[BRIEFING BOOK FOR THE MARCH 13, 2003 ODAC]{.underline}

[MEETING REGARDING ACCELERATED APPROVAL]{.underline}

[CLINICAL PHASE 4 COMMITMENTS]{.underline}

[nda 21-029 TEMODAR (temozolomide)\
SCHERING-PLOUGH CORPORATION]{.underline}

*[AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION]{.underline}*

[BRIEFING BOOK FOR THE MARCH 13, 2003 ODAC]{.underline}

[MEETING REGARDING ACCELERATED APPROVAL]{.underline}

[CLINICAL PHASE 4 COMMITMENTS]{.underline}

[nda 21-029 TEMODAR(temozolomide)\
SCHERING-PLOUGH CORPORATION]{.underline}

*[AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION]{.underline}*

[TABLE OF CONTENTS]{.underline}

I. [GENERAL INFORMATION]{.underline} 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]{.underline} 3

III\. [INFORMATION CONCERNING THE COMMITMENT STUDY]{.underline} 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]{.underline} 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]{.underline}

*[AVAILABLE]{.underline}* *[FOR PUBLIC DISCLOSURE WITHOUT
REDACTION]{.underline}*

# I. [GENERAL INFORMATION:]{.underline}

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

-   The patients with relapsed AA who have received both nitorsourea and
    procarbazine could be considered unresponsive to other therapies.

```{=html}
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```
-   The AA Phase 2 study 94-123 shows that temozolomide capsules are
    effective for the treatment of relapsed anaplastic astrocytoma in
    patients who have had prior treatment with a nitorsourea and
    procarbazine.

