# Presentation: 570358

## Genasense in Relapsed/Refractory Chronic Lymphocytic Leukemia

- Oncologic Drug Advisory Committee
- September 6, 2006

- update Footer
- w/ current “v#” on handouts

**Notes:**
Madame Chairman
Members of ODAC
Ladies and Gentlemen
Good Morning
On behalf of Genta Incorporated it is my pleasure to introduce today’s proceedings regarding the use of Genasense in relapsed/refractory CLL.

## Genasense is a novel therapeutic agent that augments the activity of chemotherapy by stimulating apoptosis through downregulation of Bcl-2

**Notes:**
Genasense is a novel, first in class therapeutic agent that augments the activity of chemotherapy by stimulating apoptosis through downregulation of Bcl-2.

## Genasense Drug Substance(Oblimersen Sodium, G3139)

**Selectively targets Bcl-2 RNA**
**Decreases Bcl-2 protein**

**Phosphorothioate backbone**

**Notes:**
Genasense is an 18 base strand of modified DNA.  Sulfur is substituted for one of the oxygen atoms in each of the phosphate groups in the DNA backbone and renders the molecule more resistant to degradation.
Genasense selectively targets Bcl-2 RNA to decrease the production of Bcl-2 protein.
As partially summarized in our briefing document, Genasense has demonstrated down-regulation of Bcl-2 in patients and particularly in lymphoid cells. 

## Genasense Indication

**Genasense in combination with Fludarabine and Cyclophosphamide is indicated ****for the treatment of patients with relapsed/refractory CLL**

**Notes:**
The sponsor is seeking approval for the following indication:
Genasense has been granted both orphan drug and fast-track designation by the FDA in recognition of the unmet medical need in this life-threatening disease.

## Agenda

| Introduction | Loretta Itri, MD |
| --- | --- |
| Relapsed/Refractory CLL | Michael Keating, MB, BS |
| Clinical Efficacy/Safety | Loretta Itri, MD |
| Risk/Benefit | Susan O’Brien, MD |
| Conclusion | Loretta Itri, MD |

**Notes:**
Following my brief remarks, Dr. Michael Keating, from  MD Anderson Cancer Center who is one of the most widely published researchers in the field of CLL will present an overview of the current management of relapsed/refractory CLL.
Following Dr. Keating’s presentation, I will return to present our data regarding the safety and efficacy of Genasense in this indication.  Then, Dr. Susan O’Brien, a  well known expert in the field of Hematologic Oncology from MD Anderson Cancer Center who has served as an advisor to ODAC in past deliberations on leukemia drugs and study endpoints, will present her assessment of the risk and benefits associated with Genasense use in CLL.  Finally I will return for a brief concluding statement.

## Expert Advisors

**Expert Advisors**

**Clinical**
- Michael Keating, MB BS	Professor of Medicine – Leukemia, MDACC
- Susan O’Brien, MD	Professor of Medicine – Leukemia, MDACC
- Kanti Rai, MB BS	Chief, Division of Hematology/Oncology, LIJMC
**Clinical Pharmacology**
- Anthony Tolcher, MD	Director, Clinical Research
- 	Cancer Therapy Research Center
**Histopathology**
- John Bennett, MD	Prof. of Pathology and Laboratory Medicine,
- 	URCC
**Cell/Molecular Biology**
- John Reed, MD, PhD	President & Chief Executive Officer
- 	The Burnham Institute
**Biostatistics**
- Richard Kay, PhD	Honorary Lecturer Biostatistics
- 	University of Cardiff
- Gary Koch, PhD	Professor of Biostatistics, UNC, Chapel Hill
**Drug Administration**
- Margaret Green, RN, OCN	Research Nurse Associate – Leukemia Program
- 	University of Chicago MC

**Notes:**
In addition to our speakers, we have with us today a distinguished group of expert advisors, including Dr. Kanti Rai, Dr. Tony Tolcher, Dr. John Bennett, Dr. John Reed, Dr. Richard Kay, Dr. Gary Koch and Ms. Margaret Green -- who are available to the committee to address any questions in their field of expertise.

## Criteria for Accelerated Approval

**Criteria for Accelerated Approval**

- Substantial evidence from well-controlled clinical trials regarding a surrogate end-point
- Surrogate end-point reasonably likely to predict clinical benefit
- Serious or life-threatening disease
- Drug must provide benefit over available therapy
- Post-marketing studies must verify clinical benefit

**Notes:**
ODAC is being asked for advice regarding the accelerated approval of Genasense in the CLL indication.  Accelerated approval requires the identification of a surrogate endpoint from well controlled clinical trials that are reasonably likely to predict for clinical benefit.  At the ODAC Meeting on accelerated approvals in March 2003 it was agreed that durable CR could serve as an appropriate surrogate in a situation of life threatening disease when the new drug provides benefit over available therapy.  Post marketing studies should be conducted to verify clinical benefit.
Data will be presented today which we believe fulfill all of these criteria and provide compelling evidence for the clinical benefit associated with the use of Genasense.

## Relapsed/Refractory Chronic Lymphocytic Leukemia

- Michael Keating, MB, BS

## CLL Patients Express Bcl-2

**CLL Patients Express Bcl-2**

- ASchena et al. Blood 1992;79:2981, BHanada et al. Blood 1993;15:1820, CRobertson et al. Leukemia 1996;10:456, DZaja F, Leuk Lymphoma 1998;28:567, EAviram et al. Eur J Haematol 2000;64:80, FKlobusicka et al. Neoplasma 2002;49:387, GMenendez et al. Leukemia 2004;18:491, HTracey et al. J Pathology 2005;206:123

**Notes:**
Eight independent publications have evaluated  Bcl-2 expression in CLL patients. Most showed that 100% of the CLL samples analyzed were Bcl-2 positive.

## Relapsed/RefractoryChronic Lymphocytic Leukemia

- Highly symptomatic
- Fever, night sweats, weight loss, fatigue, lymphadenopathy, splenomegaly
- Poor Prognosis
- Fatalities from infection or bleeding
- Limited treatment options:
- Repeat Fludarabine
- Alemtuzumab
- Rituximab (unapproved for CLL)
- Investigational agents

