# Presentation: 362941

## Gemzar® in Combination with Carboplatin as Treatment for Women with Recurrent Ovarian CancerMarch 13, 2006Richard Gaynor, MDVice President, Global Oncology Lilly Research LaboratoriesOncologic Drugs Advisory Committee Presentation

**8001.01**

## Agenda

**Introduction and Objectives ****	****	****	**
**Management of Ovarian Cancer ****	****	****	**
**Clinical Efficacy of Gemzar/Carboplatin**
**	****	****	****	****	****	**
**	**
**Safety Results and Patient Benefit ****	****	****	****	**
**Robustness of Efficacy Results **
**Risk/Benefit Overview****	****	**

**8002.01**

**Richard Gaynor, MD  **
**Vice President, Oncology ****Lilly Research Laboratories**
**Robert Ozols, MD, PhD**
**Sr. Vice President Medical Science, Fox Chase Cancer Center**
**Allen Melemed, MD**** **
**Associate Medical Director, Oncology – Eli Lilly and Co.**
**Richard Gralla, MD****Multinational Association of Supportive Care in Cancer**
**Daniel Sargent, PhD****Director, Cancer Center Statistics, Mayo Clinic**
**Tate Thigpen, MD **
**Professor of Medicine, University of Mississippi School of Medicine**

## Expert Participants

**Eli Lilly and Company**
_**Medical**_** **
**Richard Gaynor, MD**
**Marek Kania, MD, MBA **
**Martin Marciniak, PhD**
**Allen Melemed, MD**
_**Regulatory Affairs**_
**Cheryl Beal Anderson, PharmD**
**Colleen Mockbee, RPh**_** **_
_**Statistics**_
**James Symanowski, PhD**
**Annamaria Zimmermann, MS**

**External Consultants**
**Richard Gralla, MD****Multinational Association of Supportive Care in Cancer**
**Robert Ozols, MD, PhD****Sr. Vice President Medical Science, Fox Chase Cancer Center**
**Jacobus Pfisterer, MD, PhD ****Universitätsklinikum Schleswig-Holstein, Campus Kiel, Germany, AGO co-Chair, GCIG Chair**
**Dan Sargent, PhD****Director, Cancer Center Statistics, Mayo Clinic, Rochester**
**Tate Thigpen, MD****Professor of Medicine, ****University of Mississippi School of Medicine**

**8003.01**

## Ovarian Cancer Supplemental NDA 

**sNDA for ovarian cancer indication was submitted 16 June 2005 **
**Submission based on a 356 patient randomized Phase 3 study conducted by AGO-OVAR that met its primary endpoint of statistically significant improvement in progression free survival (PFS)**
**Indication**
**Gemzar in combination with carboplatin for the treatment of women with recurrent ovarian cancer that have relapsed at least 6 mo following platinum‐based therapy.**
**Dosage**
**Gemzar 1000 mg/m****2**** days 1 and 8**
**Carboplatin AUC 4 day 1**

**8004.01**

## Gemzar sNDA Ovarian Cancer 

**8005.01**

**Oncolytic agents are often used off-label**
**Gemzar alone and in combination with carboplatin listed in NCCN 2006 practice guidelines for treatment of women with recurrent ovarian cancer and is currently used in the treatment of this disease**
**“****FDA Guidance on New Treatment Indications” goals:**
**Submission of data for supplemental indications**
**Label all indications where data exists to establish safety and efficacy**
**Recognize alternative data sources from cancer clinical trial organizations with track record of high quality research**
**Current study performed by a well-known European cooperative       ****   group is consistent with FDA guidance and demonstrates the ****   efficacy of GCb in recurrent ovarian cancer**

## Regulatory Background

**8006.01**

**Historically, overall response rate has been primarily used for ****   approval in recurrent ovarian cancer**
**Lilly requested meeting with FDA to discuss potential for ****   submission (December 2004)**
**FDA agreed data package met criteria for submission**
**PFS endpoint, used in this trial, is acknowledged as a measure of clinical benefit in lung and colorectal cancers**
**Lilly will discuss that the totality of data including PFS, ORR, ****   PRO and time off chemotherapy supports full approval ****   of Gemzar /carboplatin for treatment of women with recurrent ****   ovarian cancer**

**Notes:**
Historically, overall response rate has been primarily used in this setting. Lilly met with the FDA in late 2004 and reviewed the trial design and results.  FDA agreed the data package met criteria for submission. Today we plan to discuss that the totality of the data which we feel supports full approval of Gem/Carbo for woman with recurrent ovarian cancer.