```{=html}
<!-- -->
```
-   The safety of temozolomide capsules is acceptable for this
    indication.

> In early February 1999, the sponsor submitted a protocol concept sheet
> (PCS) for a proposed post-approval study in newly diagnosed AA
> patients to be conducted by the cooperative group Radiation Therapy
> Oncology 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 approvable 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: "A Phase 1/3
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 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
> survival (PFS) with overall survival (OS) as a 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). 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 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]{.underline} [INDIVIDUAL STUDIES:]{.underline}

1\. A Phase 1/3 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, Schering-Plough Research Institute (SPRI) will
> provide Phase 1/2 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.
>
> \[Reference FDA Fax dated January 25, 2001 (Attachment #1) and FDA
> letter dated August 30, 2001 (Attachment #2)\]

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:]{.underline}

# A. Essentials of the Study Design

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

> 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 3 for the geographic
> location of sites.
>
> The initial Phase 1 safety study was conducted at the sites listed in
> Attachment 4.

2.  **Patient Population (Eligibility/Exclusion Criteria)**

> The Radiation Therapy Oncology Group (RTOG) Protocol 98-13 has been
> reviewed by the FDA on several 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)]{.underline}

-   The protocol defined eligible patient population consists of
    histologically-confirmed unifocal anaplastic astrocytoma as
    determined by central review, or mixed oligodendroglial/astrocytic
    tumors where the oligodendroglial component is less than 25% of the
    tumor mass. Patients with prior biopsy-proven low grade astrocytoma
    who now have a biopsy-proven anaplastic astrocytoma and have not
    been previously treated with either radiation or chemotherapy are
    eligible.

-   Karnofsky performance status (KPS) [\>]{.underline} 60*.*

-   Adequate bone marrow reserve hemoglobin [\>]{.underline}10 grams,
    absolute neutrophil count [\>]{.underline} 1500/mm^3^, platelets
    [\>]{.underline} 150,000mm^3^; liver function tests (AST/SGOT,
    alkaline phosphatase, total bilirubin) \<2 x upper limit of normal;
    serum creatinine \<1.5 x normal.

-   Therapy must begin within 5 weeks after tissue diagnosis.

-   Diffusion Lung Capacity Oxygen (DLCO) [\>]{.underline} 70%.

-   Pre- and post-op contrast-enhanced Magnetic Resonance Imaging (MRI).

-   If patient had only a stereotactic biopsy, then a post biopsy scan
    is not necessary.

-   Patient must sign a study-specific informed consent form prior to
    randomization.

> [Exclusion Criteria (8/17/01, 2/18/02)]{.underline}

-   Major medical illnesses or psychiatric impairments, which in the
    investigator's opinion will prevent administration or completion of
    the protocol therapy and /or interfere with follow-up.

-   Any oligodendroglial component \> 25%.

-   Tumor predominately located in the posterior fossa *(i.e. brainstem
    or cerebellum).*

-   Spinal cord tumors.

-   Evidence of spinal drop metastases or spread to non-contiguous
    meninges *(MRI of the spine not required in asymptomatic patient;
    patients will not be excluded based on pathologic evidence of local
    meningeal infiltration by underlying tumor)*.

-   Prior malignancy *(excluding in situ carcinoma of the cervix or
    non-melanomatous skin cancer)* unless disease free for at least 5
    years.

-   Prior radiation to the brain or head/neck.

-   Prior chemotherapy.

-   Active infectious process.

-   Pregnant or nursing. The effects of protocol agents in the fetus are
    unknown.

-   Inability or unwillingness to use effective contraception. This
    applies to both female and male patients.

-   Known or suspected by hypersensitivity to one of the components of
    BCNU or temozolomide or to any other nitrosourea or Dacarbazine.

3.  **Endpoints (8/15/02)**

-   Overall Survival.

-   Time to tumor progression.

-   Relative toxicities of the two regimens.

-   Correlate molecular analysis with overall survival and time to tumor
    progression.

4.  **Treatment Schema (8/15/02)**

# 

+---+--------------+---+------------------------------------------------+
| # | #            | # | #                                              |
|   |              |   |                                                |
|   | #            | R | #                                              |
| # |              |   |                                                |
|   | # [Age]      | A | #  [Arm 1]{.un                                 |
| S | {.underline} |   | derline}: Radiation Therapy: 59.4 Gy (*1.8 Gy  |
|   |              | N | x 33 fractions, 5 days a week x 6 weeks)* plus |
| T | 1\. \<50     |   |  Temozolomide 200 mg/m^2^ daily on days 1-5 of |
|   |              | D |  the first week of radiotherapy. Repeat Temozo |
| R | 2\.          |   | lomide every 28 days for a total of 12 cycles. |
|   | [\>]{.       | O |                                                |
| A | underline}50 |   |                                                |
|   |              | M |                                                |
| T |              |   |                                                |
|   |              | I |                                                |
| I |              |   |                                                |
|   |              | Z |                                                |
| F |              |   |                                                |
|   |              | E |                                                |
| Y |              |   |                                                |
+---+--------------+---+------------------------------------------------+
|   | # [KPS]      |   | #  [Arm 2]{.underline}: Radiation              |
|   | {.underline} |   | Therapy: 59.4 Gy (*1.8 Gy x 33 fractions, 5 da |
|   |              |   | ys a week x 6* *weeks*) plus BCNU (*80 mg/m^2^ |
|   | 1\. 60-80    |   | *) on days 1, 2 and 3 of the first week of rad |