**Notes:**
 There’s a general impression that CLL is a rather indolent disease, that patients live for a long time without complaints, that they’re highly responsive to chemotherapy which can be administered on a “watch-and-wait” basis, and although not curable by any means, they can be easily salvaged with other treatments when they relapse.
 That is not the disease that we are addressing today.  Patients with relapsed and refractory CLL comprise about 8,000 individuals in the U.S.  Patients who were candidates for the trials you will hear about today had relapsed from or failed to respond to standard treatments.  Unlike a newly diagnosed patient with stable lymphocytosis, these patients tend to be highly symptomatic with manifestations of the disease.  They experience fever, recurrent night sweats; they frequently lose weight and are fatigued.  They may have massive lymphadenopathy or splenomegaly that cause pain, impairs mobility, and dramatically interferes with the activities of daily life.
 These patients have a progressive disease that will kill them in a short period of time, during which time they will be afflicted with many symptoms and will commonly expire from infection due to myelosuppression and immunosuppression owing to both the disease and the chemotherapy we use to treat it.
  There’s also an impression that we have an array of treatment options for these patients.  For a long time, single alkylating agents, such as chlorambucil, had been the mainstays of standard care until fludarabine was approved.  Subsequent randomized clinical trials in previously untreated patients – including a prominent trial published in the New England Journal by my colleague Dr. Rai who is with us today - have now shown that fludarabine is superior to chlorambucil.
 I last appeared before this committee on behalf of alemtuzumab, or Campath, which was approved for fludarabine-refractory patients, and that concludes the list of approved drugs in CLL.  There’s probably no greater testament to the unmet need than to note than an investigational drug, Rituxan, is today the most widely prescribed drug for CLL in the U.S.  This use has occurred despite the evidence for very limited activity as a single-agent, and no data from any randomized trials. 

## Relapsed/Refractory CLL Treatment ObjectivePALLIATION IS NO LONGERTHE DESIRED CLINICAL ENDPOINT

**Prior to 2000:**
**Palliation**
*Partial* reduction
- Tumor volume
- Symptoms
- Peripheral blood abnormalities

**Currently:**
**Prolonged Remission**
*Complete* resolution
- Tumor volume
- Symptoms
- Peripheral blood abnormalities
*Durable* CR/nPR

**Notes:**
In the past, CLL was felt to be incurable, and all lines of care were directed toward palliation of symptoms.  In the 1990s, however, increased use of fludarabine showed that induction of complete remission was a realistic goal in an increasing proportion of patients.
• This concept of complete remission has been extremely important in hematology, since this level of objective response – not partial response - has been linked to therapeutic progress in virtually every form of leukemia.
• In relapsed and refractory patients, the proportion of patients who achieve CR has been lower; however, the benefits of CR, when achieved and when durable, remain quite valuable.  Those benefits include complete elimination of evident disease, prolonged relief of all disease-related symptoms, and recovery of blood counts.  Patients in CR are also relieved of the recurrent infectious complications attendant to immunosuppression and myelosuppression of the disease and its treatment. 

## Prior FDA Approval Studiesin Relapsed/Refractory CLL

|  | Fludarabine
(1991) | Alemtuzumab
(2001) |
| --- | --- | --- |
| Study Type | Non-randomizedPhase 1-2 | Non-randomizedPhase 2 |
| Number of pts. | 79 | 93 |
| Efficacy: |  |  |
| CR | 13%† | 2%** |
| PR | 19-35% | 31% |
| Response Duration | 15-21 mos | 7 mos |
| Safety*: |  |  |
| Died on study | 22% | 10% |
| Grade 4 neutropenia | 59% | 37% |
| Pneumonia | 16-22% | 15% |

**†****Chlorambucil failure, Non NCI-WG criteria, No CT**
***Campath ODAC presentation**
****No CT**

- Silver Bullet

**Notes:**
 As I mentioned, only two drugs have been approved in CLL over the past 15 years: fludarabine in 1991 and alemtuzumab in 2001.  Both drugs were approved on the basis of non-randomized trials.  Two, small Phase 1 and Phase 2 studies – in aggregate totaling 79 patients - were pivotal for fludarabine.  Only one study, on which I was the primary author, was considered pivotal for the efficacy of alemtuzumab, while the Sponsor contributed two smaller studies in support of the drug’s safety.  The efficacy of both drugs was evaluated primarily on the basis of partial rather than complete response, and as you can see at the bottom of this slide, both of these agents were associated with very serious and occasionally fatal complications for patients.
 As you’ll hear today, the Genasense program is the first NDA to ever include a randomized controlled trial.  One of the reasons why the briefing document compares response rates to trials in previously untreated patients is that the Genasense trial is the first and only randomized comparative trial conducted in previously treated patients. 

## CR and nPR Require Normalization of All Disease Parameters

| Parameter | CR/nPR |  | PR |
| --- | --- | --- | --- |
|  | (2 Months Minimum Duration) |  |  |
| Lymph Nodes | None | 50% decrease |  |
| Liver/Spleen | Not palpable | 50% decrease |  |
| Constitutional Symptoms | None allowed | No improvement required |  |
| ALC | < 5,000 | 50% decrease |  |
| Granulocytes
Platelets
Hemoglobin | > 1,500
> 100,000
> 11.0 | 50% improvement*
50% improvement*
50% improvement*
(*Only one parameter required) |  |
| Bone Marrow | < 30% lymphocytes
+/- presence of nodules
on bone marrow biopsy | No improvement required |  |

**NCI WG; Cheson, Blood, 1996**

- Silver Bullet

**Notes:**
Let’s have a look at endpoints in clinical trials for CLL.  In almost all forms of leukemia, complete responses – particularly complete responses that are long-lived – are clinical evidence of benefit for patients.  In fact, for all types of hematologic cancers, CR – not partial response - has been the initial basis for determining whether we’re making therapeutic progress or not, so from that standpoint CLL has been a bit of an outlier.
 In the Genasense trial, the prospectively defined endpoint was the comparative proportion of patients who achieved CR or a nodular PR.  The NCI-Working Group criteria for CR/nPR are summarized on this slide.  As you can see, a nPR requires all the criteria for a CR, including complete eradication of all disease, disappearance of all disease-related symptoms, and recovery of blood counts in every lineage.  Furthermore, the Genasense trial required documentation of disease eradication by CT or ultrasound in any patient who had a pre-existing abnormality, which is not required by the criteria and is an additional, rigorous test.
Contrast that level of response with a PR, as shown on the right.  Patients in PR retain a substantial, usually visible, burden of tumor.  They may have substantial organomegaly.  They may have no meaningful symptomatic benefit whatsoever.  Patients in PR may have limited recovery of only a single blood count abnormality, and they have extensive disease in their bone marrow. 

## Bone Marrow nPR vs. CR

**nPR with Nodule**

**CR Clear of Nodules**

**Baseline**

**Notes:**
The sole difference between CR and nPR is shown in this slide of bone marrow biopsies.

## CR and nPR Correlate withIncreased Survival in CLL

**Notes:**
With that definition in mind, it is no surprise – like every other hematologic cancer – that benefit accrues to patients who respond, and patients who have a complete response fare much better than patients whose best response is a PR or stable disease.  These plots reflect outcomes by best response in large sequential studies performed at our center in patients with relapsed and refractory CLL.  As can be seen from the graphs, in completely separate series, the survival of patients with nPR tracked closely with the outcome of patients who achieved CR in both studies, and more importantly their outcome was far superior to those patients whose best response was limited to PR.  Findings from the randomized multicenter trial of Genasense reconfirm these data from our center.
 However, as you’ll hear later, the Genasense trial does not confirm a benefit for lack of progression in relapsed/refractory patients.  This finding is really not surprising, since stable disease is usually maintained only by treatment with highly myelo- or immuno- suppressive agents. 

