# Presentation: 784165

## NDA 21-874 Genasense (G3139, oblimersen)           for the treatment of relapsed/refractory Chronic Lymphocytic Leukemia in combination with fludarabine and cyclophosphamide

- ODAC  September 6, 2006
- Robert Kane, MD

## FDA Review Team for Genasense NDA

- Project management
- Nicholette Hemingway, MPH
- Medical Review
- Robert Kane, MD,    Medical Officer
- Ramzi Dagher, MD      Team Leader
- Ann Farrell, MD, Acting Deputy Director

- Statistical Review
- Shenghui Tang, PhD  Stat Reviewer
- Rajeshwari Sridhara, PhD, Stat Team Leader
- CMC Review
- Xiao-Hong Chen, PhD
- Ravi Harapanhalli PhD
- Team Leader

## Presentation Outline 

- Statutory Requirements for marketing approval
- NCI-working group response criteria for CLL
- Approved drugs for CLL
- Activity of the control arm of study GL303
- FDA analysis of Genta NDA 21-874 (GL 303)
- Trial Design
- Primary Endpoint
- Secondary Endpoints
- Efficacy Results – What does Genasense add to the chemotherapy all patients are receiving?
- Toxicities related to Genasense
- 6.  Conclusions

## Requirements for Marketing Approval

- Substantial evidence, from
- “Adequate & well-controlled investigation_s_”
- Demonstrating efficacy with acceptable safety
- Ability to generate product labeling
- to define an appropriate patient population and  treatment dose
- These requirements apply equally for    accelerated approval or regular (full) approval

## Requirements for Marketing Approval

- FDAMA _amendments _1997 - _one_ adequate and well-controlled clinical investigation and confirmatory evidence may suffice
- FDA Guidance on Effectiveness 1998 –
-    If a single trial, must be well-conducted, internally consistent, and demonstrates a compelling result – statistically strong evidence of an important clinical benefit

## FDA Guidance: Single-study characteristics to support effectiveness

- a. _Large_, _multicenter_ study
- b. _Consistent efficacy_ across key study subsets
- 	    - i.e. severity of disease, stage, patient ages
- c. _Multiple_ studies, pairwise _comparisons_ within the  study _are consistent_
- d. _Multiple endpoints_ involving different events
- e. Statistically _very persuasive_ – “low” p-value
- f. _Results so compelling_ that an additional confirming study would be practically or ethically impossible

## CLL: NCI-WG Response categories 

- CR – complete remission of disease, normal  blood counts and marrow,  all lasting at least 2 months
- PR – 50% reduction in blood lymphocyte count AND lymphadenopathy and some improvement in blood counts lasting ≥ 2 months
- nPR – nodular PR - all elements of CR present except persisting lymphoid aggregates in marrow
- NCI-WG response categories were developed by a consensus panel in 1988 and revised in 1996
-                                                                           NCI-WG CLL, BLOOD 1996

## CLL: NCI-WG Response categories

- nPR: Clinical significance of nPR status uncertain
- Persisting marrow lymphocyte aggregates may represent residual disease or reactive normal cells or both
- Likely an intermediate outcome between CR and PR
- Achieving a PR is also a meaningful result
- What are the clinical outcomes of achieving
-    one of these response categories ?

## CLL: Time to progression by response category  with Fludarabine therapy

- CR
- nPR
- PR

- nPR and PR appear similar                                                             Keating, BLOOD, 1998

## CLL: Time-to-treatment-failure by response category after FCR therapy

-         CR
-         nPR
- PR

-                                         Keating, MJ
-       American Society of Hematology;   Annual Education Book 2003

- NR

## FDA Approvals for CLL Therapy

-    Recent CLL drug approvals are based on:
- 	- NCI-Working Group criteria using
- 	- Overall Response Rate: ORR
- 	- ORR consists of CR + nPR + PR
- 	- CR plus nPR plus PR should be combined
-      in assessing treatment effect in CLL

## FDA approved drugs for CLL

- Alkylating agents
- Chlorambucil - 1956
- Cyclophosphamide - 1959
- Fludarabine (Fludara) - 1991
- Alemtuzumab (Campath) - 2001

