# Presentation: 784517

## ARRANON® (nelarabine) InjectionNDA 21-877 

- Presentation to Oncologic Drugs Advisory Committee
- September 14, 2005

## Presentation Overview

**Introduction ****	****Peter Ho, M.D., Ph.D.**
**	****	****VP, Discovery Medicine Oncology, GSK**
**Disease Overview****	****Stephen Sallan, M.D.**
**	****	****Professor of Pediatrics, Harvard**
**	****	****Chief of Staff, Dana-Farber**
**Efficacy Summary****	****Richard Larson, M.D.**
**	****	****Professor of Medicine, Univ. of Chicago**
**	****	****Chair, Leukemia Committee, CALGB**
**Safety Summary****	****Mark Russo, M.D., Ph.D.**
**	****	****Group Director, Clinical Oncology, GSK**
**Role in Treatment   ****	****William Carroll, M.D.**
**	****	****Director, Pediatric Oncology, NYU**
**	****	****Chair, ALL Committee, COG**
**Conclusion****	****Peter Ho, M.D., Ph.D. **

## Additional Participants 

**Susan Blaney, M.D. ****	****Texas Children’s Cancer Center**
**Dan DeAngelo, M.D., Ph.D.****	****Dana-Farber Cancer Institute **
**Joanne Kurtzberg, M.D. ****	****Duke University **
**Varsha Gandhi, Ph.D. ****	****M.D. Anderson Cancer Center**
**Arthur Forman, M.D. ****	****M.D. Anderson Cancer Center**

## Additional GSK Participants 

**Christopher Abissi **
**Ohad Amit **
**Andrew Beelen**
**Janet Begun **
**Michelle Casey **
**Ellen Cutler**
**Roxanne Jewell **

**Nelson Johnson **
**Tom Lampkin**
**Paolo Paoletti **
**Maria Richie**
**Debasish Roychowdhury **
**Robert Watson **

## Proposed Indication

**A****RRANON**® (nelarabine) Injection is indicated for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens

## ARRANON® (nelarabine)

- Purine nucleoside phosphorylase (PNP) deficiency
- T-cell lymphopenia
- Abnormal guanine nucleoside metabolism
- Ara-G mimics PNP deficiency state
- T-cells targeted for selective destruction
**ARRANON** is a soluble pro-drug of Ara-G
- First clinical trial in 1993
- NCI collaborative development
- CALGB & COG pivotal studies
- Cooperative group data for submission

## ARRANON® (nelarabine)

**A****RRANON** demonstrates
- Pharmacological selectivity for T-cells
- Clinical efficacy
- in children and adults
- in relapsed and refractory disease
- Well characterized safety profile
- Favorable benefit-risk profile in heavilypre-treated patients
- Meets a significant unmet medical need
- No proven effective alternative therapy available for T-ALL and T-LBL

## Disease Overview

**Stephen Sallan, M.D.**Professor of Pediatrics, HarvardChief of Staff, Dana-Farber

## Overview of Patients with T-ALL / T-LBL

- Rare diseases (N~1600/yr)
- T-cell ALL & LBL differ only by % lymphoblasts in bone marrow
- Most in older children & young adults
- Much biology age-independent
- 	- e.g., Notch 1 mutations in ~ 50%
- 	- e.g., Gene expression signatures

## Current Treatment

- Multi-agent chemotherapy at time of diagnosis and at 1st relapse
- Treatment with curative intent
- At diagnosis – chemotherapy
- 1st relapse – chemotherapy to induce a 2nd complete remission; then curative stem cell transplant

## Pediatric Patients with ALL at Diagnosisby Immunophenotype

**Pediatric Patients with ALL at Diagnosis****by Immunophenotype**

**	**** ****	****	**_**T-cell**_**	**_**B-cell**_**	**_**P-value**_
**Induction Failure****	****  12%****	****  2%****	****<0.0001**
**Induction Death****	****   ****	****  3.2%****	****  0.7%****	****  0.02**
**Leukemia Relapse****	****  11%****	****  18%****	****  0.06**

- Goldberg et al. JCO. 2003.

- Figure 1              T-ALL  n=125              B-ALL  n=1130

## Patients with T-ALL / T-LBL at 1st Relapse

- ~500 patients per year
- Treatment is with curative intent: multi-agent chemotherapy followed by a SCT
- Outcome for T-cell ALL patients transplanted in 2**nd** remission is approximately 40% at two years for children and adults.
- Treatment related mortality can be 5-10%.

## Outcome After Second Relapse (Patients with T-ALL, N=13)

- Sather, et al. COG (unpublished)

## Current Drugs in Multi-Agent Regimens

- Vincristine
- Prednisone
- Dexamethasone
- Asparaginase
- Daunorubicin
- Doxorubicin

- 6-MP
- 6-TG
- Methotrexate
- Cyclophosphamide
- Etoposide
- Cytarabine

- New drugs are needed for patients with relapsed and refractory disease.

## Efficacy Overview

**Richard Larson, M.D.**Professor of Medicine, Univ. of ChicagoChair, Leukemia Committee, CALGB

## Pivotal Studies

**Adult: CALGB19801**
**A Phase II Study of Nelarabine (506U78) in Subjects with Refractory or Relapsed T-Lineage Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL)**** **
**	****	****DeAngelo et al.  Blood. 2002; ****100(11):198a (Abstract 743).**
**Pediatric: COG P9673**
**A Phase II Study of 506U78 in Patients with Refractory T-Cell Malignancies**
**	****	****Berg et al.  JCO. 2005; 23(15):3376-82.**

## Efficacy Endpoint Definitions

## Rationale for CR* Endpoint

- Similar to CRi and CRp for patients with AML
- Heavily pretreated patients
- may never have full hematologic recovery
- benefit from the absence of disease
- Retreatment & Stem Cell Transplant
- may occur prior to full hematologic recovery

- CR* was agreed with FDA June 1997

## Patients with T-ALL/T-LBL

- Prior Therapy
- One prior induction/regimen
- Primary refractory disease
- Relapsed disease
- Two or more prior inductions/regimens
- Refractory disease
- Relapsed disease
- Refractory
- Primary refractory disease
- Less than CR following most recent induction attempt

## Adult: CALGB 19801

- Open-label, multicenter Phase II study
- Median age: 34 years (range: 16-66 years)
- Refractory or relapsed T-ALL or T-LBL
- Dose*: 1500 mg/m2 days 1, 3, 5, every 21 days
- Two cycles for induction plus two for consolidation
- 39 patients treated:
- 11 patients with 1 prior multi-agent induction/regimen
- 28 patients with ≥ 2 prior multi-agent inductions/regimens
- Enrolled over 37 months
- * Recommended Dose

## Adult: CALGB 19801 Response Rate & Duration≥ 2 Prior Inductions (N=28) 

| Response | CR | CR plus CR* |
| --- | --- | --- |
| Response Rate | 18% | 21% |
| Median Duration of Response (weeks) | 
29 | 
24 |
| Duration of Response (weeks) | 15 to 195+ | 4 to 195+  |

- CR = complete response with full hematologic recoveryCR* = complete response without full hematologic recovery CR plus CR* = total of patients achieving best response in either category

## Adult: CALGB 19801  CR+CR* Rates

- Brackets represent 95% confidence intervals for (CR+CR*)

## Adult: CALGB 19801  CR+CR* Rates

- Brackets represent 95% confidence intervals for (CR+CR*)

## Adult: CALGB 19801  CR+CR* Rates

- Brackets represent 95% confidence intervals for (CR+CR*)

## Adult:  CALGB 19801 Duration of Best Response (≥2 prior multi-agent inductions)

- + Response on-going at last evaluation

## Adult: CALGB 19801 Duration of Best Response (1 prior multi-agent induction)

## Adult: CALGB 19801 Overall Survival(≥ 2 Prior Multi-Agent Inductions)

- + Alive at last contact

## Adult: CALGB 19801 Overall Survival

- + Alive at last contact

## Pediatric: COG P9673

- Open-label, multicenter Phase II study
- Refractory or relapsed T-ALL or T-NHL
- Dose*: 650 mg/m2 days 1-5, every 21 days
- Median: 11 years (range 3-20 years)
- 151 patients treated across 4 strata
- At the recommended dose
- 31 patients with 1 prior multi-agent induction
- 39 patients with ≥2 prior multi-agent inductions
- Enrolled over 61 months
- * Recommended Dose

## Pediatric: COG P9673 Response Rate & Duration≥ 2 Prior Inductions (N=39) 

| Response | CR | CR plus CR* |
| --- | --- | --- |
| Response Rate | 13% | 23% |
| Median Duration of Response (weeks) | 9 | 9 |
| Duration of Response (weeks) | 5 to 36 | 3 to 42  |

- CR = complete response with full hematologic recoveryCR* = complete response without full hematologic recovery CR plus CR* = total of patients achieving best response in either category

## Pediatric: COG P9673  CR+CR* Rates 

- Brackets represent 95% confidence intervals for (CR+CR*)

## Pediatric: COG P9673  CR+CR* Rates

- Brackets represent 95% confidence intervals for (CR+CR*)

## Pediatric: COG P9673  CR+CR* Rates 

- Brackets represent 95% confidence intervals for (CR+CR*)

## Pediatric:  COG P9673 Duration of Best Response (≥2 prior multi-agent inductions)

## Pediatric:  COG P9673 Duration of Best Response  (1 prior multi-agent induction)

- + Response on-going at last evaluation

## Pediatric: COG P9673 Overall Survival(≥ 2 prior multi-agent inductions)

- + Alive at last contact

## Pediatric: COG P9673 Overall Survival 

- + Alive at last contact

## Response Rate – Supportive Trials of Patients with Relapsed/Refractory T-ALL/T-LBL 

| Age Group | Study | N | CR
% |
| --- | --- | --- | --- |
| Adult | TRC 9701
Special Exceptions
  (Univ Frankfurt) | 24
16
 | 13%
56% |
| Adult 
 | PGAA1001
PGAA1002
PGAA1003 | 14
3
8 | 29%00 |
| Pediatric
 | PGAA1001
PGAA1002
PGAA1003 | 18
5
2 | 33%
40%
50% |
| Total |  | 90 |  |

## Neutrophil Recovery Following Allogeneic Transplant

|  | Adult
CALGB 19801a | Pediatric
COG P9673a |
| --- | --- | --- |
| Subjects with available data | n=6  | n=21 |
| Neutrophils (≥500/μL x3 days) | 3 (50%) | 20 (95%) |

- a  Based on retrospective data collection.  Data not available on all subjects.

**Neutrophil Recovery Following Allogeneic Transplant**

## Neutrophil Recovery Following Allogeneic Transplant

|  | Adult
CALGB 19801a | Pediatric
COG P9673a |  | Univ of Frankfurtb |
| --- | --- | --- | --- | --- |
| Subjects with available data | n=6  | n=21 |  | n=18  |
| Neutrophils (≥500/μL x3 days) | 3 (50%) | 20 (95%) |  | 17 (94%)  |

- b  Report provided by Investigator.  Patients enrolled in Special Exceptions Program.

- a  Based on retrospective data collection.  Data not available on all subjects.

**Neutrophil Recovery Following Allogeneic Transplant**

## Efficacy Summary≥ 2 Prior Multi-Agent Inductions

|  | AdultCALGB 19801 | Pediatric COG P9673 |
| --- | --- | --- |
| CR plus CR* | 21% | 23% |
| Duration of CR plus CR* |  4 to 195+ weeks | 3 to 42 weeks |
| Median Overall Survival | 21 weeks | 13 weeks |
| 1-year Survival | 29% | 14% |

## Efficacy Conclusions

**Clinically meaningful benefit as shown by:**
- Induction of complete remission
- Consistent rates of remission
- Adult and pediatric patients
- Patients with relapsed and refractory disease
- Across Phase I and II studies
- Duration of response
- Documented successful transplantation
- One year survival

## Safety

**Mark Russo, M.D., Ph.D.**Group Director, Clinical Oncology, GSK

## Safety Overview

- Safety populations
- Phase I experience
- Hematologic adverse events
- Non-hematologic adverse events
- Neurologic adverse events
- Mortality due to adverse events

## Safety Populations

- 980 patients have received ARRANON
- Full safety database - 459 patients
- Adult dose of 1500 mg/m2 on days 1,3,5
- 36 CALGB19801 + 67 PGAA2003
- 103 patients
- Pediatric dose of 650 mg/m2 daily times 5
- 84 patients COG P9673

## Phase I Experience

- 181 patients (141 Adult, 40 Pediatric)
- Dose Range: 104 mg/m2 – 2900 mg/m2
- Schedules tested:  Daily X 5; Daily X 3; Days 1, 3, 5
- Neurotoxicity was dose-limiting
- Adult Phase II Day 1, 3, 5 – 2200 mg/m2 decreased to 1500 mg/m2
- Pediatric Phase II Daily X 5 – 1200 mg/m2 decreased to 650 mg/m2

## Grade 4 Hematologic Adverse Events Regardless of Relationship

|  | Adult
N=103 | Pediatric
N=84 |
| --- | --- | --- |
| Neutropenia | 49% | 62% |
| Anemia | 14% | 10% |
| Thrombocytopenia | 22% | 32% |