## Background on Gemzar

**8007.01**

**Pyrimidine anti-metabolite with broad activity across ****   numerous tumor types**
**Over 1.3 million patients treated globally with Gemzar**
**FDA regular approvals for:**
**Pancreas (single agent – 1996)**
**NSCLC (combination with cisplatin – 1998)**
**Metastatic Breast Cancer (combination with paclitaxel – 2004)**
**Gemzar plus carboplatin (GCb) combinations are used ****   extensively in lung, breast, and bladder cancers**
**Gemzar as a single agent, and in combination with ****   carboplatin, has been extensively studied in ovarian cancer**
**Safety profile well-characterized with relatively low toxicity**

## Objectives of Presentation

**8008.01**

**Gemzar plus carboplatin is an effective, less neurotoxic treatment option for women with recurrent ovarian cancer**

**Gemzar is active in ovarian cancer**
**Gemzar plus carboplatin provides a clinical benefit for women with recurrent ovarian cancer**
**Superior PFS, overall and complete response rates**
**Robust and internally consistent efficacy**
**Improved patient reported outcomes and time off chemotherapy**
**Safe and well-tolerated regimen **
**No new safety issues**
**Low incidence of neurotoxicity**

## Management of Ovarian Cancer  

Robert Ozols, MD, PhD Sr. Vice President Medical Science Fox Chase Cancer Center

**Robert Ozols, MD, PhD**** ****Sr. Vice President Medical Science ****Fox Chase Cancer Center**

**8009.01**

## Ovarian Cancer – Current Clinical Practice

**20,180 new cases and 15,310 deaths estimated in 2006**
**Current standard therapy for initial treatment: **
**Debulking surgery followed by Cb + paclitaxel**
**After 1****st****-line treatment with Cb + paclitaxel therapy for advanced stage disease:**
**75% of patients will achieve a complete clinical remission**
**Of those, 75% will ultimately relapse **
**Median disease-free interval of < 2 years**
**Median survival after relapse is 18-24 mo**
**Neuropathy is a significant issue following initial therapy**
**75% - 80% have grade 1-4 neurotoxicity**
**30% of patients with **_**>**_** grade 2 neurosensory toxicity**
**7% of patients with **_**>**_** grade 2 neuromotor toxicity **

**8010.01**

## Chemotherapy for Platinum-Resistant Disease

**Platinum-free interval at time of relapse **
**Platinum resistant**
**Platinum sensitive**
**Residual toxicity, performance status, co-morbid conditions**
**Platinum resistant: <6 mo interval between treatment and PD**
**Current treatment options**
**Liposomal doxorubicin***
**Topotecan***
**Paclitaxel***
**Gemzar**
**Response rates for platinum-resistant patients ~10%**
**Time to progression for platinum-resistant patients ~3 mo**

**Chemotherapy for Platinum-Resistant Disease**

**8011.01**

***    FDA-approved agent**

## Efficacy Results of Select Single-Agent Chemotherapies in Ovarian Cancer

|  | Liposomal doxorubicin | Topotecan | Paclitaxel |
| --- | --- | --- | --- |
| Patient Population | Recurrent / Platinum-resistant | Recurrent /Platinum – resistant | Recurrent  |
| N (Number and phase of studies) | 384(3 Ph 2, 1 Ph 3) | 223(1 Ph 2, 1 Ph 3) | 499(2 Ph 2, 1 Ph 3) |
| ORR, % | 0 – 22* | 14 – 21 | 13 – 22 |
| Median TtPD, mo | 3.7** | 2.6 – 4.4 | 2.8 – 4.4 |

***    Does not include an outlier study in which no responders were reported******  Combined data from all three studies**

**8499.01**

**Notes:**
Efficacy results from registration trials for approved agents in recurrent ovarian cancer, according to their package insert

## Gemzar Monotherapy: Recurrent Ovarian Cancer

**8013.01**

|  | Lund | Friedlander | Von Minckwitz |
| --- | --- | --- | --- |
| Patient Population | Platinum-resistant | Recurrent | Recurrent |
| N | 42 | 36 | 36 |
| ORR, % | 19 | 14 | 22 |
| CR, % | 0 | 6 | 5 |
| Median TtPD, mo | 2.8 | 3.0 | 3.6 |

**Notes:**
Gemzar monotherapy efficacy results in platinum-resistant disease are comparable to already approved agents
Less toxic regimen, very few transfusions

## Chemotherapy for Platinum-Sensitive Disease and Combination Therapy

***    FDA-approved agent**

**8498.01**

**Platinum sensitive: ******** 6 mo interval between treatment and PD **
**Current treatment options based on Cb therapy**
**Single Agent***
**Combination with Gemzar, paclitaxel**
**ICON 4**
**Important proof-of-concept for use of combination **
**Improved OS and PFS **
**Toxicities limit utility**
**High percent of neurotoxicity (**_**>**_**Gr. 2 = 20%)**
**Only 45% patients received prior taxane in ICON 4**
**Neurotoxicity may be higher in US due to standard of care in 1****st**** line (Carbo plus paclitaxel)**

## AGO-OVAR Development of Gemzar 

**Effective, less neurotoxic regimen needed in recurrent disease**
**Gemzar and Cb both active agents**
**AGO-OVAR**
**Well-established European cooperative group specializing in gynecological malignancies**
**Member of Gynecological Cancer Intergroup**
**Organization of 15 international cooperative groups**
**Participated in ICON 4 (OVAR 2.2), withdrew due to toxicity**
**Evaluated safety and efficacy of GCb in Ph 1/2 (SO026)**
**Observed low incidence of neurotoxicity**
**Designed JHQJ / OVAR 2.5**
**GCb is effective regimen in treatment of recurrent disease**

