelphia

PA

Lutheran General Hospital

Park Ridge

IL

University of Wisconsin Hospital

Madison

WI

Marshfield Clinic

Marshfield

WI

Columbia Hospital-St. Mary's

Milwaukee

WI

Virtua Memorial Hospital Burlington County

Mount Holly

NJ

Halifax Hospital ROC

Dayton Beach

FL

McGill University

Montreal

Canada

Notre Dame Hospital/University of Montreal

Montreal

Canada

Wyoming Valley Health Care System - Hospital

Wilkes Barre

PA

Montefiore Medical Center

Bronx

NY

Akron City Hospital

Akron

OH

Emory University Affiliated Hospitals

Atlanta

GA

Beth Israel Medical Center

New York

NY

21st Century Oncology, Inc.

Ft. Myers

FL

University of Louisville

Louisville

KY

Vanderbilt University Medical Center

Nashville

TN

University of Miami

Miami

FL

Washington University

St. Louis

MO

University of Alabama at Birmingham Medical Center

Birmingham

AL

University of Cincinnati

Cincinnati

OH

St Louis University Hospitals

St. Louis

MO

Upstate Carolina CCOP

Spartansburg

SC

McLaren Regional Cancer Center

Flint

MI

University Hospitals of Cleveland

Cleveland

OH

Fox Chase Cancer Center

Philadelphia

PA

Mercy Hospital

Scranton

PA

Florida Radiation Oncology Group

Jacksonville

FL

St Mary Regional Cancer Center

Langhorne

PA

Reading Hospital and Medical Center

Reading

PA

Delaware County Memorial Hospital

Drexel Hill

PA

St. Elizabeth Medical Center

Edgewood

KY

South Jersey Hospital Systems

Camden

NJ

Monmouth Medical Center

Long Branch

NJ

Group Name

City

State/Country

University of California San Francisco

San Francisco

CA

University of California Davis Medical Center

Sacramento

CA

Mt. Diablo Medical Center

Concord

CA

Joe Arrington Cancer Research & Treatment Center

Lubbock

TX

LDS Hospital

Salt Lake City

UT

Foundation for Cancer Research and Education

Phoenix

AZ

Dixie Medical Cancer Center

East St. George

UT

Memorial Hospital

Colorado Springs

CO

Northwest Community Clinical Oncology Program

Tacoma

WA

John F Kennedy Medical Center

Edison

NJ

Albert Einstein Medical Center

Philadelphia

PA

Wake Forest University Baptist Medical Center

Winston-Salem

NC

Ingalls Memorial Hospital

Harvey

IL

Central Illinois CCOP

Decatur

IL

The Schiffler Cancer Center

Wheeling

WV

Lehigh Valley Hospital

Allentown

PA

Anne Arundel Medical Center

Annapolis

MD

University of Texas-MD Anderson Cancer Center

Houston

TX

Gulf Coast MBCCOP

Mobile

AL

St. Anthony Cancer Care Institute at St. Anthony Hospital

Oklahoma City

OK

The Christ Hospital

Cincinnati

OH

MD Anderson Cancer Center - Orlando

Orlando

FL

Mary Bird Perkins Cancer Center

Baton Rouge

LA

Cleveland Clinic Foundation

Cleveland

OH

Natalie Warren Bryant Cancer Center at St. Francis Hospital

Tulsa

OK

University of Texas Medical Branch

Galveston

TX

Medical College of Wisconsin

Milwaukee

WI

Community Memorial Hospital

Menomoee Falls

WI

Gunderson Clinic

Lacrosse

WI

Methodist Cancer Center

Omaha

NE

Western Pennsylvania Hospital

Pittsburgh

PA

St. Vincent Regional Cancer Center CCOP

Green Bay

WI

Cross Cancer Institute - University of Alberta

Alberta

Canada

Henry Ford Hospital

Detroit

MI

Wayne State University

Detroit

MI

Northwest Community Hospital

Arlington Heights

IL

Michigan Cancer Research Consortium CCOP

Ann Arbor

MI

University of Utah Health Science Center

Salt Lake City

UT

Green Mountain Oncology Group

Bennington

VT

University of South Alabama Cancer Center CCOP

Mobile

AL

Dartmouth Hitchcock Medical Center

Hanover

NH

Baptist Hospital of Miami

Miami

FL

Christiana Care Health Services, Inc.

Christiana

DE

Dayton CCOP

Dayton

OH

Bay Area Tumor Institute CCOP

Oakland

CA

University of Western Ontario

London, Ontario

Canada

Alta Bates Hospital Comprehensive Cancer Center

Oakland

CA

California Pacific Medical Center

San Francisco

CA

Cancer Care Center, Inc

Salem

OH

Mayo Radiation Oncology Center

Jacksonville

FL

Cancer Treatment Center

Wooster

OH

Cottonwood Hospital

Murray

UT

 

Attachment 24: Sites participating in the safety assessment (Study 98-13)

Group Name

City

State

Kansas City CCOP

Kansas City

MO

Metro-MN CCOP

Minneapolis

MN

Cancer Research for the Ozarks

Springfield

MO

Southeast Cancer Control Consortium, Inc. CCOP

Winston-Salem

NC

Thomas Jefferson University Hospital

Philadelphia

PA

Lutheran General Hospital

Park Ridge

IL

Rochester General Hospital

Rochester

NY

University of Wisconsin Hospital

Madison

WI

Vanderbilt University Medical Center

Nashville

TN

University of California Davis Medical Center

Sacramento

CA

Joe Arrington Cancer Research & Treatment Center

Lubbock

TX

Foundation for Cancer Research and Education

Phoenix

AZ

Dixie Medical Cancer Center

East St. George

UT

Wake Forest University Baptist Medical Center

Winston-Salem

NC

Ingalls Memorial Hospital

Harvey

IL

Central Illinois CCOP

Decatur

IL

Cleveland Clinic Foundation

Cleveland

OH

Natalie Warren Bryant Cancer Center at St. Francis Hospital

Tulsa

OK

University of Texas Medical Branch

Galveston

TX

University of Utah Health Science Center

Salt Lake City

UT

Dayton CCOP

Dayton

OH