## Adult: Grade 3/4 Non-Hematologic Adverse Events (N=103)

- Includes all grade 3/4 events occurring in at least 3 subjects

## Pediatric: Grade 3/4 Non-Hematologic Adverse Events (N=84)

- Includes all grade 3/4 events occurring in at least 3 subjects

## Adult: Drug-related NeurologicAdverse Events (N=103)

- Includes all grade 3/4 neurologic events

## Adult: Neurologic Adverse Events Regardless of Relationship (N=103)

- Includes all grade 3/4 neurologic events

## Pediatric: Drug-related Neurologic Adverse Events (N=84)

- Includes all grade 3/4 neurologic events

## Pediatric: Neurologic Adverse Events Regardless of Relationship (N=84)

- Includes all grade 3/4 neurologic events

## Incidence of Neurologic Adverse Events Regardless of Relationship

|  | 
Grade 3
 | 
Grade 4 |
| --- | --- | --- |
| Adults (N=103) | 10% | 3% |
| Pediatric (N=84) | 11% | 8% |

## Resolution of Neurologic Adverse Events Regardless of Relationship

|  | Resolved | Unresolved* | Unknown |
| --- | --- | --- | --- |
| Adults (1500 mg/m2)
217 events | 47%
 | 24% | 28% |
| Pediatrics (650 mg/m2)
80 events | 63%
 | 18% | 20% |

- *includes 2 patients with fatal neurologic events (1 Adult, 1 Pediatric)

## Clinical Presentation of Neurologic Adverse Events  (1)

**Somnolence**
- Onset often on day of administration
- Drowsiness, increased sleep
- Usually reversible, within days
- Not clinically significant

## Clinical Presentation of Neurologic Adverse Events (2)

**Peripheral Neuropathies**
- Onset generally after administration
- Mostly sensory
- Numbness/dysesthesia of lower extremities
- Similar to that seen with vincristine and taxanes
- Occasionally motor
- Resolution may take several months
- Severe ascending polyneuropathy seen in 14 of 980 patients (1.5%)

## Nine in 187 patients  (5%)
Six in adults, N=103
Three in pediatrics, N=84
Two (1%) attributed to ARRANON
Coma
Status epilepticus

- Six in adults, N=103
- Three in pediatrics, N=84
- Two (1%) attributed to **A****RRANON**
- Coma
- Status epilepticus

**Mortality Due to Adverse Events****at Proposed Doses **

## Safety Conclusions

- Hematologic events were most common, and manageable
- Neurologic events were frequent in this population
- Most were grade 1 or 2
- 13% G3/G4 for adults
- 19% G3/G4 for pediatrics
- 1% of patients had fatal related adverse events
- Recommended doses have acceptable risk for this patient population

## Role of ARRANON in Treatment

**William L. Carroll, M.D.**
- Director, Pediatric Oncology, NYUChair, ALL Committee, Children’s Oncology Group

## Evaluation of New Agents for T-ALL/T-LBL

**Treatment Setting - Relapsed/Refractory Disease**** **
- Heavily pretreated patients
- Historically treatment is usually individualized based on response to prior therapy
- Stem cell transplantation is often the intention of treatment, chemotherapy used to induce remission
**Rationale - Clinical Trials**
- Evaluate ability to induce complete remission in heavily pretreated patients
- Randomized studies not possible in relapsed or refractory setting
- Integrate most promising compounds that provide clinical benefit into front-line therapy

## ARRANON 
Provides clinical benefit in patients with:
Two or more prior inductions
Notable CR rates, especially for the treatment setting
One prior induction 
Single agent activity at least equal to that provided by aggressive multi-agent regimens
Safety profile in patients with: 
Relapsed or refractory disease 
Acceptable adverse event profile 
Newly diagnosed disease  
Proven ability to combine with multi-agent therapy AALL00P2 (new diagnosis higher risk T ALL)

- Provides clinical benefit in patients with:
- Two or more prior inductions
- Notable CR rates, especially for the treatment setting
- One prior induction
- Single agent activity at least equal to that provided by aggressive multi-agent regimens
- Safety profile in patients with:
- Relapsed or refractory disease
- Acceptable adverse event profile
- Newly diagnosed disease
- Proven ability to combine with multi-agent therapy AALL00P2 (new diagnosis higher risk T ALL)