## FDA approved drugs for CLL

- Fludarabine – 1991
- Two studies; single-agent, single-arm design
- Given after alkylating agent therapy
- Response criteria were _all_ responders: CR plus PR

|  | N | CR | PR | ORR | Response duration (median) | Survival 
for all pts  (median)  |
| --- | --- | --- | --- | --- | --- | --- |
|  MD Anderson | 48 | 13% | 35% | 48% | 1.75 years | 43 weeks  |
|  SWOG | 31 | 13% | 19% | 32% | 1.25 years | 52 weeks |
| Mean Hemoglobin and Platelet counts increased also. |  |  |  |  |  |  |

## FDA approved drugs for CLL

- Alemtuzumab (Campath) – 2001
- Three studies; single-agent, single-arm design
- after alkylating agents and Fludarabine (a 3rd line Rx)
- Response criteria were _all_ responders:  CR plus PR

|  | N | Prior therapy

 AA          Flu |  | CR | PR | ORR | Response 
Duration 
median |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Study 1 | 93 | 100% | 100%
** | 2% | 31% | 33% | 7 mo |
| Study 2   | 32 | 100% | 34% | 0% | 21% | 21% | 7  mo |
| Study 3 | 24 | 92% | 100% | 0% | 29% | 29% | 11 mo |
|   AA, Alkylating agent;  Flu, fludarabine;  
  **All were Flu refractory in study 1 |  |  |  |  |  |  |  |

## Combination drug therapy for CLL: Flu/Cy

- Fludarabine (Flu) + Cyclophosphamide (Cy)

| 
Prior Therapy: | 
N | 
CR (%)  | Nodular nPR   (%)  | 
PR 
(%)  | Overall 
Response  (%) 
CR+nPR+PR |
| --- | --- | --- | --- | --- | --- |
|   None | 34 | 35 | 29 | 24 | 88 |
|  Alkylating agents | 20 | 15 | 25 | 45 | 85 |
|  Alkylating agent  plus  fludarabine  (Sens) | 46 | 12 | 17 | 51 | 80 |
|  Alkylating agent  plus fludarabine  (Res) | 28  | 3  | 13  | 26  | 39  |
| Sens: sensitive to last therapy = responded then later relapsed
 Res: refractory to last therapy = failed to respond or progressed on last therapy and majority also were judged refractory to alkylating agents    (O’Brien et al) |  |  |  |  |  |

## NDA 21-874

- One phase 3 clinical study: Genta study GL303
- Two arm, randomized, unblinded, multicenter add-on design study of Genasense with Flu/Cy
- Population: Patients with relapsed or refractory CLL who require therapy and who have previously received fludarabine
- Sample size calculation (N = 200)
-  chosen to demonstrate a 44% response rate
-  and an absolute increment of 20% in response
-  over the control arm response rate of 24%

## Genta Protocol GL303

- Central Randomization using random permutated block; stratification by 3 factors:
- Responsive _versus_ refractory to prior fludarabine (responsive was defined as prior fludarabine response and ≥ 6 months before the patient required additional CLL therapy)
- 1 to 2 prior treatment regimens _versus_ 3 or more prior regimens
- Response to last prior therapy > 6 months in duration _versus_ ≤ 6 months in duration

## GL303

- Primary endpoint chosen by Genta:              response rate, defined as the CR + nPR responders
- Primary statistical analysis: continuity-corrected Pearson Chi-Square test of response rate         using the intention-to-treat population
- Response assessment performed by a blinded clinical expert, the study principal investigator

## GL303 Secondary Efficacy Endpoints as stated in GL303 protocol and Clinical Study Report

- Overall response rate: ORR                              All responders (CR + nPR + PR)
- Time To Disease Progression (TTP)
- Overall Survival
- Duration of Response
- ‘Clinical Benefit’ elements -

## Pre-specified ‘Clinical Benefit’ elements: GL303 protocol version 7

- 1.  Resolution of:
- B-symptoms (night sweats, fever)
- impaired mobility due to lymphadenopathy
- impaired cosmesis
- abdominal discomfort due to hepatosplenomegaly
- early satiety
- 2.  Resolution or reduction in massive splenomegaly
- 3.  Relative improvement in ECOG performance status
- 4.  Improvement in disease-related anemia
- 5.  Improvement in fatigue score

## GL303 study

- No composite symptom endpoint or ‘symptom-free interval’ endpoint was pre-specified
- 6 protocol revisions
- one additional final statistical analysis plan submitted in August 2004

## GL303 – therapy plan

- Genasense (G) plus Flu/Cy arm
- G: 3 mg/kg/day days 1-7;  continuous IV infusion requiring indwelling IV access catheter and infusion pump
- ALL patients, on both arms,                            received same chemotherapy (Flu/Cy)
- Fludarabine 25 mg/m2/day plus
- Cyclophosphamide 250 mg/m2/day
- Each given daily times 3 days
- Every 28 day cycles, total of 6 planned, for both groups

## GL303 – therapy plan

- All patients also required:
-  G-CSF for at least 7 days per cycle
- sulfamethoxazole-trimethoprim 1 tab bid 3 days every week during and for 6 months after therapy
- acyclovir 400 mg tid PO daily (or equivalent) during and for 6 months after therapy
- erythropoietin 40,000 IU/week subcutaneously was advised for all symptomatic patients with hemoglobin values of < 10 g/dL
- Antiemetics prior to treatment with Flu/Cy
- Central venous access catheter for Genasense

## GL303 Timeline

- First patient enrolled:                         August 2001
- Last patient enrolled:                             June 2003
- Last patient completed therapy:   December 2003
- Data cutoff for analysis:               September 2004
- Survival data cutoff:		 	          June 2006       (all patients followed for ≥ 3 years)
- 100 study sites / 241 patients randomized
- NDA submitted:			 December 2005

## GL303: Results

- Two study arms appear well-balanced for baseline disease and patient characteristics
- - At baseline, ~ 60% were judged to be Fludarabine refractory in each study arm
- Average time from diagnosis of CLL to study enrollment was approximately 6 yrs
- Chemotherapy drug exposure was similar on  both study arms
- Median number of cycles was 4 for each group
- Patients completing all 6 cycles:
- 37% on Flu/Cy
- 30% on Genasense plus Flu/Cy

##  Response rate for the Genta primary endpoint:   CR + nPR patients

| GL303 
N= 241 | G  plus
Flu/Cy (120)
n | 
Flu/Cy (121)
n | 
P value |
| --- | --- | --- | --- |
|            CR      | 11   | 3 |  |
|          nPR        | 9 | 5 |  |
|  CR + nPR

      [95% CI] |  20

16.7%

[10.5%, 24.6%] | 8 

   6.6%

[2.9%, 12.6%] | 0.025 a |

- a: Pearson chi square test, continuity corrected

##  Response Rate: ORR: All responding patients (CR + nPR + PR) protocol secondary endpoint 

|     GL303 
   N= 241 |    G  plus
Flu/Cy (120)  | 
 Flu/Cy  (121)  |  |
| --- | --- | --- | --- |
|                        CR + nPR         n
                                                %
 |  20  
 (16.7%) |  8   
  (6.6%)
 |  |
|  |  |  |  |
|                                   PR          n |  29 |  46 |  |
| ORR:  CR + nPR + PR      n
                                            % |  49

  41% |  54   

   45% |  |

##  Response duration for all responders (CR + nPR + PR)  secondary endpoint

-     FDA analysis: there is no difference in duration              of response between the two study arms in GL303

## Time to progression- TTP (All patients)

-      **No difference was demonstrated between the two treatment arms (logrank p = 0.83; hazard ratio = 1.03).  **
**    ****In each arm, 27% were censored (mature analysis)**

**Median TTP:**
**       ****Flu/Cy   9 mo**
**G + Flu/Cy  6 mo**

## GL303: Overall survival (OS)

**   ****The Final OS analysis was performed in June 2006 as pre-specified, after all patients were followed at least 3 years from enrollment. No difference was demonstrated (HR = 0.99) **

- GL303: Overall survival

## Pre-specified ‘Clinical Benefit’ elements: GL303 protocol version 7

- 1.  Resolution of:
- B-symptoms (night sweats, fever)
- impaired mobility due to lymphadenopathy
- impaired cosmesis
- abdominal discomfort due to hepatosplenomegaly
- early satiety
- 2.  Resolution or reduction in massive splenomegaly
- 3.  Relative improvement in ECOG performance status
- 4.  Improvement in disease-related anemia
- 5.  Improvement in fatigue score

