The protocols for each phase III, placebo controlled randomized study (414-94-2 and 514-94-2) stated that Stratum 3 patients (those with MTT volume >20 cm3) would not be analyzed for efficacy, but would be included in all other analyses. The Analysis Plan stated that Stratum 3 patients would be analyzed descriptively. This appendix separately summarizes the disease characteristics, MTT response rates, and Patient Benefit rates in Stratum 3, including inferential comparison of MTT response rates in the CDDP/epi gel and placebo groups. Stratum 3 (MTT >20 cm3) was closed after the enrollment of 46 patients. Response rate and benefit rates were lower in Stratum 3 than in Stratum 1 or 2.
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Table A4-1: Patients enrolled in Stratum 3 |
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|
Study |
CDDP/epi Gel |
Placebo Gel |
TOTAL |
|
414 |
14 |
9 |
23 |
|
514 |
17 |
6 |
23 |
|
TOTAL |
31 |
15 |
46 |
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Table A4-2: Treatment Termination Status – Stratum 3, