NDA#21-240 Histamine Dihydrochloride FDA Review December 13, 2000.

NDA#21-240Histamine Dihydrochloride

FDA ReviewDecember 13, 2000

Division of Oncology Division of Oncology Drug ProductsDrug Products

22

CDER/DODP Review Team

Medical Reviewers: Judy H. Chiao , M.D.Donna Griebel, M.D. (TL)

Statisticians: Rajeshwari Sridhara, Ph.D.Gang Chen, Ph.D. (TL)

Biopharm: Gene Williams, Ph.D.Atiqur Rahman, Ph.D. (TL)

Pharm/Tox: John Leighton, Ph.D.Margaret Brower. (TL)

Chemistry: N. Chidambaram, Ph.D.Eric Duffy, Ph.D. (TL)

CSO: Sean Bradley, R.Ph

Dotti Pease (TL)


33

Indication

Indicated for adjunct use with IL-2 inthe treatment of adult patients with

advanced metastatic melanoma that

has metastasized to the liver


44

Outline of FDA Review

• Biology of metastatic melanoma• Regulatory History• Review issues (MP-US-M01)

– Is survival difference in the ITT population (N=305) a persuasive finding?

– Is survival difference in the liver subgroup (N=129) a persuasive finding?

– Is the Histamine/IL-2 combination a well tolerated regimen?


55

Metastatic Melanoma

• Chemo-resistant• IL-2-based therapy effective in a

minority of patients • Survival varies from < 4 to >12

mons – influenced by prognostic factors– difference in survival could be due to

imbalances in prognostic factors rather than the treatment


66

Prognostic Factors

• Number of organs involved by metastasis• Site of metastasis

– skin/lymph node vs. lung vs. others LDH• Low Albumin• Disease free interval • Prior disease stage • Performance status• Sex


77

Regulatory History

Summary of DODP comments on the design of registration studies for H/IL-2

– Two well controlled studies sufficiently powered to show superiority of the histamine/IL-2 combination over IL-2 alone

– Pre-stratification with prognostic factors to ensure that the arms were balanced in patient characteristics that might affect survival


88

Regulatory History

– The International phase 3 study could not serve as a second well-controlled study

• Different treatment regimen: Histamine/IL-2 plus INF- vs DTIC alone

– Single arm study MA-0103 could not serve as a second well-controlled study

• Could not demonstrate the added benefit of histamine to IL-2 without a IL-2 alone arm

• Could not reliably evaluate survival in the absence of a control arm


99

MP-US-M01: Study Design

• Open-label, RCT• NOT stratified by any prognostic factors • NOT stratified by the presence of liver

metastasis at study entry• Primary endpoint: overall survival


1010

Statistical Analysis Plan

• Original Protocol (7/1/97):– The primary objective is to evaluate

the efficacy and safety of H/IL-2 in patients with metastatic melanoma who have not been treated or have failed other first-line therapies

– Patients will be stratified in subgroup analyses: liver vs. no liver mets; prior treatment with DTIC or no DTIC


1111


• Last patient randomized on 3/26/99• Revised statistical plan (6/24/99):

– The primary objective is to evaluate the clinical efficacy of H/IL-2 as compared to IL-2 alone in patients with metastatic melanoma

– ITT subset will be used as the primary subset– All efficacy endpoints will be summarized for

non-exploratory subgroup of patients with liver metastases at study entry


1212


• Revised statistical plan (9/14/99):– Three subgroups will be analyzed

• Patients with liver metastases at study entry• Patients from centers enrolling 7 patients• Patients with liver metastases from centers

enrolling 7 patients

• Final statistical plan (11/18/99)– Two Null Hypotheses: ITT and liver

subgroup


1313

Review Issue #1

Is survival difference in the ITT

population a persuasive finding?


1414

FDA Comments

• Cut-off dates (3/8/00, 9/8/00) were NOT prespecified in the protocol

• FDA review of last f/u date of each patient– 40 patients alive on 9/8/00– 33 (83%) had last f/u 30 days past 9/8/00– 4 died after 9/8/00

3 deaths on H/IL-2: 9/12, 9/18, 10/101 death on IL-2: 10/12


1515

Median Survival (months): ITT

Events (%) IL-2N=153

H/IL-2N=152

3/8/00 243 (80%) 8.0(6.0, 9.2)

8.9(6.9, 10.4)

9/8/00 265 (87%) 8.0(6.0, 9.2)

8.9(6.9, 10.4)

Last f/u 269 (88%) 8.0(6.0, 9.2)

8.9(6.9, 10.4)


1616

Hazard Ratio and P-value: ITT

Events (%) Hazard Ratio(CI)

P-value

3/8/00 243 (80%) 0.822(0.638,1.051)

0.1255

9/8/00 265 (87%) 0.788(0.619, 1.004)

0.0526

Last f/u 269 (88%) 0.798(0.628, 1.015)

0.0650


1717

Overall Survival: ITT(Cut-off date: 3/8/00)

: H/IL-2 (N=152)---: IL-2 (N=153)

Log Rank p=0.1255

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0100 300 500 700 900

Survival days

Proportion


1818

Overall Survival: ITT(Cut-off date: 9/8/00)

: H/IL-2 (N=152)---: IL-2 (N=153)

Log Rank p=0.0526Proportion

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0100 300 500 700 900 1100

Survival Days


1919

Overall Survival: ITT(FDA using most recent f/u data)

: H/IL-2 (N=152)---- : IL-2 (N=153)

Log Rank p=0.0650

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0100 300 500 700 900 1100

survival days

Proportion


2020

FDA Comments

• P-values of survival analysis are not adjusted for multiple comparisons


2121

FDA Comments

• Lack of internal consistency across the subgroups


2222

Median Survival (months): Subgroups

IL-2 H/IL-2 P-value

Liver subgroup(N=129)

5.0(3.9, 6.7)

9.2(6.4, 12.7)

0.0033

No Liver metsubgroup (N=176)

10.3(8.6, 12.3)

8.7(6.6, 10.4)

0.7808

Skin/node/lung only(N=82)

12.0(9.3, 15.4)

10.4(9.0, 13.8)

0.8217


2323

Survival in Liver Met Subgroup: N=129 (Cut-off date: 9/8/00)

: H/IL-2 (N=55)----: IL-2 (N=74)

Log Rank p=0.0033

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0100 300 500 700 900 1100

Survival days

Proportion


2424

Survival in No Liver Met Subgroup: N=176 (Cut-off date: 9/8/00)

: H/IL-2 (N=97)---- : IL-2 (N=79)

Log Rank p=0.7806

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0100 300 500 700 900 1100

Survival days

Proportion


2525

Survival in Patients with Skin/Node/Lung Only Disease: N=82 (Cut-off date: 9/8/00)

: H/IL-2 (N=45)----: IL-2 (N=37)

Log Rank p=0.8217

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0100 300 500 700 900 1100

Survival days

Proportion


2626

FDA Comments

• No supporting evidence from tumor response rate, time to tumor progression


2727

Secondary endpoint: Response

IL-2N=153

H/IL-2N=152

CR 1* 0*

PR 3 4

*different from the applicant’s analysis


2828

Difference between FDA’s TTP and the applicant’s

FDA• TTP censored on the

day of last imaging studies

• Death not counted PD unless PD on imaging studies

• PD based on the day of imaging studies

Applicant• TTP censored on the

last day patient was known to be alive

• All deaths counted as PD

• PD based on the day when imaging studies were read


2929

Time to Tumor Progression: FDA Analysis in ITT (N=243)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 100 200 300 400

TTP days

: H/IL-2 (N=124)----: IL-2 (N=119)

Log Rank p=0.4108Proportion


3030

FDA Comments on Efficacy: ITT

– Survival difference in the ITT population did

not reach statistical significance. – P-value dependent on cut-off dates, which

were not prespecified in the protocol – Lack of internal consistency across

subgroups– No supporting evidence from tumor

response, time to tumor progression


3131

Review Issue #2

Is survival difference in the liver met

subgroup a persuasive finding ?


3232

FDA Comments

• Imbalances in prognostic factors consistently favor the histamine/IL-2 arm


3333

Patient Characteristics in the Liver Subgroup

IL-2N=74

H/IL-2N=55

Female 38% 51%KPS=0 59% 64%DFS>4 yrs 24% 36%No prior chemo 72% 82%No. of dis site =1 9% 24%*CNS mets 8% 2%LDH>ULN 53% 58% Albumin 28 % 20%

*P=0.047 by Fisher’s Exact Test


3434

FDA Comments

• Large shifts in hazard ratio and p-value in the FDA adjusted analysis indicate that these imbalances contributed to the observed survival difference in the liver subgroup


3535

Adjusted Survival Analysis of the Liver Subgroup (Cut-off 9/8/00)

Hazard Ratio(CI)

P-value

Unadjusted 0.572(0.392, 0.835)

0.0033

Adjusted forimbalances

0.655(0.424, 1.013)

0.0573*

*P-value = 0.1146 after adjusting for 2 primary hypotheses


3636

FDA Comments

• The treatment effect of the histamine/IL-2 combination is most apparent in the small group of patients (N=20) with liver only disease.