**8014.01**

## PFS for Evaluation of Ovarian Cancer Agents

**8018.01**

**Recognized as an important endpoint for 1****st**** and 2****nd**** line treatment of ovarian cancer patients, according to the Ovarian Cancer Consensus Conference**
**Not confounded by post discontinuation therapies**
**Survival may be confounded with multiple lines of therapy**
**Represents efficacy of only study therapy**
**Earlier identification of active treatments**
**PFS in conjunction with other efficacy parameters (ORR, CR, QoL) can be a measure of clinical benefit in ovarian cancer**
**AGO JHQJ / OVAR 2.5 met the primary endpoint of a statistically significant improvement in PFS**

## Clinical Efficacy	

Pivotal Study JHQJ / OVAR 2.5

Allen Melemed, MD
Associate Medical Director,Eli Lilly and Co.

**Pivotal Study JHQJ / OVAR 2.5**
**Allen Melemed, MD**
**Associate Medical Director,****Eli Lilly and Co.**

**8021.01**

## GCb Submission for Recurrent Ovarian Cancer

**8022.01**

| Study ID | Phase | ORR (%) | Median PFS (mo) | Median Survival (mo) |
| --- | --- | --- | --- | --- |
| JHQJ / OVAR 2.5 | Phase 3 | 47.2 | 8.6 | 18.0 |
| OVAR 2.4 / O026 | Phase 1-2 | 62.5 | 10.0 | 22.5 |
| JHRW | Phase 2 | 62.5 | 9.6 | 26.9 |

**Additional Supportive Studies in ovarian cancer:**** **
**Three Phase 2 studies using Gemzar + carboplatin **
**Ten Phase 2 studies using Gemzar monotherapy**

## Study Design for JHQJ / OVAR 2.5

**Gemzar 1000 mg/m2  D1+8 Carboplatin AUC 4 D1 q 3w  for 6 cycles**

**Carboplatin AUC 5 D1 q 3w for 6 cycles**

**Stratified at central AGO office by:**
**Platinum-free interval****(PFI) (6-12 or > 12 mo)**
**Type of 1st-line****platinum therapy****(platinum-paclitaxel ****or other platinum therapy)**
**Bidimensionally****measurable disease ****(yes or no) **

**Study Design for JHQJ / OVAR 2.5**

**8024.01**

## Key Trial Features: Study Endpoints

**8025.01**

**Randomized Phase 3 study **
**AGO, NCIC-CTG, EORTC**
**12 countries, 105 investigators**
**Primary Endpoint: PFS**** **
**Time from randomization to progressive disease (PD) or death **
**Patients who were alive without PD were censored at last visit **
**85% power to detect 41% improvement in PFS (HR=0.71) at ********=0.05 (requiring ~300 events)**
**Secondary Endpoints:**
**Overall survival **
**Response rate**
**PRO (measured by EORTC QLQ-C30, OV28 instruments)**
**Toxicity **

## Methodology for Disease Assessment for Study JHQJ / OVAR 2.5

**8027.01**

**Disease assessments every 6 weeks on-study**
**Radiologic imaging studies (same method as baseline)**
**Physical examination for tumor size**
**Thirty days after study discontinuation (V101) disease ****    assessments occurred every 3 mo **
**Using the same method as baseline**
**Determination of events for PFS: **
**Death**
**Objective tumor progression **
**Clinical progression (performance status decline of 2 levels; progressive peritoneal carcinomatosis with increasing bowel dysfunction; increased ascites requiring palliative drainage)**

## Patient Characteristics for JHQJ / OVAR 2.5

**8030.01**

|  | GCb (N=178) |  | Cb (N=178) |  |
| --- | --- | --- | --- | --- |
| Mean age, years (range) |   58.1 (36.0-78.0) |  |   56.5 (21.0-81.0) |  |
| ECOG PS, n (%) |  |  |  |  |
| 0-1 | 162 (91.0) |  | 165 (92.7) |  |
| 2 |   11 (6.3) |  |     9 (5.2) |  |
| FIGO stage at initial diagnosis, n (%) |  |  |  |  |
| Ia-IIIa |  |   38 (21.3) |  |   26 (14.6) |
| IIIb-IIIc |  | 113 (63.5) |  | 129 (72.5) |
| IV |  |   27 (15.2) |  |   22 (12.4) |
| First-line therapy, n (%) |  |  |  |  |
| Platinum |  | 178 (100) |  | 178 (100) |
| Platinum and paclitaxel |  | 122 (68.5) |  | 120 (67.4) |
| Platinum-free interval, n (%) |  |  |  |  |
| 6-12 months |  |   71 (39.9) |  |   71 (39.9) |
| >12 months |  | 105 (59.0) |  | 106 (59.6) |

## JHQJ / OVAR 2.5 Primary Endpoint: Progression-Free Survival

**GCb:  median = 8.6 mo ****Censoring: 12.4%**

**Cb:  median = 5.8 mo****Censoring: 12.9%**

**8031.01**

**Cb Arm (N=178)**

**GCb Arm (N=178)**

**Log-rank p-value = 0.0038**
**Unadjusted HR = 0.72 (0.57 to 0.90)**
**Adjusted HR* = 0.71 (0.57 to 0.89)**

***  Adjusted for PFI, Tumor size**

## JHQJ / OVAR 2.5 Efficacy Results: Overall Survival 

**Proportion Surviving**

**Months**

**Median = 18.0 mo ****Censoring: 18.5% **

**Median = 17.3 mo ****Censoring: 22.5%**

**8032.01**

**Cb Arm (N=178) **

**GCb Arm (N=178)**

***  Adjusted for PFI, Tumor size and performance status**

**Log-rank p-value = 0.8977**
**Unadjusted HR = 0.98 (0.78 to 1.24)**
**Adjusted* HR = 0.92 (0.72 to 1.16)**

## JHQJ / OVAR 2.5 Post-Discontinuation Therapy

|  | Percent of Patients |  |
| --- | --- | --- |
| Post-discontinuation therapy | GCb (N=178) | Cb(N=178) |
| Any post-discontinuation therapy | 83.7 | 78.7 |
| Chemotherapy | 75.8 | 72.5 |
|     1 regimen | 16.3 | 13.5 |
|     2 regimens | 12.4 | 15.7 |
|     3 or more regimens      | 9.6 | 10.7 |
|     Unspecified number of regimens | 37.6 | 32.6 |
| Hormonal, immuno or biological therapy | 19.7 | 18.0 |
| Radiation | 5.1 | 9.6 |
| Other therapy – not specified | 15.7 | 15.2 |

**8033.01**

## JHQJ / OVAR 2.5: Overall Response Rate

|  | GCb Arm (N=178) | Cb Arm(N=178) | Chi-square p-value |
| --- | --- | --- | --- |
| ORR      (95% CI) | 47.2% (39.9 - 54.5) | 30.9% (24.1- 37.7) | 0.0016 |
| CR Rate   (95% CI) | 14.6% (9.4 to 19.8) | 6.2% (2.6 to 9.7) | 0.0092 |

**8354.01**

## Efficacy Conclusions

**Well designed, Phase 3, co-operative group study**
**Patient characteristics well-balanced**
**Study population representative of a high-risk recurrent ovarian cancer patients**
**High percent of prior taxane therapy**
**Primary endpoint (PFS) is highly significant in favor of the combination arm**
**28% reduction in risk**
**Overall and complete response rates are significantly improved in the GCb arm vs the Cb arm**

**8054.01**

**Gemzar plus carboplatin demonstrated clinically meaningful benefit for women with recurrent ovarian cancer**

## Safety Results and Patient Benefit 	

Pivotal Study JHQJ / OVAR 2.5

Richard Gralla, MD Multinational Association of Supportive Care in Cancer

**Pivotal Study JHQJ / OVAR 2.5**
**Richard Gralla, MD**** ****Multinational Association of Supportive Care in Cancer**

**8021.01**

## Objectives

**Patient safety**** **
**Toxicities and adverse events**
**Significant consequences **
**Translating PFS improvement to patient benefit**
**Patient reported outcomes  **
**Time off chemotherapy**

**8410.01**

## JHQJ / OVAR 2.5: Selected Grade 3/4 Toxicities Regardless of Causality

**8038.01**

|  | Percent of Patients |  |  |  |
| --- | --- | --- | --- | --- |
|  | GCb Arm (N=175) |  | Cb Arm (N=174) |  |
|  | Grade 3 | Grade 4 | Grade 3 | Grade 4 |
| Hemoglobin | 22.3* | 5.7 | 8.6 | 2.3 |
| Neutrophils | 41.7* | 28.6* | 10.9 | 1.1 |
| Platelets | 30.3* | 4.6 | 10.3 | 1.1 |
| Nausea | 6.3 | 0 | 2.9 | 0 |
| Vomiting | 5.7 | 0 | 2.3 | 0.6 |
| Diarrhea | 3.4 | 0 | 0.6 | 0 |
| Constipation | 6.3 | 1.1 | 2.9 | 0 |

*** **** ****p-value <0.01**

## JHQJ / OVAR 2.5: Maximum CTC Neurotoxicity in Patients with Pre-Existing Neuropathy at Baseline

|  | Max. Neuropathy On Study (%) |  |  |  |
| --- | --- | --- | --- | --- |
| Patients with neuropathy at baseline | Gr 1 | Gr 2 | Gr 3  | Gr 4 |
| GCb Arm (N=38) |  |  |  |  |
|    Motor Neuropathy | 0 | 0 | 2.6 | 0 |
|    Sensory Neuropathy | 0 | 10.5 | 2.6 | 0 |
| Cb Arm (N=29) |  |  |  |  |
|    Motor Neuropathy | 0 | 0 | 0 | 0 |
|    Sensory Neuropathy | 0 | 6.9 | 6.9 | 0 |