## Summary

- Relapsed/Refractory CLL:
- Rapidly progressive
- Highly symptomatic
- Resistant to chemotherapy
- Fatalities due to infection and/or bleeding
- Limited medical options
- CR/nPR is the most relevant current endpoint in CLL
- Unmet medical need

**Notes:**
In summary, patients with relapsed/refractory CLL have a progressive, highly symptomatic, and ultimately fatal disease with very few treatment options.  As with all forms of leukemia, patients who benefit are the patients in whom major responses can be achieved.  Not surprisingly, benefit is maximized in those patients who achieve the best response.
 The clinical trials results show that CR/nPR unquestionably reflects a superior outcome for patients compared with partial responses.  CR/nPR patients also have complete relief of symptoms, recovery of blood counts, and prolonged survival compared with any other, lesser category of response.
 Despite the limited options that are available, I believe we have made progress over the past 15 years in CLL.  Data from our sequential studies, as well as the randomized trials reviewed in the briefs, clearly suggest that new agents are improving CR rates in CLL, which is the key to maintaining therapeutic progress in this illness.  The increase in CR/nPR observed with Genasense is of a magnitude similar to other active agents in CLL that we believe will ultimately transform therapy for this unmet need.

## Clinical Efficacy & Safety

- Loretta Itri, MD

## Genasense CLL Program

- Phase 1-2 Single agent (N=40)
- Part A - dose finding
- Part B - efficacy and safety
- Phase 3 (N=241)
- Randomized pivotal combination study with chemotherapy
- Safety Database (N>1000)

**Notes:**
The Genasense Program in CLL consisted of 2 studies:
 A Phase I-II single agent dose finding and efficacy study
 A randomized Phase III study
Both studies were conducted in relapsed or refractory CLL patients.
These disease specific findings are supported by a safety database of more than 1000 patients who received Genasense either in single arm or randomized studies in a variety of cancer types.

## Genasense Phase 1-2 (Part A) Relapsed/Refractory CLL (N=14)

- Established MTD 3mg/kg/day (5-7 day CIV infusion)
- Dose limiting toxicities
- Cycle 1 infusion reactions
- High spiking fever, rigors and hypotension
- Tumor lysis syndrome
- Other side effects
- Nausea, fatigue, thrombocytopenia

**Notes:**
In the Phase I-II study, doses ranging from 3-7 mg/kg were evaluated using a 5-7 day continuous IV infusion.  At doses higher than 3 mg/kg a dose-limiting first cycle reaction consisting of fever, rigors, hypotension as well as thrombocytopenia with or without tumor lysis was observed.

## Genasense Phase 1-2 (Part B) Single Agent Efficacy Relapsed/Refractory CLL(N=26)

| Anti Leukemic Response | n |  (%) |
| --- | --- | --- |
| ≥ 50%  CLL cells | 11/22 | 50 |
| ≥ 50%  Lymph nodes | 7/22 | 32 |
| ≥ 50%  spleen | 7/17 | 41 |
| PR | 2/26 | 8 |
| Stable | 12/26 | 46 |

**Median number of prior regimens = 3**
**Genasense  3 to 7 mg/kg/d x 5-7d**
**O’Brien et al., J Clin Oncol, 2005**

**Notes:**
At the established Phase II dose of 3mg/kg, single agent Genasense demonstrated clear anti-tumor activity.  In addition to the 2 patients who achieved a PR according to strict NCIWG criteria, approximately half of these very heavily pre-treated patients demonstrated a reduction in circulating CLL cells, lymph nodes or splenomegaly.

## GL303

- Pivotal Randomized Phase 3 Study of Fludarabine and Cyclophosphamide
- with or without Genasense in Relapsed/Refractory CLL

**Notes:**
Based upon the results obtained in Phase II study ...

## GL303 Phase 3 Study Design

**241 patients**
**Relapsed/refractory: ≥ 1 fludarabine regimen**
**Stratification:**
**Fludarabine “refractory” vs. non-refractory**
**No. of prior regimens: 1-2 vs. ≥ 3**
**Response to last therapy: > 6 vs. ≤ 6 months**

**Notes:**
We conducted Study GL303, the first randomized trial in advanced CLL to be performed in support of a licensing application. 
This was a multicenter, multinational trial in which 241 patients were randomly assigned on a 1-to-1 ratio to receive Flu/Cy chemotherapy plus Genasense or chemotherapy alone.  Before randomization, patients were stratified on the basis of response to prior treatment including: refractoriness or relapse after prior fludarabine therapy; the number of prior regimens – 2 or fewer regimens versus 3 or more; and whether the duration of response to last therapy was more or less than 6 months.
As stated in FDA briefing package, this protocol was amended 6 times; no patients were treated on the first version; the majority of the remaining revisions were to update the safety warnings. The last  revision was to increase follow up to 3 years.

## Fludarabine Sensitivity Criteria*

- Refractory
- Failure to achieve at least a PR
- 	or
- Recurrence within 6 months of treatment
- Relapsed
- Recurrence after ≥ PR lasting ≥ 6 months

*** Identical to criteria employed in Alemtuzumab BLA**

**Notes:**
Definitions of responsiveness to prior fludarabine are outlined here.
Patients were required to have received at least one prior Fludarabine containing regimen and at least 2 prior cycles of Fludarabine.
A patient was considered ‘refractory’ to fludarabine if he failed to achieve at least a PR during the last Fludarabine treatment, or if a PR was achieved but lasted less than 6 months.
A patient was called ‘relapsed’ if after the last treatment with fludarabine they achieved at least PR of at least 6 months duration.

## Protocol Therapy  Dosing Regimens

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Days**

**Genasense 3mg/kg/day CIV days 1-7**

**Fludarabine**

**Fludarabine**

**Fludarabine**

**CTX**

**CTX**

**CTX**

**1**

**2**

**3**

**Fludarabine**

**Fludarabine**

**CTX**

**CTX**

**Randomization**

**Fludarabine**
**     ****25 mg/m****2**** **

**CTX**
**     ****250 mg/m****2**

**Notes:**
Patients randomized to Genasense received the drug as an out-patient for 7 consecutive days by continuous IV infusion using a portable, ambulatory infusion pump.  After 4 days of Genasense alone, fludarabine and Cytoxan were given together with Genasense for the following 3 days.  Patients randomized to chemotherapy alone received the same doses of Flu/Cy on the same daily x 3 schedule, and cycles were repeated every 28 days.  Patients were evaluated for response monthly while actively receiving therapy, and then every two months until the time of progression, up to a maximum of 3 years from randomization.  

## Protocol Endpoints

- Primary endpoint
- CR + nPR
- NCI-WG criteria
- CT/US confirmation
- Central blinded expert review
- Secondary endpoints
- Response duration (CR + nPR, CR + nPR + PR)
- Overall response (CR + nPR + PR)
- Time to progression
- Overall survival
- Clinical benefit
- Safety

**Notes:**
The prospectively defined, primary objective of the study was to compare the relative proportion of patients on each arm who achieved a major response – defined as complete responses or nodular partial responses. 
Responses were classified using NCI Working Group criteria and were determined after a blinded, central review of both clinical parameters and bone marrow.  In addition to standard criteria, in order to qualify as a CR or nPR, the protocol required normalization of any abnormalities determined on baseline CT or ultrasound examinations.
Secondary objectives included comparisons of response duration, overall response, time-to-progression, overall survival, clinical benefit, and safety. 
The sponsor was blinded to study arm, patient identification and all results during the study.  Additionally, the database was maintained offsite by an external contract research organization.

## Central Blinded Assessment of Response and Disease Progression

- Histopathologic review of bone marrow
- Dr. Gregory Threatte
- Clinical response assessment
- Dr. Kanti Rai
- Disease progression determination
- Dr. Kanti Rai

**Notes:**
All patients were assessed for response and progression of disease by central blinded review.  Dr. Gregory Threatte, Chairman of the Department of Histopathology, SUNY Upstate Medical University  and National Morphology Reviewer for CALGB, performed histopathologic review of all bone marrow samples, and Dr. Kanti Rai, author of the Rai staging system for CLL, assessed all patient data for clinical response and disease progression according to NCIWG criteria as well as CT/US findings.

## Demographics and Baseline Characteristics

|  | GFC
(N=120) | FC
(N=121) |
| --- | --- | --- |
| Age, yrs (median) | 63 | 63 |
| Male / Female | 89 / 31 | 89 / 32 |
| ECOG PS ≥ 1, n (%) | 78 (66) | 80 (68) |
| Time from diagnosis, months (median) | 70 | 58 |
| Hgb, median (range)    | 12 (7-16) | 12 (7-17) |
| Platelets, median (range)   | 130 (24-291) | 120 (16-344) |
| B-microglobulin > 4, n (%) | 52 (43) | 47 (39) |
| Elevated LDH, n (%) | 53 (44) | 52 (43) |
| Splenomegaly, n (%) | 51 (42) | 51 (42) |
| Splenectomy, n (%) | 11 (9) | 4 (3) |

**Notes:**
As observed by FDA in their briefing document, most baseline variables were well-balanced. Overall, no differences were was observed for age, gender and race. Baseline characteristics involving laboratory and physical examination factors were similarly well balanced. There were a few small imbalances: Although not shown on this slide, there were more patients > 75 years of age in the Genasense arm.  Median time from diagnosis was longer by approximately 1 year in the Genasense arm but was not statistically significant. There was also a slight increase in the number of patients with a history of splenectomy in the Genasense arm.

## Baseline Active Disease Signs and Symptoms

|  | GFC
(N=120)
n (%) | FC
(N=121)
n (%) |
| --- | --- | --- |
| Weight loss (> 10% prior to study) | 17 (14) | 15 (12) |
| Extreme Fatigue (≥ Gr 2) | 35 (29) | 30 (25) |
| Fever (> 100.5° F ≥ 2 weeks) | 7 (6) | 4 (3) |
| Night sweats | 43 (36) | 38 (31) |
| Worsening anemia or thrombocytopenia | 48 (40) | 40 (33) |
| Massive splenomegaly (> 6 cm)  | 29 (24) | 22 (18) |
| Lymphadenopathy | 111 (93) | 109 (90) |
| Progressive lymphocytosis | 62 (52) | 55 (46) |

**P<0.05**

**Notes:**
Individual signs and symptoms characterizing active disease as prospectively captured on the CRF were well balanced between arms.
Although the individual signs and symptoms were relatively evenly distributed, when taken together, there were statistically significantly more patients on the Genasense arm with evidence of active and/or symptomatic disease.

## Stratification Factors

|  | GFC
(N=120)
n (%) | FC
(N=121)
n (%) |
| --- | --- | --- |
| Fludarabine sensitivity |  |  |
| Relapsed | 51 (43) | 50 (41) |
| Refractory | 69 (58) | 71 (59) |
| Number of prior regimens |  |  |
| 1-2 | 60 (50) | 63 (52) |
| ≥ 3 | 60 (50) | 58 (48) |
| Response to last therapy |  |  |
| > 6 months | 54 (45) | 52 (43) |
| ≤ 6 months | 66 (55) | 69 (57) |

**Notes:**
A presentation of patients according to stratification factors reveals that the majority of patients (approximately 60%) had disease refractory to fludarabine.  The average or mean number of prior regimens received was 3.  More than half the patients had a response to last therapy of 6 months or less in duration.

## Prior Chemotherapy Well Balanced

|  | GFC
(N=120) | FC
(N=121) |
| --- | --- | --- |
| Fludarabine cycles, mean (SD) | 7 (5.8) | 5.5 (3.2) |
| Cytoxan/Chlorambucil | 84 (70%) | 86 (71%) |
| Rituximab | 34 (28%) | 34 (28%) |
| Alemtuzumab | 7 (6%) | 9 (7%) |
| Other | 68 (57%) | 71 (59%) |

**Notes:**
Good balance was observed for prior therapies.

## Randomized Phase 3 Study Relapsed/Refractory Chronic Lymphocytic Leukemia

- Efficacy

**Notes:**
The primary efficacy endpoint of this study was achieved.

## Primary Endpoint AchievedSignificant Increase in CR/nPR

**n=5**

**n=9**

**n=3**

**n=11**

**GFC**

**FC**

**CR**

**nPR**

**Major**
**Response**
**(%)**

**17%**

**7%**

**CR/nPR p=0.025 (Chi-Square)**

- Silver Bullet

**Fisher’s exact test: CR/nPR****	****p=0.016**
**                                 ****CR only****	****p=0.03**

**Notes:**
The addition of Genasense to the standard combination of fludarabine and cyclophosphamide resulted in a 17% rate of CRs and nPRs as compared to only 7% for the control arm.
This difference is statistically significant with a p value of 0.025 by the continuity corrected chi square test.  This difference remains significant if one chooses to look at CRs only as well in which case the result remains significant with a p value of 0.03 by Fisher Exact Test.
These results have been independently confirmed by FDA review.

## CR/nPR Significantly More Durable with Genasense/FC

**CR/nPR Significantly More Durable with Genasense/FC**

**From Date of Initial Response**

|  | GFC | FC |
| --- | --- | --- |
| Median | Not Reached | 22 mos |
| Events/N | 5/20 (25%) | 6/8 (75%) |
| HR | 0.29 |  |

**P=0.031**

- Silver Bullet

_**GFC**_

_**FC**_

**Notes:**
In addition to a significantly greater number of major responses, there was also a significant difference noted in the durability of these responses.
With 2 years minimum follow-up, only 5 of the 20 patients (25%) who achieved a major response in the Genasense arm had relapsed as compared with 6 of 8 patients (75%) in the control arm.  
The median duration of response in the FC arm was 22 months and has not yet been reached in the Genasense arm.  The median duration of major response in the Genasense arm is estimated to exceed 36 months.
This difference is significant with a p value of 0.031.

## CR/nPR Duration of Response During Treatment and Post Treatment

**CR/nPR Duration of Response During Treatment and Post Treatment**

- 6

- 0

- 18

- 24

**FC**

**GFC**

- 30

- 12

- 36

- 42

**+ **** ****= Ongoing**

**Months**

- Silver Bullet

**Median Duration Post Chemo**
** ****GFC = Not Reached (est. >31 mos)**
** ****FC = 20 mos**

**Notes:**
Duration of response during and after completion of chemotherapy are shown here.  Each bar represents a CR or nPR patient.  The blue denotes the period of time from start of remission while patient was receiving chemotherapy.  As you can see, the post-chemotherapy durations of response are quite long.  The duration of remission post-chemotherapy is designated in yellow.  The median duration of remission post-chemotherapy in the GFC arm has not been reached but is expected to exceed 31 months.  This compares very favorably with a median of only 20 months in the control arm.
As you can see, the majority of responses in the Genasense arm are ongoing as of last assessment.

## Four-Fold Increase in CR/nPR in Chemosensitive Patients

|  | GFC
(N=120) | FC
(N=121) |
| --- | --- | --- |
| Fludarabine sensitivity |  |  |
| Relapsed | 13/51 (25) | 3/50 (6) |
| Refractory | 7/69 (10) | 5/71 (7) |
| Number of prior regimens |  |  |
| 1-2 | 14/60 (23) | 4/63 (6) |
| ≥ 3 | 6/60 (10) | 4/58 (7) |
| Response to last therapy |  |  |
| > 6 months | 12/54 (22) | 3/52 (6) |
| ≤ 6 months | 8/66 (12) | 5/69 (7) |

**Notes:**
Improvement in the incidence of major response was distributed across all pre-specified strata and was numerically superior for patients who received Genasense in all subsets.
In patients who had retained sensitivity to chemotherapy as manifested by fludarabine relapsed status, less prior chemotherapy or the ability to maintain a response for longer than 6 months, the benefit for the Genasense treated population was more than four times greater than the control arm.  

## Overall Response Rate (ORR*) and Response Duration 

**Overall Response Rate (ORR*) ****and Response Duration **

*** ORR  = CR/nPR + PR**

|  | GFC | FC |
| --- | --- | --- |
| ORR % | 41 | 45 |
| Events n(%) | 31/49 (63) | 38/54 (70) |
| Hazard ratio | 0.76 |  |
| P | 0.26 |  |

_**GFC**_

_**FC**_

**Notes:**
Overall response rate was similar between the two groups. 
Response duration overlapped initially, but separation between the curves begins at 16 months and there is a trend favoring the GFC group which is driven by the CR/nPRs thereafter.

## Time to Progression Intent-to-Treat Population

**Time to Progression ****Intent-to-Treat Population**

|  | GFC | FC |
| --- | --- | --- |
| Events n(%) | 87/120 (73) | 88/121 (73) |
| Hazard ratio | 1.03 |  |
| Logrank P | 0.83 |  |

_**GFC**_

_**FC**_

**Notes:**
At 2 years, time to progression was not significantly different between the two arms. 

## TTP ≥ 2 Years Correlates with Response (CR/nPRs Have Greatest Benefit)

***P<0.0001 1 DF Chi-Square Test of Trend**
**Numerator is number with observed TTP **_**>**_** 2 years**

**Notes:**
Although the overall TTP curves were not different, the percentages of patient with a progression-free duration of 2 years or more were remarkably greater for the CR/nPR population.  Only a few patients with PR of response had not progressed by 2 years.

## Overall SurvivalIntent-to-Treat Population

**Overall Survival****Intent-to-Treat Population**

|  | GFC | FC |
| --- | --- | --- |
| Median	 | 33.8 | 32.9 |
| Events n(%) | 58/120 (48%) | 62/121 (52%) |
| Logrank P | 0.96 |  |
| HR	 | 0.99 |  |
| 95% C.I.	 | 0.69-1.42 |  |

_**GFC**_

_**FC**_

**Notes:**
With 3 years of follow-up, overall survival for the ITT population was not different between arms.

## Survival ≥ 3 Years Correlates with Response (CR/nPRs Have Greatest Benefit)

***P<0.0001 1 DF Chi-Square Test of Trend**
**Numerator is number with observed survival **_**>**_** 3 years**

**Notes:**
But, like TTP at 2 years, 3 yr. survival correlated with best response.  Only 8 percent of patients with less than a PR survived for 3 years as did 37% of the PR patients. In important contrast, 61% of the CR/nPR patients were still alive at 3 years.

## Durable Symptom Relief Correlates With Response (CR/nPR Have Longest Symptom Free Duration)

|  | CR/nPR | PR | <PR |
| --- | --- | --- | --- |
| Symptomatic at baseline, n | 18 | 61 | 121 |
| Symptom-free* |  |  |  |
| ≥ 6 Month | 94% | 59% | 6% |
| ≥ 1 Year | 83% | 36% | 1% |
| ≥ 2 Years | 44% | 10% | 0 |

- Silver Bullet

- For each time point, **P<0.0001 1 DF Chi-Square Test of Trend**

- *Includes B-symptoms, fatigue, symptoms due to hepatosplenomegaly, lymphadenopathy, or other

**Notes:**
This is the first randomized trial in the salvage setting in which symptom data were routinely and prospectively collected.
Although as noted by FDA, there were no between arm differences for individual symptoms, it is nevertheless clear that major symptom benefit, as measured by the clearance of all of these pre-defined symptoms for a period of at least 6 months in patients who had any of the symptoms on this slide at baseline, is associated with the achievement of CR/nPR.  Almost all patients in this category, but virtually no patient with less than a PR experienced meaningful benefit. 
PRs are associated with an intermediate degree of benefit, but they are not very durable.  With additional follow up, 83% of CR/nPR patients have achieved at least 1 year of symptom free status whereas only 36% of PRs remained symptom-free for the same period of time.  All of these findings are statistically significant and support the appropriateness of CR/nPR as the primary endpoint in this study.