## GL303 Results

- The FDA analyzed each of Genta's secondary ‘clinical benefit’ elements separately, as pre-specified in the protocol
- FDA agrees with Genta's stated conclusions in the ODAC briefing document:  “Analyses of clinical benefit endpoints show no statistically significant difference in findings between treatment groups."
- More patients receiving Genasense required                red cell transfusions (36% versus 29%)
- More patients receiving Genasense required       platelet transfusions (18% versus 5%)
- These individual “clinical benefit” elements were the components for the calculation of the composite endpoint  “symptom-free time.” This endpoint was not pre-specified and was calculated by adding discontinuous times

## GL303 Results

- Additional exploratory analyses by FDA noted      no improvement in response with addition of Genasense:
- For patients ≥ age 65
- For women
- For patients judged by Genta as Fludarabine refractory, for either the (CR + nPR) subgroup or  for all responders (CR+nPR+PR)
- For any of the other stratification factors

**Notes:**
See backup slides

## GL303: Adverse Events (AEs)

| (NCI CTC version 2) 

Patients with at least one  | G plus Flu/Cy
N = 115
n    (%) | 
Flu/Cy
N = 115
n    (%) |
| --- | --- | --- |
| Adverse Event (AE) | 115 (100) | 112 (97) |
| AE leading to drug
discontinuation overall |  40  (34.8) |  40  (34.8) |
| AE ≥ Grade 3 (severe) |  91   (79) |  75   (65) |
| Serious AEs * |  66   (57) |  37   (32) |
| serious AE considered related to study treatment  |  46   (40) |  24   (21) |
| AE leading to death |    9   (7.8) |    5   (4.3) |

- *Serious AEs: Death, Immediately life-threatening AE,
- hospitalization, disability

## GL303 Results: Safety Population (AEs)

|  | All grades |  | Grade 3-4 |  |
| --- | --- | --- | --- | --- |
| Preferred term | G-FC
(N=115)
% | FC
(N=115)
% | G-FC
(N=115)
% | FC
(N=115)
% |
| At least 1 TEAE  | 100  | 97  | 50  | 44  |
| Nausea  | 72  | 48  | 8  | 2  |
| Fever  | 48  | 29  | 3.5  | 2.6 |
| Fatigue  | 44  | 31  | 6  | 4  |
| Vomiting  | 30  | 23.5  | 5  | 1  |
| Headache  | 23.5  | 14  | 1  | 3  |
| Dyspnea  | 21  | 16.5  | 4  | 2  |
| Dehydration  | 17  | 2  | 1  | 1  |

## GL303 Results: Hematologic toxicity

| Anemia  | 39  | 42  | 11  | 10  |
| --- | --- | --- | --- | --- |
| Neutropenia  | 24  | 33  | 12  | 13  |
| Thrombocytopenia  | 49  | 40  | 33 | 20  |
| Bleeding | 19 | 8 | 3.5 | 1.7 |

|  | All grades |  | Grades  3-4 |  |
| --- | --- | --- | --- | --- |
|  | G-FC
(N=115)
% | FC
(N=115)
% | G-FC
(N=115)
% | FC
(N=115)
% |

- Grade 3 thrombocytopenia  < 50,000
- Grade 3 bleeding usually indicates need for RBC transfusion

**Notes:**
CSR pages 161-162

## Genasense administration issues

- The 7 day IV Infusion every 28 days requires
- Indwelling Intravenous access catheter
- Infusion pump
- Maintenance of the infusion: home health or clinic
- Catheter-related complications

**Notes:**
CSR 12.6.3; page 163

## Genasense Catheter-related complications

-    *Also includes pain, redness, swelling, bruising, oozing, infiltration at the catheter site

| GL303 | Genasense +
Flu/Cy (115)
  n        % | 
Flu/Cy (115)
 n      % |
| --- | --- | --- |
| Total Catheter-related infusion complications* |  18     16%  |  3     2.6% |
|   - Catheter Infections |  11 |  1 |
|   - Venous thrombosis |  2 |  0 |

**Notes:**
CSR 12.6.3; page 163

## Conclusions

- Genasense
- in combination with fludarabine and cyclophosphamide
- for the treatment of relapsed/refractory Chronic Lymphocytic Leukemia