3737

Median Survival (months): Liver Subgroups

IL-2 H/IL-2 P-value

Liver subgroup: N=129(I=74, H/I=55)

5.0(3.9, 6.7)

9.2(6.4, 12.7)

0.0033

Liver involvement only:N=20 (I=7, H/I=13)

3.8(3.0, 4.6)

13.3(6.4, 28.1)

0.0006

Liver and outside liver:N=109(I=67, H/I=42)

5.5(4.2, 8.2)

7.7(4.0, 11.9)

0.0743


3838

FDA Comments

• No supporting evidence of tumor response, time to tumor progression


3939

Secondary endpoint: Response in the Liver Subgroup

IL-2N=74

H/IL-2N=55

CR 0 0

PR 0 2


4040

Time to Tumor Progression: LM Subgroup (N=96)

: H/IL-2: N=42---- : IL-2: N=54

Log Rank p=0.1315

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

50 100 150 200 250 300 350

"f TTP days

Surviving


4141

FDA Comments on Efficacy in the Liver Subgroup

• Imbalances in prognostic factors consistently favor the histamine/IL-2 arm.

• These imbalances contributed to the observed survival difference between the two arms (FDA adjusted analysis)

• Treatment effect of the histamine/IL-2 combination is most apparent in the small group of patients with liver only disease

• No supporting evidence from tumor response, time to tumor progression


4242

Review Issue #3

Is the histamine/IL-2 combination a well tolerated treatment regimen?


4343

0

5

10

15

20

25

30

35

1 2 3 4 5 6 7 8

Maximum Number of Cycles Completed

Pe

rce

nt

of

Pa

tie

nts


4444

IL-2 Regimen

D 1 D 2 D 3 D 4 D 5Wk 1 BID BID

Wk 2 BID BID BID BID BID

Wk 3 BID BID

Wk 4 BID BID BID BID BID


4545

Histamine/IL-2 Regimen

D 1 D 2 D 3 D 4 D 5Wk 1 BID

BIDBIDBID BID BID BID

Wk 2 BIDBID

BIDBID

BIDBID

BIDBID

BIDBID

Wk 3 BIDBID

BIDBID BID BID BID

Wk 4 BIDBID

BIDBID

BIDBID

BIDBID

BIDBID

----------------

IL-2Hist.


4646

Compliance with Treatment

• Vials or pre-filled syringes were not returned to study sites to check for compliance

• Inadequate assessment by patient diary:– Original protocol did not require the use of a

diary– 201 patients did not complete diaries

(dosing information available on 76 patients from home care records)


4747

MP-US-M01: Safety

ITT ITT-LM

IL-2N=153

H/IL-2N=152

IL-2N=74

H/IL-2N=55

Dose forAE*

14% 13% 16% 2%

Gr 3-4 tox 60% 54% 66% 58%

Death 10% 11% 14% 18%

*Applicant’s report


4848

Death within 30 Days of Last Dose

• 33 patients (11%) died within 30 days of last dose of study medication– 20 died in the liver subgroup (16%)

• Cause of death:– 3 deaths (H/IL-2) attributed to study medication by the

applicant– 2 deaths (IL-2) of unknown causes– 12 deaths: cannot rule out study medication by FDA– 16 deaths related to progression (11 had documentation)


4949

Grade 3 Toxicity

ITT Liver Subgroup

IL-2N=153

H/IL-2N=152

IL-2N=74

H/IL-2N=55

Asthenia 12% 12% 11% 13%

Edema/ascites 10% 6% 9% 11%Dyspnea 7% 5% 9% 4%Nausea 7% 5% 12% 7%Vomiting 5% 6% 8% 7%Anorexia 6% 2% 3% 0%Altered MS 5% 3% 5% 4%Headache 2% 7% 0% 11%


5050

Grade 4 Toxicity

• 6% patients suffered grade 4 toxicity.

• Specific types of grade 4 toxicities were rare (incidence 1%):

MI, cardiac arrest, CHF, hypotension, syncope, seizure, ascites, dyspnea, liver failure


5151

Safety from Single Arm Study MA-0103

• 90 patients enrolled in the study– 16 (18%) died within 30 days of the

last dose

• 35 had liver metastases– 8 (23%) died within 30 days of the

last dose


5252

Safety from Single Arm Study MA-0103

• 49 patients (54%) suffered grade 3 toxicities

asthenia (16%) chest pain (7%)nausea (8%) edema/effusion

(6%) vomiting (7%) anorexia (3%)headache (8%) dyspnea

(3%)altered MS (2%)


5353

Overall Summary

• Only ONE study• Survival difference in the ITT

population did not reach statistical significance


5454

Overall Summary

• Survival difference in the subgroup of patients with liver metastases should be interpreted with caution– Imbalances in prognostic factors favor H/IL-2

arm– Effect of these imbalances precludes a

reliable assessment of the efficacy of the histamine/IL-2 combination

– No supportive evidence from tumor response rate or time to tumor progression


5555

Overall Summary

• 58% suffered grade 3-4 toxicities and 11% died within 30 days of the last dose of study medications– Not possible to assess whether toxicities were due to underlying

disease or treatment in the absence of a non-IL-2 arm– Grade 3-4 toxicities in recent DTIC trial is 36% and death within

30 days is 8 %

• Poor documentation of patient compliance precludes adequate assessment of treatment tolerability

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NDA#21-240 Histamine Dihydrochloride FDA Review December 13, 2000.

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