**8040.01**

## JHQJ / OVAR 2.5:  Overview of Adverse Events

**8037.01**

|  | N (Percent of Patients) |  |  |
| --- | --- | --- | --- |
|  | GCb Arm (N=175) | Cb Arm (N=174) | p-value |
| Serious adverse events |  |  |  |
|     All  | 49 (28.0) | 37 (21.3) | 0.1718 |
|     Possibly related to study drug | 29 (16.6) | 17 (9.8) | 0.0810 |
| Discontinuations due to AEs |  |  |  |
|     All | 19 (10.9) | 17 (9.8) | 0.8606 |
|     Possibly related to study drug | 14 (8.0) | 14 (8.0) | 1.0000 |

## JHQJ / OVAR 2.5:  Selected Grade 3/4 Non-Laboratory Toxicities Regardless of Causality

|  | Percent of Patients |  |  |  |
| --- | --- | --- | --- | --- |
|  | GCb (N=175) |  | Cb (N=174) |  |
|  | Grade 3 | Grade 4 | Grade 3 | Grade 4 |
| Hemorrhage | 1.8 | 0.6 | 0 | 1.1 |
| Febrile neutropenia | 1.1 | 0 | 0 | 0 |
| Neuropathy – sensory | 1.1 | 0 | 2.3 | 0 |
| Neuropathy – motor  | 1.1 | 0 | 0.6 | 0 |

**8039.01**

## JHQJ / OVAR 2.5: Overview of Hospitalizations and Deaths

**8429.01**

|  | N, (Percent of Patients |  |  |
| --- | --- | --- | --- |
|  | GCb Arm (N=175) | Cb Arm (N=174) | p-value |
| Patients hospitalized due to AE* |  |  |  |
|       All | 44 (24.7) | 32 (18.0) | 0.1545 |
|     Possibly related to study drug | 29 (16.3) | 16 (9.0) | 0.0547 |
|  |  |  |  |
| Deaths |  |  |  |
|     On study (during treatment period) | 4 (2.3) | 3 (1.7) | 1.0000 |
|     Within 30-day poststudy follow up | 1 (0.6) | 2 (1.1) | 0.6228 |

*** **** ****Based on all randomized patients, N=178 per arm**

## JHQJ / OVAR 2.5 Safety Conclusions

**GCb is a safe and well-tolerated regimen**
**No new safety issues emerge in JHQJ / OVAR 2.5**
**Certain hematologic Gr 3/4 toxicities increased in GCb arm**
**Clinically significant sequelae occurred at low and comparable rates**
**Low incidence of neurotoxicity**

**8041.01**

**Gemzar plus carboplatin is a safe regimen for treatment of  women with recurrent ovarian cancer. **

## Patient Benefit

**Patient reported outcomes**
**EORTC QLQ-C30 cancer specific instrument**** ****    (validated – Aaronson, 1993 and Groenvold, 1997)**
**EORTC QLQ-OV28 ovarian specific instrument ****    (validated – Cull, 2001 and Greimel, 2003)**
**AUC**
**Analysis to 10-Point Change**
**Time off chemotherapy**
**Duration of time patients were off chemotherapy **

**8430.01**

## JHQJ / OVAR 2.5: Patient Reported Outcome Assessment Methodology 

**8434.01**

**Total of 22 symptom scales included in the EORTC QLQ-OV28 ****    and EORTC QLQ-C30**
**Symptoms most relevant to ovarian patients**
**Nausea/vomiting**
**Constipation**
**Diarrhea**
**Abdominal / GI (i.e. bloating) **
**Fatigue**
**Pain**
**Anorexia**
**Study designed to treat patients for 6 cycles or to progression**
**Compliance rate completing PRO instrument ~90%**

## JHQJ / OVAR 2.5: Percent of Patients with Symptoms* at Baseline

***  Nausea/vomiting, constipation, diarrhea, abdominal GI symptoms, fatigue, pain, or anorexia**

**Cb Arm **

**GCb Arm**

**8436.01**

**0**

**1**

**2**

**3**

_**>**_**4**

**Number of Symptoms**

**60**

**50**

**40**

**30**

**20**

**0**

**10**

**Percent of Patients**

**Most Frequent Symptoms:**
**Fatigue ****	****	****	****86%**
**Abdominal symptoms ****	****	****84% ****Pain ****	****	****	****	****71%**