## Guidance: Single-study characteristics to support effectiveness

- a. _Large_, _multicenter_ study
- b. _Consistent efficacy_ across key study subsets
- 	    - i.e. severity of disease, stage, age
- c. _Multiple_ studies, pairwise _comparisons_ within the  study
- d. _Multiple endpoints_ involving different events
- e. Statistically _very persuasive_ – low p-value
- f. _Results so compelling_ that a second confirming study would be practically or ethically impossible

## GL303 

- In single-arm, single-agent studies in advanced and previously treated diseases, response rates provide preliminary evidence of drug activity and may be of regulatory interest if persuasive in magnitude and duration
- In parallel group phase 3 trials, meaningful treatment effects are better assessed by comparisons of TTP, PFS, and OS, reflecting treatment effects on the entire study population

## GL303

- Genasense is described as a targeted therapy designed to inhibit the Bcl-2 pathway. However, in this study of CLL patients, no evidence is provided that Genasense inhibits Bcl-2 in these CLL patients or that altering Bcl-2 is beneficial for any group of CLL patients

## GL303 – Conclusions  (1)

- Study GL303 is a two-arm, phase 3 unblinded add-on design trial to demonstrate the effect of adding Genasense to chemotherapy (Flu/Cy)
- Study GL303 is complete and provides mature data on response, time to progression, and overall survival.

## GL303 – Conclusions  (2)

- Response:
- The CR+nPR response rate was increased by 10%, to 17%, with the addition of Genasense
-  The overall response rate was lower            with the addition of Genasense, 41%,  compared with 45% for the control arm Flu/Cy
- Duration of response:
- For _all_ responders, there is no improvement in duration with the addition of Genasense

## GL303 – Conclusions  (3)

-   The addition of Genasense to the Flu/Cy regimen provided:
-    - no improvement in time to progression
-    - no improvement in overall survival

## GL303 – conclusions  (4)

- All other pre-specified analyses, as performed by Genta and confirmed by FDA, show no improvements with the addition of Genasense for any of the secondary clinical benefit endpoints:
- Resolution of B symptoms
- Resolution or reduction of massive splenomegaly
- Improvement in ECOG performance status
- Disease-related anemia or red cell transfusions
- Changes in fatigue

## GL303 – conclusions  (5)

- The symptom-free time analysis, a composite of the individual ‘clinical benefit’ elements, was not pre-specified, is composed of discontinuous time intervals, and should be considered exploratory
- Although not pre-specified, an analysis of ‘symptom-free time’ for _all_ responders                     (CR plus nPR plus PR) shows no difference between the two study arms

##   GL303 – Conclusions  (6)

-    Toxicity is increased by the addition of Genasense to the control drug regimen, and Genasense administration requires a continuous intravenous infusion with    central venous catheter and maintenance of an external infusion pump for 7 days monthly

## Slide 49

## Question for the committee

-      Given these safety and efficacy results, does this single, open-label study fulfill the requirements that a single study should meet to demonstrate substantial evidence of effectiveness?

## Backup slides

## Genta table of Symptom-free duration for patients with symptoms at baseline 

- If baseline SX present, NO DIFF in SX free duration

- days

## Subset Analyses

- Exploratory; limited by small numbers
- Gender
- Age
- Baseline Fludarabine resistance (Genta specified)
- Baseline LDH                                       “
- Baseline platelet count                         “
- Baseline hemoglobin                            “

## Analysis of primary endpoint response group (CR plus nPR) by Gender

| 
Gender | G3139 
plus Flu/Cy
N = 120 |  | 
Flu/Cy
N = 121 |  | 
  odds ratio |
| --- | --- | --- | --- | --- | --- |
|  | N | n   
(%) | N |   n   
(%) |  |
| Male | 89 | 18  
(20.2) | 89 |   6  
(6.7) | 3.5 |
| Female | 31 |  2  
(6.5) | 32 |  2  
(6.3) | 1.03 |

- Table 14.2.4.2.1; ISE

## Analysis of primary endpoint response group (CR plus nPR) by Age  

| 
Age group | G3139
 plus Flu/Cy      N = 120 |  | 
Flu/Cy
N = 121 |  |
| --- | --- | --- | --- | --- |
|  | N |  n   
(%) | N | n   
(%) |
| < 65 years | 67 | 12 
 (18%) | 69 | 2  
 (3%) |
| ≥ 65 years | 53 |  8  
(15%) | 52 | 6  
(12%) |