|   |              |   | iotherapy and on days 56, 57, and 58, then eve |
|   | 2\. 90-100   |   | ry eight weeks for four cycles for a total of  |
|   |              |   | six cycles (*maximum BCNU dose 1440 mg/m^2^*). |
+---+--------------+---+------------------------------------------------+
|   | #            |   |                                                |
|   |              |   |                                                |
|   | # [Surgery]  |   |                                                |
|   | {.underline} |   |                                                |
|   |              |   |                                                |
|   | 1\. Biopsy   |   |                                                |
|   | only         |   |                                                |
|   |              |   |                                                |
|   | 2\.          |   |                                                |
|   | Resection    |   |                                                |
+---+--------------+---+------------------------------------------------+

> The following 2 arms have been closed:
>
> [Pilot#1, Arm 4, 15 patients]{.underline}: Radiation Therapy: 59.4
> *(1.8 Gy x 33 fractions, 5 days a week x* *6 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/m^2^*). *(closed 3/15/01)*
>
> [Pilot#2, Arm 5, 14 patients:]{.underline} Radiation Therapy: 59.4
> *(1.8 Gy x 33 fractions, 5 days a week x 6 weeks*) plus BCNU 150
> mg/m^2^ on day 5 of radiotherapy and Temozolomide 150 mg/m^2^ 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/m^2^)*. *(closed 5/2/02)*

5.  **Efficacy and Safety Monitoring**

> 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).

<table>
<colgroup>
<col style="width: 40%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="5"><p>Pilot #1, Arm 4 (n=15)</p>
<p>Grades</p></td>
<td colspan="5"><p>Pilot #2, Arm 5 (n=12)</p>
<p>Grades</p></td>
</tr>
<tr class="even">
<td></td>
<td>1</td>
<td>2</td>
<td>3</td>
<td>4</td>
<td>5</td>
<td>1</td>
<td>2</td>
<td>3</td>
<td>4</td>
<td>5</td>
</tr>
<tr class="odd">
<td>Auditory/Hearing</td>
<td>0</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td>Blood/Bone Marrow</td>
<td>3</td>
<td>3</td>
<td>1</td>
<td>5</td>
<td>0</td>
<td>3</td>
<td>1</td>
<td>2</td>
<td>3</td>
<td>0</td>
</tr>
<tr class="odd">
<td>Thrombocytopenia</td>
<td>2</td>
<td>3</td>
<td>4</td>
<td>2</td>
<td>0</td>
<td>1</td>
<td>2</td>
<td>6</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td>Cardiovascular (General)</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>1*</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="odd">
<td>Constitutional Symptoms</td>
<td>5</td>
<td>4</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td>Dermatology/Skin</td>
<td>4</td>
<td>4</td>
<td>1*</td>
<td>0</td>
<td>0</td>
<td>3</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="odd">
<td>Gastrointestinal</td>
<td>5</td>
<td>4</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>4</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td>Hepatic</td>
<td>4</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="odd">
<td>Infection/Febrile Neutropenia</td>
<td>0</td>
<td>0</td>
<td>3</td>
<td>2</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td>Metabolic/Laboratory</td>
<td>3</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>2</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="odd">
<td>Musculoskeletal</td>
<td>0</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td>Neurology</td>
<td>1</td>
<td>2</td>
<td>2*</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="odd">
<td>Ocular/Visual</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td>Pain</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="odd">
<td>Pulmonary</td>
<td>1</td>
<td>3</td>
<td>1*</td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>1</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td>Renal/Genitourinary</td>
<td>4</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="odd">
<td>Maximum Toxicity per Patient</td>
<td>0</td>
<td>5</td>
<td>3</td>
<td>5</td>
<td>1</td>
<td>3</td>
<td>1</td>
<td>4</td>
<td>3</td>
<td>0</td>
</tr>
<tr class="even">
<td>Maximum Non-Hema Tox per Patient</td>
<td>1</td>
<td>6</td>
<td>4</td>
<td>2</td>
<td>1</td>
<td>5</td>
<td>3</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
</tbody>
</table>

  -------- ------------ --------------------- ------- -------------- -----------
  \*Case   Arm          Toxicity              Grade   Most recent    Days from
  number                                              cycle of       Start of RT
                                                      chemotherapy   

  3        Pilot #1,    Pulmonary: Dyspnea    3       1              28
           Arm 4                                                     

  7        Pilot #1,    Dermatology:          3       2              45
           Arm 4        rash/desquamation                            

  13       Pilot #1,    Neurology: confusion  3       6              259
           Arm 4                                                     

  14       Pilot #1,    Cardiovascular        5       2              Unk
           Arm 4        (General):                                   
                        thrombosis/embolism                          

  15       Pilot #1,    Neurology: vertigo    3       6              199
           Arm 4                                                     
  -------- ------------ --------------------- ------- -------------- -----------

> As per the second annual report by the RTOG, which was submitted to
> the FDA on 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.

6.  **Statistical Design**

##### Sample Size

> 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)

### Phase 1 Arm *(8/17/01)*

> 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/m^2^
> to 150mg/m^2^. 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%).

-   [Patient Accrual]{.underline} (Arm 5; 8/15/02)

> An additional 14 patients were accrued to assess further the
> combination of the RT+temozolomide+BCNU. The dose of temozolomide was
> 150 mg/m^2^ p.o. daily on days 1-5 with BCNU 150 mg/m^2^ 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.

-   [Randomization]{.underline}

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