## GL303:Relapsed/Refractory Chronic Lymphocytic Leukemia

- Safety

## Non-Hematologic Adverse Events

|  |  % Grade 3  |  | % Grade 4 |  |
| --- | --- | --- | --- | --- |
| All-grade events occurring in ≥ 20%  | GFC | FC | GFC | FC |
| Nausea | 8 | 2 | 0 | 0 |
| Fatigue | 6 | 3 | 0 | 2 |
| Vomiting | 5 | 1 | 1 | 0 |
| Dyspnea | 4 | 2 | 1 | 0 |
| Pyrexia | 4 | 3 | 0 | 0 |
| Constipation | 2 | 1 | 0 | 0 |
| Headache | 1 | 3 | 0 | 0 |

- Silver Bullet

**Notes:**
The most common Grade 3-4 adverse events occurring during study are noted here.
As a single agent Genasense is known to produce flu-like symptoms as well as nausea.  Therefore, it is not surprising that these events are occurring with greater frequency in the Genasense arm.  Note that there was no increase in Grade 4 events.

## Hematologic Toxicity

**Hematologic Toxicity**

| 

 | GFC
(N=115)
n (%) | FC
(N=115)
n (%) |
| --- | --- | --- |
| Neutropenia (Gr 3-4)
	G-CSFAntibioticsOpportunistic infectionsFebrile neutropenia | 22 (19)
98 (85)114 (99)5 (4)13 (11) | 28 (24)
111 (97)113 (98)8 (7)9 (8) |
| Anemia (Gr 3-4)
	ErythropoietinRBC Transfusion | 17 (15)
42 (37)41 (36) | 17 (15)
36 (31)33 (29) |
| Thrombocytopenia (Gr 3-4)
	Platelet Transfusions | 38 (33)
21 (18) | 23 (20)
6 (5) |

- Silver Bullet

**Notes:**
Neutropenia and anemia were not different between arms. The incidence of opportunistic infections and the percentages of patients who received antibiotics and growth factors was similar across the treatment groups. There was a higher incidence of Grade 3-4, mostly Grade 3, thrombocytopenia in the Genasense arm with an associated increase in platelet transfusions. 

## PlateletsMedian and Inter-quartile Range

**Notes:**
Platelet counts by cycle with median and inter-quartile ranges are shown here.  The major difference in platelet counts appeared primarily in Cycle 1.  
Recovery to baseline for all grade events of thrombocytopenia was similar between arms whether patients had baseline platelet counts above or below 100,000. Recovery was equally longer between arms when patients entered the study already thrombocytopenic.

## Platelet Transfusions and Bleeding Events

|  | GFC
(N=115) | FC
(N=115) |
| --- | --- | --- |
| Transfusions | 21  | 6  |
| Transfusions with platelet count |  |  |
|       >25K | 6 | 2 |
|       >10 - <25K | 12 | 3 |
|       <10K | 3 | 1 |
| Bleeding events associated with transfusions | 2* | 2+ |
|       >10 - <25K | 2 | 1 |
|       <10K | 0 | 1 |

*** 1 grade 3, 1 grade 2**
**+ 1 grade 1, 1 grade 3**

**Notes:**
As previously stated, platelet transfusions were increased in the Genasense arm and occurred primarily in Cycle 1 in patients with lower baseline counts.   
There are more platelet transfusions given without associated bleeding in the Genasense arm, again primarily in Cycle 1, which probably reflects a lower threshold for transfusion with a new drug.  
The number of platelet transfusions administered for low platelets associated with bleeding events was very low and similar between arms.  

## Hematologic ParametersMedian and Inter-quartile Range

**Hematologic Parameters****Median and Inter-quartile Range**

**Notes:**
Importantly, for this significantly myelo-suppressed population, neutrophil counts and hemoglobin were not adversely affected by the addition of Genasense.  The curves for median neutrophil count and hemoglobin by cycle are shown here and are virtually superimposable.

## Deaths and Discontinuations(On Study)

| Treatment Related | GFC(N=115)
n (%) | FC(N=115)
n (%) |
| --- | --- | --- |
| AE leading to discontinuation  |   29 (25) |   27 (24) |
| AE with outcome of death |   5 (4) | 2 (2) |
| Sepsis | 2 | 1 |
| Tumor lysis syndrome/First cycle reaction                                                                                                                     | 2 | 0 |
| Elevated creatinine (progressive disease) | 1 | 0 |
| Pseudomonal pneumonia | 0 | 1 |

- Silver Bullet

**Notes:**
Overall, adverse events which occurred during study or within 30 days of the last dose and led to discontinuation were balanced. 
Adverse events with an outcome of death were also balanced with the exception of two deaths in the Genasense arm which were related to a first cycle infusion reaction and tumor lysis syndrome in one patient each in Cycle 1. 

## Infusion Reactions

- Reaction:
- Spiking fever, nausea, dehydration, rigor, back pain, hypotension, renal insufficiency
- Lymphoid malignancies only
- Incidence: 1.7% at 3 mg/kg
- Preventive/supportive care:
- Hydration, antiemetics, analgesics and observation

**Notes:**
Infusion-related reactions are increasingly associated with active drugs commonly used for CLL.
With Genasense, these reactions are largely confined to the first treatment cycle, and they can be ameliorated by vigilant observation and hydration, as well as timely intervention with antipyretics and antiemetics as warranted in order to prevent both sensible and insensible fluid loss.

## Hospitalizations: Grade 3-4 AEs

|  | GFC
(N=115)
n (%) | FC
(N=115)
n (%) |
| --- | --- | --- |
| Febrile neutropenia | 10 (9) | 3 (3) |
| Sepsis | 3 (3) | 2 (2) |
| Catheter related infection | 3 (3) | 1 (1) |
| Anemia | 0 | 3 (3) |
| Pneumonia | 1 (1) | 4 (4) |

- Gr 3-4 AEs >3%

**Notes:**
Hospitalizations for Grade 3 or 4 adverse events were increased in the Genasense arm, particularly in Cycle 1.  The specific adverse events leading to hospitalization with an incidence greater than 3% are shown here.  Febrile neutropenia was the most commonly cited reason for admission, although documented infections, such as sepsis and pneumonia, are relatively well-balanced.  Since Genasense is known to cause fever, it is not unlikely that the higher incidence of ferbile neutropenia is at least in part due to drug related fever and not infection.  Actual days in the hospital support this hypothesis since approximately 25% of patients were hospitalized for less than 3 days and 50% for less than one week.

## Catheter-Related Events

- Protocol catheter requirement for Genasense
- Infection
- No grade 4 events
- Hospitalization:	GFC - 3, FC - 1
- Treatment interruption:	GFC-  1, FC - 1
-  Thrombosis
- No grade 4 events
- Two Grade 3 events in GFC arm: subclavian vein and jugular vein thrombosis

**Notes:**
Because administration of Genasense requires an in-dwelling catheter, related adverse events were increased.  The two major complications associated with catheters are infection and thrombosis.  
No Grade 4 events occurred for either complication.  There were 2 more related hospitalizations due to infection, but no increase in treatment interruptions.
Two Grade 3 thrombotic events involving the upper extremity were noted in the Genasense arm.