- Table 14.2.4.1.1; CSR

## Analysis of primary endpoint response (CR+nPR)    by baseline fludarabine sensitivity or resistance

- Table 14.2.4.11.1, ISE

| Baseline 
Flu sensitive | G3139 plus Flu/Cy
N = 120 |  | Flu/Cy
N = 121 |  |
| --- | --- | --- | --- | --- |
|  | N | n      
(%) | N | n    
(%) |
|         YES | 51 | 13  
(25.5) | 50 | 3    
(6.0) |
|          NO | 69 | 7     
(10.1) | 71 | 5    
(7.0) |

## Analysis of response for all responders (CR+nPR+PR) by baseline fludarabine sensitivity or resistance

**     ****If baseline Flu refractory:  numerically better response without addition of Genasense             **Table 14.2.4.11.2, ISE

| 
Baseline 
Flu sensitive | G3139 plus Flu/Cy
N = 120 |  | Flu/Cy
N = 121 |  |
| --- | --- | --- | --- | --- |
|  | N | n     
(%) | N | n    
(%) |
|         YES | 51 | 29  
(56.9) | 50 | 27  
(54.0) |
|          NO | 69 | 20  
(29.0) | 71 | 27  
(38.0) |

## Analysis of response (CR plus nPR) by baseline LDH level 

- Table 14.2.4.12.1, ISE

| Baseline 
LDH level | G3139 plus Flu/Cy
N = 120 |  | Flu/Cy
N = 121 |  |
| --- | --- | --- | --- | --- |
|  | N | n     
(%) | N | n     
(%) |
| Non-elevated | 63 | 16  
(25.4) | 63 | 5  
 (7.9) |
| Elevated | 53 | 4    
(7.5) | 52 | 3  
 (5.8) |

## Analysis of response (CR plus nPR) by baseline platelet count 

- Table 14.2.4.9.1, ISE

| Baseline 
platelet count | G3139 plus Flu/Cy
N = 120 |  | 
Flu/Cy
N = 121 |  |
| --- | --- | --- | --- | --- |
|  | N | n  
 (%) | N | n   
(%) |
|   ≥ 100,000/uL | 77 | 18  
(23.4) | 78 |  8   
(10.3) |
|  < 100,000/uL | 43 | 2   
 (4.7) | 43 | 0 |

## Analysis of response (CR plus nPR) by baseline hemoglobin 

- Table 14.2.4.8.2; ISE

| Baseline hemoglobin | G3139 plus Flu/Cy
N = 120 |  | 
Flu/Cy
N = 121 |  |
| --- | --- | --- | --- | --- |
|  | N | n  
(%) | N | n  
(%) |
|   ≥ 11 g/dL | 87 | 18  
(20.7) | 82 | 7  
(8.5) |
|   < 11 g/dL | 32 | 2   
(6.3) | 39 | 1  
(2.6) |

## CR/nPR by prior systemic therapy and treatment group

- Genta table 25; CSR page 116           b: P value from Fisher exact test

## Protocol No. GL303 Confidential – Genta Inc.               (Page 47 of 68)

- Version 7; April 16, 2004
- 13.1.2 Secondary efficacy variables include:
- • Overall response rate (CR + n-PR + PR)
- • Survival
- • Duration of Response
- • Time to Disease Progression (TTP)
- • Clinical Benefit defined as:
- ° Resolution of B-symptoms (impaired mobility due to lymphadenopathy,
-    impaired cosmesis, abdominal discomfort due to hepatosplenomegaly,
-    early satiety, night sweats, fever)
- ° Resolution or reduction in massive splenomegaly
- ° Relative improvement in performance status
- ° Improvement in disease-related anemia
- ° Improvement in fatigue as measured by the Brief Fatigue Inventory (BFI)

## Slide 63

## Genasense – Additional Efficacy studies

- In a randomized study in multiple myeloma, Genasense failed to improve the overall response rate or time to progression using an add-on design of Genasense plus Dex versus Dex alone.
- In relapsed AML, a phase 2 study of Genasense plus Gemtuzumab (GO) showed a 25% CR rate. GO alone was approved on a 30% CR rate.
- In a large, randomized study in melanoma, Genasense failed to show a survival or PFS benefit using an add-on design of Genasense plus DTIC versus DTIC alone.
- 1:  ASH 2004; abstract #1477 GMY302
- 2:  Leukemia Research 2006; 30:777-783.
- 3:  ODAC proceedings, 2004