## JHQJ / OVAR 2.5: AUC Results for QoL Scales/Items Relevant to Ovarian Cancer

**JHQJ / OVAR 2.5: AUC Results for QoL Scales/Items Relevant to Ovarian Cancer**

**8137.01**

**Cb Arm **

**GCb Arm**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**Symptom**

**Percent of Maximum AUC**

**Overall improvements in the GCb arm in 21 of 22 scales**
**Sign test <0.0001**

##  JHQJ / OVAR 2.5 -  Global Quality of Life:  10-Point Changes (% Improved and Time to Worsening)

** ****JHQJ / OVAR 2.5 -  Global Quality of Life:  10-Point Changes (% Improved and Time to Worsening)**

**8438.01**

**Global****QoL**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**Percent of Patients**

**Cb Arm **

**GCb Arm**

**Percent of Patients**
**Improved by at Least ****10 Points** **(p = 0.106)**

## Patient Benefit

**Patient reported outcomes**
**EORTC QLQ-C30 cancer specific instrument**** ****    (validated – Aaronson, 1993 and Groenvold, 1997)**
**EORTC QLQ-OV28 ovarian specific instrument ****    (validated – Cull, 2001 and Greimel, 2003)**
**AUC**
**Analysis to 10-Point Change**
**Time Off Chemotherapy**
**Duration of time patients were off chemotherapy **

**8430.01**

## JHQJ / OVAR 2.5: Time Off Chemotherapy 

**JHQJ / OVAR 2.5: Time Off Chemotherapy **

**HR (95% CI):  0.80 (0.64 – 0.99)****Log-rank p-value:  0.0417   **

**Probability**

**1.0**

**0.8**

**0.6**

**0.4**

**0.2**

**0.0**

**0.1**

**0.3**

**0.5**

**0.7**

**0.9**

**0.0**

**0**

**6**

**12**

**18**

**24**

**30**

**36**

**42**

**Months**

**GCb median=5.6 months; e=169; 5.1% censoring**

**Cb median=2.6 months; e=165; 7.3% censoring**

**8433.01**

## JHQJ / OVAR 2.5: Patient Benefit Conclusions

**8041.01**

**Gemzar plus carboplatin shows improved patient benefit with low toxicity and longer time off chemotherapy.**

**The GCb regimen is safe with an acceptable toxicity profile **
**Quality of life and patient reported outcome differences between the arms consistently favor the GCb regimen**
**Women on the GCb regimen experienced a significantly greater time off chemotherapy following study therapy**

## 
Robustness of JHQJ / OVAR 2.5 Efficacy Results

Daniel J Sargent, PhD
Director, Cancer Center StatisticsMayo Clinic, Rochester

**Robustness of JHQJ / OVAR 2.5 ****Efficacy Results**
**Daniel J Sargent, PhD**
**Director, Cancer Center Statistics****Mayo Clinic, Rochester**

**8042.01**

## Objectives

**Confirm robustness of the primary endpoint PFS**
**Sensitivity analyses **
**Consistency of results in key subgroups**
**Assess possible impact of investigator bias**
**PFS **
**Response rate**
**Investigator vs independent assessments**

**8043.01**

## Robustness of PFS Results in Study JHQJ / OVAR 2.5

**8366.01**

**Sensitivity analysis including only objective progressions (SA1)**
**Clinical progressions ignored**
**Sensitivity analysis including only documented objective progressions (SA3)**
**Clinical progressions ignored **
**Objective progressions without lesion measurements ignored**
**Objective progressions following missed / incomplete assessments back-dated**
**Interval trimmed at 7 mo or at study discontinuation (V101)**

## JHQJ / OVAR 2.5: Sensitivity Analysis Including Only Objective Progressions (SA1)

**0.0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**Progression Free Probability**

**0**

**6**

**12**

**18**

**24**

**30**

**36**

**Progression Free Survival Time (Months)**

**8363.01**

**GCb: Median:  9.7 mo ; events=148; Cens: 16.9%**

**Cb: Median:  6.7 mo ; events=149; Cens: 16.3%**

**HR (95% CI):  0.76 (0.60 – 0.95)****Log-rank p-value:  0.0157   **

**Cb Arm **

**GCb Arm**

**JHQJ / OVAR 2.5: Sensitivity Analysis Including Only Objective Progressions (SA1)**

## JHQJ / OVAR 2.5: Sensitivity Analysis Including Only Documented Objective Progressions (SA3)

**8365.01**

**GCb Median :  6.7 mo Events=47****Cens: 73.6%**

**Cb Median:  5.2 mo Events=84****Cens: 52.8%**

**HR (95% CI):  0.45 (0.32 – 0.64)****Log-rank p-value:  <0.0001 **

**Cb Arm **

**GCb Arm**

**JHQJ / OVAR 2.5: Sensitivity Analysis Including ****Only Documented Objective Progressions (SA3)**

## JHQJ / OVAR 2.5: Summary of New Sensitivity Analyses for PFS

**8362.01**

|  | Median GCb(censoring) | Median Cb(censoring) |  LR p-valueHR |
| --- | --- | --- | --- |
| Primary PFS  | 8.6 mo(12.4%) | 5.8 mo(12.9%) | 0.00380.72 |
| Sensitivity Analysis Including Only Objective Progressions (SA1) | 9.7 mo(16.9%) | 6.7 mo(16.3%) | 0.0157 0.76 |
| Sensitivity Analysis Including Only Documented Objective Progressions (SA3) | 6.7 mo(73.6%) | 5.2 mo(52.8%) | <0.00010.45 |

## JHQJ / OVAR 2.5: Internal Consistency of PFS in Subgroups

| Subgroup |  | HR (95% CI) | Interaction p-value |
| --- | --- | --- | --- |
| Age | <60 y | 0.74 (0.54-1.01) | 0.8552 |
|  | >60 y | 0.70 (0.51-0.97) |  |
| Performance status | 0 | 0.69 (0.50-0.95) | 0.7392 |
|  | 1 or 2 | 0.73 (0.53-1.01) |  |
| Platinum-free | 6-12 mo | 0.69 (0.49-0.98) | 0.7500 |
| interval | >12 mo | 0.72 (0.54-0.97) |  |
| 1st Line paclitaxel | Yes | 0.61 (0.47-0.80) | 0.0704 |
|  | No | 0.91 (0.61-1.36) |  |
| Median tumor area | <18.7 | 0.84 (0.60-1.17) | 0.1636 |
| (cm2) | >18.7 | 0.60 (0.43-0.83) |  |

**8049.01**

## JHQJ / OVAR 2.5: Independent Assessment of Response Rate

**8035.01**

**Process for independent review:**
**All imaging films submitted by the investigator were given to the review board**
**Patients needed to have a baseline and one subsequent radiologic image**
**Ultrasound and physical exam data were not included in the review**
**Members of the review board (3 outside radiologists) were blinded to the treatment arm, investigator assessment and target lesions**
**Independent assessment was performed on the subset of 222 patients with radiologic imaging available**
**Reduced power**

## JHQJ / OVAR 2.5: Response in Independently Reviewed Cohort (Investigator vs Independent)

|  | Independent Review |  |
| --- | --- | --- |
| Investigator Assessment | Responders | Non-Responders |
| Responders | 66 | 25 (11%) |
| Non-Responders | 26 (12%) | 105 |

**JHQJ / OVAR 2.5: Response in Independently Reviewed Cohort (Investigator vs Independent)**

**8053.01**

## JHQJ / OVAR 2.5: Response Rate in Independently Reviewed Cohort

|  | Independently Reviewed | Investigator Assessed |
| --- | --- | --- |
| GCb, (N=121) |  |  |
|     Response Rate | 46.3% | 46.3% |
|      CR/PR | 11/45 | 15/41 |
| Cb, (N=101) |  |  |
|      Response Rate | 35.6% | 34.7% |
|      CR/PR | 4/32 | 4/31 |
| p-value | 0.1091 | 0.0794 |

**JHQJ / OVAR 2.5: Response Rate in Independently Reviewed Cohort**

**8052.01**

## Conclusions

**Primary endpoint (PFS) is statistically convincing and internally consistent**
**Multiple sensitivity analyses confirm robustness of primary analysis **
**Significant benefit reproduced in key patient subgroups**
**No evidence of investigator bias**
**Results from independent review of response consistent with investigator assessment**
**Concordance analysis showed no bias**
**Similar overall response rates among independent and investigator assessments**

**8054.01**

## Concluding Remarks  
Benefit-Risk Summary:
OVAR 2.5 in Context

Tate Thigpen, MD
Professor of Medicine, University of Mississippi School of Medicine

**Benefit-Risk Summary:**
**OVAR 2.5 in Context**
**Tate Thigpen, MD**
**Professor of Medicine, ****University of Mississippi School of Medicine**

**8055.01**

## PFS is an Appropriate Measure of Treatment Activity in Ovarian Cancer

**8018.01**

**Recognized as an important endpoint for 1****st**** and 2****nd**** line treatment of ovarian cancer patients, according to the Ovarian Cancer Consensus Conference**
**AGO-OVAR was the host for the 2004 meeting**
**Not confounded by post discontinuation therapies**
**Survival may be confounded with multiple lines of therapy**
**Represents efficacy of only study therapy**
**PFS differences can alter treatment practices**
**PFS in conjunction with other efficacy parameters can be a measure of clinical benefit in ovarian cancer**

## Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference- 2004

**8514.01**

## PFS is an Appropriate Measure of Treatment Activity in Ovarian Cancer

**8018.01**

**Recognized as an important endpoint for 1****st**** and 2****nd**** line treatment of ovarian cancer patients, according to the Ovarian Cancer Consensus Conference**
**AGO-OVAR was the host for the 2004 meeting**
**Not confounded by post discontinuation therapies**
**Survival may be confounded with multiple lines of therapy**
**Represents efficacy of only study therapy**
**PFS differences can alter treatment practices**
**PFS in conjunction with other efficacy parameters can be a measure of clinical benefit in ovarian cancer**

## JHQJ / OVAR 2.5 Efficacy Results

**8058.01**

|  | JHQJ / OVAR 2.5(N=356) |
| --- | --- |
| Efficacy Results |  |
|    PFS (primary endpoint) | 8.6 mo vs 5.8 moHR = 0.72 (p=0.0038) |
|    ORR | 47.2% vs 30.9%p-value = 0.0016 |
|    CR | 14.6% vs 6.2%p-value = 0.0092 |
|    Patient Reported Outcomes | Consistent trend for improvement |

**JHQJ / OVAR 2.5 Efficacy Results**

## Impact of Subsequent Chemotherapy on Survival for Recurrent Ovarian Cancer

**8497.01**

**Subsequent therapy for ovarian cancer may impact survival results**
**Cisplatin vs paclitaxel vs paclitaxel/cisplatin**
**Dox/Cyclo vs Cis/Dox/Cyclo **
**Frequency of subsequent therapy in studies of platinum-sensitive recurrent ovarian cancer**
**ICON 4 (3****rd**** line therapy not reported) **
**Standard practice in UK would be no 3****rd****-line therapy**
**JHQJ / OVAR 2.5 (75% patients received 3****rd****-line therapy)**

## Advancing the Treatment of Recurrent Ovarian Cancer

**Advancing the Treatment of Recurrent Ovarian Cancer**

**Standard of care in front-line ovarian cancer is Cb plus paclitaxel **
**Neurotoxicity is a frequent complication of this treatment**
**Standard of care in recurrent platinum-sensitive ovarian cancer is platinum-based therapy**
**Combination therapy has shown improvements in efficacy over single agent Cb in recurrent ovarian cancer**
**Effective, less neurotoxic regimen is needed**

## GCb is a Valuable Treatment Option for Patients with Recurrent Ovarian Cancer

**GCb is a Valuable Treatment Option for Patients with Recurrent Ovarian Cancer**

**Gemzar plus carboplatin showed an advantage over carboplatin **
**Clinically meaningful improvements in PFS that were robust, internally consistent, and statistically significant **
**Significantly greater overall and complete response rates**
**Manageable and well-characterized safety profile**
**Infrequent**** ****neurotoxicity and alopecia**
**Longer period without a decline in QoL **
**Longer time without need for further chemotherapy**
**JHQJ / OVAR 2.5 is a positive study with regard to its primary endpoint, PFS, and supporting endpoints**

**Gemzar plus carboplatin is an effective treatment option for women with recurrent ovarian cancer.**

## Back ups presented

## JHQJ / OVAR 2.5: Pre- and Post-Discontinuation Assessment Intervals

**8384.01**

|  | Weeks |  |  |  |
| --- | --- | --- | --- | --- |
|  | On-Treatment* |  | Off-Treatment** |  |
| Summary Statistics | GCb (N=168) | Cb(N=159) | GCb(N=117) | Cb(N=80) |
| 25th Percentile | 5.4 | 5.0 | 4.6 | 4.4 |
| Median | 6.3 | 6.1 | 8.3 | 8.3 |
| 75th Percentile | 7.7 | 7.6 | 10.0 | 10.5 |

***   Intervals between disease assessment dates******  Intervals between office visit dates**

## JHQJ / OVAR 2.5: Clinical versus Objective Progressions

|  | N (Percent of Patients) |  |  |  |
| --- | --- | --- | --- | --- |
|  | On-Treatment |  | Off-Treatment |  |
| Progressive Disease | GCb (N=35) | Cb(N=70) | GCb(N=117)* | Cb(N=80)** |
| Clinical Progression | 1 (3) | 7 (10) | 28 (24) | 16 (20) |
| Objective Progression | 34 (97) | 63 (90) | 92 (79) | 66 (82.5) |

**Three patients were counted twice, all 3 patients had both larger/new lesions and deteriorating ****   conditions as the basis of PD**
**** Two patients were counted twice, both patients had larger/new lesions and deteriorating ****   conditions as the basis of PD**

**8050.01**

## JHQJ / OVAR 2.5: Measurement Methods at Baseline

|  | Number of Patients (%) |  |
| --- | --- | --- |
| Method | GCb(N=178) | Cb(N=178) |
| CT-Scan | 126 (71) | 110 (62) |
| Ultra Sound | 39 (22) | 51 (29) |
| Physical Exam | 14 (8) | 21 (12) |
| MRI | 5 (3) | 6 (3) |
| Chest X-ray | 1 (0.6) | 1 (0.6) |
| Gynecological Exam | 1 (0.6) | 1 (0.6) |

**8321.01**

## JHQJ / OVAR 2.5: EORTC QLQ-C30 Within Arm Changes Over Time

| QLQ-C30 | GCb Arm (N=154) | Cb Arm (N=152) |
| --- | --- | --- |
| Global QoL | Improved | Stable |
| Physical functioning | Stable | Stable |
| Role functioning | Stable | Stable |
| Cognitive functioning | Stable | Stable |
| Emotional functioning | Improved | Improved |
| Social functioning | Stable | Stable |
| Fatigue | Stable | Stable |
| Nausea/vomiting | Worsened | Worsened |
| Pain | Improved | Improved |
| Dyspnea | Stable | Stable |
| Sleep disturbance | Improved | Improved |
| Appetite loss | Improved | Improved |
| Constipation | Stable | Stable |
| Diarrhea | Stable | Stable |
| Financial impact | Stable | Stable |

**8387.01**