**Patients with Relapsed or Refractory ****T-ALL/T-LBL**

## Phase III Randomized Trial – COG AALL0434

- Randomized, multi-center, cooperative group trial (COG)
- N=640 patients with T-ALL, aged 1-30 years
- Study design
- Modified BFM regimen  (based on legacy CCG-1961C and identical to current AALL0232 study for higher risk B precursor ALL)
- Randomized to (high and intermediate risk patients):
- with or without ARRANON
- high dose MTX vs escalating IV MTX (aka Capezzi MTX)
- Primary endpoint:  EFS at 4 years
- Safety Phase: first 20 consecutive high risk patients
- Efficacy phase: interim analyses at 20%, 40%, 60%, 80%, and 100% of the expected total # events

## AALL0434 Efficacy Phase High and Intermediate Risk Patients

**V**
**P**
**L**
**D**

**Backbone Regimen:  BFM (CCG 1961C)**
**Induction                        Consolid.         Interim           Delayed        Maintenance ****	****	****	****                       Main.              Intens.****	****	**

**ARRANON**

**Without  ARRANON **

- A

- A

- A

- A

- A

- A

- A

- A

- A

- A

- A

- A

## Phase III Randomized Trial – AALL0434

**A****RRANON** administration
- 650 mg/m2 for five consecutive days
- Consolidation, delayed intensification and maintenance
- Assessment of:
- Event free survival
- Minimal residual disease  post consolidation

## ARRANON – Role in Treatment

**A****RRANON** provides
- clinical benefit, and
- acceptable risk to benefit profile
**A****RRANON** is an effective treatment for patients with relapsed or refractory T-ALL/T-LBL

## Conclusions

**Peter Ho, M.D., Ph.D.**VP, Discovery Medicine Oncology, GSK

## Conclusions

- T-ALL/T-LBL ≥ 2nd relapse or refractory disease
- Poor prognosis and no standard of care
**ARRANON:**  Acceptable safety profile
- Expected & manageable non-neurological (incl. hematologic) adverse events for indicated population
- Neurological adverse events
- Low grade events are common
- Grade 3 / 4 events are less common, but require prescriber attention

## ARRANON:  Clinically meaningful benefit as single agent in T-cell ALL/LBL
Consistent demonstration of CR
Second and third line patients
Refractory patients
Children and adults
CR durable and allowed time for transplantation
Demonstrable survival at one year
Overall favorable benefit - risk profile for the proposed population of relapsed or refractory patients

- Consistent demonstration of CR
- Second and third line patients
- Refractory patients
- Children and adults
- CR durable and allowed time for transplantation
- Demonstrable survival at one year
- Overall favorable benefit - risk profile for the proposed population of relapsed or refractory patients

**Conclusions**

## Additional Slides Presented

## Response Duration – Confounding Factors (Patients achieving CR or CR*)

| Pt ID | Duration (wks)* | Event | Transplant | Systemic Rx |
| --- | --- | --- | --- | --- |
| 1131 | 9 | Transplant | Y | - |
| 79729 | 6 | Transplant | Y | - |
| 1081 | 4 | Transplant | Y | - |
| 1132 | 4 | Transplant | Y | - |
| 1039 | 2 | Transplant | Y | - |
| 78326 | 195+ | Censored | N | N |
| 82137 | 30 | Relapse | N | Y |
| 77798 | 19 | Relapse | N | N |
| 83908 | 15 | Relapse | Y | - |
| 1093 | 12 | Relapse | N | Y |
| 1062 | 10 | Toxicity | N | Y |
| 1036 | 6 | Relapse | N | Y |
| 76143 | 4 | Relapse | N | Y |
| 1109 | 3 | Relapse | N | Y |
| 1068 | 3 | Infectious Death | N | N |

- * From initial response (≥ mCR) to transplant, systemic Rx, or relapse

- Duration
- ≥ 8 Weeks

- Duration
- < 8 Weeks

- Transplanted in Remission

## Nervous System Serious Adverse Eventspre and post January 1, 1999

## Transplantation by Response

| Transplantation post nelarabine | CR or CR* | < CR* |
| --- | --- | --- |
| Adult:  CALGB 19801
      ≥ 2 prior therapies
      1 prior therapy | 
2/6
2/3 | 
2/221
1/8 |
| Pediatric:  COG P9673
      ≥ 2 prior therapies
      1 prior therapy | 
4/9
12/15 | 
4/302
5/163 |

- Includes one mCR
- Includes one mCR and one mPR
- 3.     Includes one mPR

## Adult: CALG19801 Survival (CR+CR* Subjects, ≥2 prior multi-agent inductions)

- + Indicates alive at last evaluation

## Pediatric:  COG P9673 Survival (CR+CR* Subjects, ≥ 2 prior multi-agent inductions)

- + Indicates alive at last evaluation