## GM301: Melanoma study

-    A randomized, open-label, phase 3 trial of Genasense plus DTIC versus DTIC alone as initial systemic chemotherapy for advanced melanoma.
-    Presented to ODAC in May 2004

## GM301: Melanoma study   Hematologic Toxicity 

| G (Genasense, G3139)
 | G + DTIC
 (N = 371)
n 
(%) | DTIC 
(N = 360)
n 
(%) |
| --- | --- | --- |
| Grade 3 - 4  
Neutropenia | 79 
(21%) | 45 
(12%) |
| Grade 3 - 4 Thrombocytopenia | 58 
(16%) | 23 
(6%) |

**GM301: Melanoma study****   Hematologic Toxicity**

## GM301: Melanoma studyNon-hematologic Toxicity 

|       AE | G + DTIC | DTIC |
| --- | --- | --- |
|  | n   (%) | n   (%) |
|      Nausea | 231 (62%) | 169 (47%) |
|      Pyrexia | 197 (53%) |   63 (18%) |
|      Fatigue | 170 (46%) | 142 (39%) |
|      Vomiting | 139 (38%) |  75 (21%) |
| Infections  |    123 (33%) |    65 (18%) |
| Anorexia |    114 (31%) |    56 (16%) |
| Headache  |      97 (26%) |    47 (13%) |

## GM301: Melanoma studyNon-hematologic Toxicity 

|         AE | G + DTIC | DTIC |
| --- | --- | --- |
|  | n  (%) | n  (%) |
|      Rigors |     76 (21%) |    16 (4%) |
|      Influenza-like Illness |   19 (5%) |       3 (0.8%) |
|  Injection site infection |   24 (7%) |    4 (1%) |
|   Injection-site Reactions |   21 (6%) |    5 (1%) |
|           Upper extremity  
              thrombosis* |   18 (5%) |       3 (0.8%) |
| *Axillary vein, Subclavian vein, Jugular vein, injection site thrombosis and superior vena caval syndrome  |  |  |

**GM301: Melanoma study****Non-hematologic Toxicity**

## FDA Approved drugs for CLL

- Chlorambucil 1956
- Leukemia and lymphoma
- In CLL, a decrease in lymphocyte counts
- In some patients, return to normal blood counts, reduction of lymph nodes and spleen noted

## FDA Approved drugs for CLL

- Cyclophosphamide – 1959
- Note, this was before the efficacy requirements  of 1962 amndts to the Act
- In CLL, a marked decrease in lymphocyte counts occurred
- ‘Fair to good results’ in RCS and LSA
- ‘Excellent results’ were observed in giant follicular lymphoma
- 1966 label – reduction in tumor size should be assessed

## FDA Approved drugs for CLL

- Alkylating agents: chlorambucil, cyclophosphamide
- Fludarabine:
- “the treatment of patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen.”
- Alemtuzumab (Campath)
- "for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. (Determination of the effectiveness of Campath is based on overall response rates.)

## Some other drugs used for CLL but lacking FDA approval for this use

- Rituximab
- Pentostatin
- Cladribine
- Doxorubicin
- Mitoxantrone
- Vincristine

## Genta analysis of TTP

## CLL: Criteria indicating need for therapy

** **A** **minimum of one of the following disease-related symptoms present:
- (a) Weight loss >10% within the previous 6 months.
- (b) Extreme fatigue (ie, ECOG PS 2 or worse; cannot work or unable to perform usual activities).
- (c) Fevers of greater than 100.5”F for > 2 weeks without infection.
- (d) Night sweats without evidence of infection.
- (2) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and / or thrombocytopenia
- (3) Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid
- (4) Massive (ie, >6 cm below the left costal margin) or progressive splenomegaly
- (5)* *Massive nodes or clusters (ie, > 10 cm in longest diameter) or progressive lymphadenopathy
- (6) Progressive lymphocytosis with an increase of *>50% *over a 2-month period, or an anticipated doubling time of less than 6 months
-                                                                   NCI-WG, BLOOD 1996