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NDA#21-240Histamine Dihydrochloride
FDA ReviewDecember 13, 2000
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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)
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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Indication
Indicated for adjunct use with IL-2 inthe treatment of adult patients with
advanced metastatic melanoma that
has metastasized to the liver
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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?
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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Statistical Analysis Plan
• 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
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Statistical Analysis Plan
• 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
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Review Issue #1
Is survival difference in the ITT
population a persuasive finding?
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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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)
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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FDA Comments
• P-values of survival analysis are not adjusted for multiple comparisons
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FDA Comments
• Lack of internal consistency across the subgroups
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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
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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FDA Comments
• No supporting evidence from tumor response rate, time to tumor progression
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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Secondary endpoint: Response
IL-2N=153
H/IL-2N=152
CR 1* 0*
PR 3 4
*different from the applicant’s analysis
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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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
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Review Issue #2
Is survival difference in the liver met
subgroup a persuasive finding ?
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FDA Comments
• Imbalances in prognostic factors consistently favor the histamine/IL-2 arm
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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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.
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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FDA Comments
• No supporting evidence of tumor response, time to tumor progression
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Secondary endpoint: Response in the Liver Subgroup
IL-2N=74
H/IL-2N=55
CR 0 0
PR 0 2
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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Review Issue #3
Is the histamine/IL-2 combination a well tolerated treatment regimen?
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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.
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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)
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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)
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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%
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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%)
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Division of Oncology Division of Oncology Drug ProductsDrug Products
5353
Overall Summary
• Only ONE study• Survival difference in the ITT
population did not reach statistical significance
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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
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Division of Oncology Division of Oncology Drug ProductsDrug Products
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