## Other Complications

|  | GFC
(N=115) | FC
(N=115) |
| --- | --- | --- |
| Opportunistic infection | 5 | 8  |
| Autoimmune hemolytic anemia | 3 | 0 |
| Autoimmune thrombocytopenia | 0 | 1 |
| Second malignancies | 1+ | 4* |

**+****	****Waldenstrom’s Macroglobulinemia**
*******	****AML, PTCL, Hodgkin’s disease, MDS **

**Notes:**
Other complications associated with advanced CLL, including opportunistic infection, autoimmune hemolytic anemia, autoimmune thrombocytopenia and second malignancies did not occur with greater frequency on either arm.

## Summary and Benefit–Risk Assessment

- Susan M. O’Brien, MD

**Notes:**
I would like to lead off by noting that I was the primary investigator and treated many patients on the original Phase I trial of single-agent Genasense in CLL, so I am very familiar with its activity and side effects.  In my discussion, I want to provide a context for the data you have just seen; in regards to how these data compare relative to other trials in CLL, and assess the benefit-risk ratio.  From this discussion, the clinical significance of the addition of Genasense to chemotherapy will be established.

## ThrombocytopeniaPlatelet Count by Cycle

**Notes:**
Let’s start with some specific risks.  Genasense was associated with an increase in thrombocytopenia.  This finding led to an increase in platelet transfusions, but was not associated with an excess in serious bleeding.
In addition, the cycle-by-cycle analysis suggests two observations: first, that thrombocytopenia was primarily limited to the first cycle; and second, that it was most common in patients with platelet counts that were low at the time of entry.  And note that in Cycle 1 although the median platelet count was lower in the group that received Genasense it was still around 80,000, which is quite an acceptable number.

## Adverse Reactions

**Adverse Reactions**

- Tumor lysis syndrome
- Seen with active anti-leukemia agents
- Infusion-related reactions
- Common to many CLL therapies
- 70-80% incidence with monoclonal antibodies

**Notes:**
As you’ve heard, Genasense-induced tumor lysis was seen in two patients on this trial.  Paradoxically, this is actually not that unattractive a side-effects to a leukemia doctor, where seeing tumor lysis makes us know we have an active agent.  We are well-versed in dealing with its prophylaxis and therapy.
We found that infusion reactions and tumor lysis were dose-limiting in Phase 1.  In Phase 3, which used the MTD we had established of 3 mg per kilogram per day, the incidence was about 1 to 2%.  These reactions are typical for many drugs that are known to be active in CLL, including rituximab and alemtuzumab, where the incidence is significantly higher.   Like tumor lysis, most CLL physicians are familiar with the prophylaxis and treatment of these side effects.

## Genasense Does Not Worsen Neutropenia

**Notes:**
By contrast, a very positive point is that Genasense did not increase neutropenia.  This is important because the major causes of morbidity and mortality in patients with CLL receiving any type of chemotherapy are myelosuppresion and infections.  So, if we can add in an agent that increases CR/nPR rates without increasing neutropenia and the cocomitant risk for infection this is certainly advantageous. 

## Approval Studies in CLL

|  | Fludarabine
(1991) | Alemtuzumab
(2001) | Genasense/FC
(2006) |
| --- | --- | --- | --- |
| Study Type | Non-Rand | Non-Rand | Randomized |
| Efficacy |  |  |  |
| Number of pts. | 79 | 93 | 241 |
| CR/nPR | 13%† | – |   17% |
| CR | – |   2% | 9% |
|  | No CT Confirmation | No CT Confirmation | CT/US Confirmed |
| PR | 19-35%† | 31% |  24% |
| Safety |  |  |  |
| Number of pts. | 133 | 149 | 120 |
| Grade 4 neutropenia | 59% | 37% |   7%* |
| Pneumonia | 16-22% | 15% | 6% |
| Died on study | 22% | 10% | 8% |

**†****Non NCI-WG criteria**
***GCSF use**

- Silver Bullet

**Notes:**
Let’s examine how the Genasense package compares with the prior approval in relapsed/refractory CLL.  As previously noted, fludarabine was approved in 1991, and alemtuzumab in 2001.  There were fewer than 100 patients in these single-arm pivotal trials. The endpoint was overall response, and for both drugs these were primarily short-lived PRs.  The median response duration for alemtuzumab was less than 6 months. 
In the Genasense NDA, in addition to the Phase 1-2 study, the pivotal study was a randomized trial that included 241 patients, 120 of whom were randomized to receive Genasense.  We’ve discussed the stringency of the prospectively defined primary endpoint.  This endpoint was met, and its duration was significantly longer compared to controls.  As seen in the lower half of this slide, the morbidity and mortality on this study were the lowest of the 3 trials.

## Addition of Genasense Converts PRs into Durable CR/nPRs

**0**

**10**

**20**

**30**

**40**

**50**

**FC**

**GFC**

**Sensitization**

**Notes:**
The percentage of patients achieving the primary endpoint in this trial, a CR/nPR response, was significantly greater in those patients receiving Genasense.  Since we are using this agent to enhance chemosensitivity, we see a higher quality response in some patients with the ability to respond to chemotherapy.  Overall response rates are similar which I don’t think is surprising since enhancing chemosensitivity implies some baseline sensitivity to the treatment and completely refractory patients would be unlikely to be affected by such an approach.  The magnitude of benefit in this case was substantial in that the CR/nPR rate was more than doubled with the addition of Genasense.

## GL303 – Relapsed/Refractory CLLCR/nPR Superior to PR for TTP

**Proportion of Subjects Without PD**

**Months from Randomization**

**CR** **vs PR= p <0.0001**

**CR vs nPR= p = 0.21**

**nPR** **vs PR= p = 0.0007**

**GL303 – Relapsed/Refractory CLL****CR/nPR Superior to PR for TTP**

**Notes:**
As predicted, CR/nPR remissions were very durable and similar in quality.  These remission durations were significantly better than those seen in patients only achieving a PR.

## Response Considerations

- How does the pattern of response compare to that seen in other trials in relapsed/refractory CLL?
- How does the magnitude of improvement compare with other trials, and is it clinically important?

**Notes:**
I want to address two issues that were brought in the FDA brief.  
The first is: How does the pattern of response compare to that seen in other trials in relapsed/refractory CLL?
The second: Is the improvement in the primary endpoint of sufficient magnitude to be clinically important?
As we’ve noted, there are no other randomized trials to compare these results.  That said, there is experience in this patient population to evaluate these data.  They derive from the large sequential studies that have been conducted at our center over the past 10 years, including fludarabine, the Flu/Cy regimen that was the control arm in this trial, and most recently the combination of Flu/Cy plus rituximab.  Data from this trial was published earlier this year by Dr. Bill Weirda.  