-   [Analyses Plans]{.underline}

> *[Interim Analyses of Endpoints (8/15/02)]{.underline}*
>
> 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 H~0~ 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)]{.underline}*
>
> 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 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)]{.underline}*
>
> 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)]{.underline}*
>
> 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]{.underline}*
>
> 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
> 1 component of the study was initiated June 16, 2000. Enrollment was
> suspended on March 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 3 study. An additional cohort of 15 patients was added to the
> Phase 1 plan. The 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 1 did not support
> starting 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 3 study was submitted to IRBs beginning on 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 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 January 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 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:]{.underline}

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

1.  **Changes in Medical Practice**

> 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.

2.  **Natural History of the Disease**

> 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.

3.  **Safety Considerations**

> 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 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 3 portion
> (BCNU/temozolomide plus radiation therapy) of the current study.

4.  **Timelines**

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

  --------------------------------------- -------------------------------
  Initiation first Phase 1 study          June 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                   January 25, 2002

  Safety data sent to FDA                 July 11, 2002

  Revised Phase 3 protocol to FDA         October 8, 2002

  Initiation of Phase 3                   October 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. If the
> target of last patient enrollment by the end of 2004 is achieved, an
> analysis of survival is anticipated by 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

![](media/image1.png){width="6.7in" height="8.3in"}

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)**

![](media/image2.png)

![](media/image3.png){width="6.0in" height="8.0in"}**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)**

![](media/image4.png){width="5.3in" height="6.2in"}

**Attachment** **3**: 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     Dubuque         IA
  Finley Hospital                                             

  Yakima Valley Memorial Hosp                 Yakima          WA

  Providence Cancer Therapy Center            Anchorage       AK

  Sutter Health Western Division Cancer       Greenbrae       CA
  Research Group                                              

  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.   Winston-Salem   NC
  CCOP                                                        

  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 -         Wilkes Barre    PA
  Hospital                                                    

  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 Birmingham      AL
  Center                                                      

  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      Sacramento      CA
  Center                                                      

  Mt. Diablo Medical Center                   Concord         CA

  Joe Arrington Cancer Research & Treatment   Lubbock         TX
  Center                                                      

  LDS Hospital                                Salt Lake City  UT

  Foundation for Cancer Research and          Phoenix         AZ
  Education                                                   

  Dixie Medical Cancer Center                 East St. George UT

  Memorial Hospital                           Colorado        CO
                                              Springs         

  Northwest Community Clinical Oncology       Tacoma          WA
  Program                                                     

  John F Kennedy Medical Center               Edison          NJ

  Albert Einstein Medical Center              Philadelphia    PA

  Wake Forest University Baptist Medical      Winston-Salem   NC
  Center                                                      

  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      Houston         TX
  Center                                                      

  Gulf Coast MBCCOP                           Mobile          AL

  St. Anthony Cancer Care Institute at St.    Oklahoma City   OK
  Anthony Hospital                                            

  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.  Tulsa           OK
  Francis Hospital                                            

  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         Canada
  Alberta                                                     

  Henry Ford Hospital                         Detroit         MI

  Wayne State University                      Detroit         MI

  Northwest Community Hospital                Arlington       IL
                                              Heights         

  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   Mobile          AL
  CCOP                                                        

  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    Oakland         CA
  Center                                                      

  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** **4**: 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      Lubbock          TX
  Center                                                          

  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.     Tulsa            OK
  Francis Hospital                                                

  University of Texas Medical Branch             Galveston        TX

  University of Utah Health Science Center       Salt Lake City   UT

  Dayton CCOP                                    Dayton           OH
  ---------------------------------------------- ---------------- -----------