## Response and TTP in Relapsed CLLFlu/Cy vs. Flu/Cy/Rituximab

**Months**

**Historical comparison of sequential studies****	****Adapted from Weirda et al., Cancer 2006**

|  | FC | FCR |
| --- | --- | --- |
| CR/nPR | 28% | 42% |
| ORR | 67% | 72% |

**Time-to-Progression: Responders Only**

**No CT**

**Response and TTP in Relapsed CLL**Flu/Cy vs. Flu/Cy/Rituximab

**FCR**

**FC**

**Notes:**
Let’s look at the Flu/Cy vs. FCR experience.  As shown in this slide, the addition of rituximab to Flu/Cy increased the CR/nPR rates from 28% to 42%.  Note, however, that our results reflect single-center data and no requirement for CT confirmation.  Nonetheless, when PRs are added into the response mix, there was no difference in overall response.  There was also no difference in time-to-progression, even in this responders-only analysis.
We find an identical pattern of response with Genasense – namely, a substantial increase in CR/nPR, longer response duration, but no difference in ORR or TTP.  I don’t find that surprising since my belief is that until we have regimens that produce CR/nPR in the majority of patients on the trial we will not substantially impact the overall curves.
 Secondly, how does the absolute magnitude of improvement compare and is it clinically important.  Again, we have no randomized trials in the relapsed/refractory setting.

## Recent Randomized Studies in CLL

**Notes:**
However, let’s look at two of the largest and most recent multicenter randomized trials in front-line patients.  Each tested Flu/Cy versus Fludarabine, and one trial employed confirmatory CT scanning for the first time.  We see that the absolute improvement in CR rates is definitely within the range that we find for CR/nPR increase for Genasense, which was the only one tested in the relapsed/refractory setting.
 These randomized trials, and the non-randomized data that have been published for rituximab, have in fact transformed the way we treat CLL patients, so the answer is yes:  The results seen with Genasense are certainly of a quality and magnitude to be clinically important.

## GL303 Relapsed/Refractory CLL CR/nPR Duration of Response During Treatment and Post Treatment

**GL303 Relapsed/Refractory CLL ****CR/nPR Duration of Response During Treatment and Post Treatment**

- 6

- 0

- 18

- 24

**FC**

**GFC**

- 30

- 12

- 36

- 42

**+ **** ****= Ongoing**

**Months**

- Silver Bullet

**Median Duration Post Chemo**
** ****GFC = Not Reached (est. >31 mos)**
** ****FC = 20 mos**

**Notes:**
The bottom line is that in patients who respond to this agent the benefit is quite clear.  You are transforming PRs into a higher quality category of response. Post-chemotherapy durations of response are quite long.  The median duration of remission post-chemotherapy (designated in yellow) in the GFC arm has not been reached but is expected to exceed 31 months.  This compares very favorably with a median of only 20 months in the control arm.
As you can see, the majority of responses in the Genasense arm are ongoing as of last assessment.
There is no question that Genasense increased major responses and response durations.  The standard of care is immunosuppresive and myelosuppresive.  The ability to add an agent that increases major responses and does not increase infectious complications is a genuine advance in the treatment of CLL.

## Confirmatory Study in Previously Untreated CLL

**SPA requested**
**Multicenter, open label study (N=722)**
**Primary Endpoint: PFS**
**Stratification:**
**FISH: 17p****- ****vs. 11q****-**** vs. Other**
**Rai stage**
**LDH**
**Investigative center**

**Notes:**
As required for accelerated approval, we have designed a confirmatory trial which is undergoing final special protocol assessment by the FDA.  As already agreed with the FDA, this study will be performed in previously untreated patients who will be randomized to receive the combination of Flu/Rituxan +/- Genasense infusion and the primary endpoint will be PFS with the stratification as listed on this slide.  The sponsor had planned all best efforts to initiate this trial prior to ODAC, however, clarification regarding the methodology of blinded response assessment is till being reviewed.
More than 110 sites have already been qualified or are in process.  Earliest results are expected to be available in approximately 5 years, and Genta is firmly committed to the completion of this important study.

## GL303 Relapsed/Refractory CLLCriteria Met for Accelerated Approval

| Substantial evidence from well-controlled clinical trial | Study GL303 |
| --- | --- |
| Serious or life-threatening disease | Relapsed /Refractory CLL |
| Surrogate end-point for clinical benefit | Durable CR/nPR predict forTTP, OS and symptom benefit |
| Benefit over available therapy | Superior to Flu/Cy |
| Confirmatorypost-marketing study | SPA near final |

**Notes:**
Today you have heard a presentation of substantial evidence from our randomized, well controlled study, GL303, of Genasense combined with standard chemotherapy in patients with relapsed or refractory chronic lymphocytic leukemia– a life threatening disease with limited therapeutic options.  The Genasense plus Flu/CY regimen was clearly superior to Flu/CY alone as measured by a statistically significant increase in the centrally reviewed and independently confirmed primary endpoint of CR/nPR rate. In this study, the achievement of a CR or nPR was also associated with a significant likelihood of a greater than 2 year time to progression, a greater than 2 year symptom free duration and a greater than 3 year overall survival.  
Lastly, the sponsor has designed a large confirmatory trial which is very near final in the SPA process and which will verify the clinical benefit of the current study. 

## Reduction in Tumor Volume May Serve as a Surrogate for Clinical Benefit1,2

- FDA Guidance on Surrogacy of Reduction in Tumor Volume3
- The association of reduction in tumor volume is stronger in the setting of
- Undetectable tumor volume
- 17 vs. 7% CR/nPR (p=0.025)
- Reduction is durable
- GFC median duration of response estimated to exceed 36 months (not yet reached) vs. 22 months
- Reduction extends beyond the period of toxic agent administration
- GFC median duration of response estimated to exceed 31 months (not yet reached) vs. 20 months

- Silver Bullet

**1****	****Guidance for Industry: Providing Clinical Evidence for Effectiveness for Human Drug and Biological Product (Oncology Supplement) May 1998**
**2****	****Reinventing the Regulation of Cancer Drugs - March 1996**
**3****	****BLA Reference number 99-0786 (Alemtuzumab)**

**Notes:**
The FDA reiterated additional guidance on the acceptability of response as a surrogate endpoint at the Alemtuzumab ODAC meeting.  
The association between response and clinical benefit is deemed to be stronger when first, the tumor volume is undetectable.  In our study in which the primary endpoint of CR/nPR is associated with undetectable disease, the addition of Genasense significantly improved major responses.  
Second, when the reduction in tumor volume is durable.  In this study the addition of Genasense was associated with a marked improvement in the durability of major responses.  
And, lastly, when the reduction extends beyond the period of chemotherapy administration.  In this study the addition of Genasense was associated with remarkable improvement in the duration of response after the completion of chemotherapy for major responses.  
We believe that our data have met all the criteria set forth by FDA for accelerated approval and hope that you will be in agreement.

## Slide 67

**Notes:**
In closing, I would like to thank the patients, their families, physicians, nurses and research professionals who made this study possible. Thank you very much for your attention. I will be happy to address any questions the committee may have at this time.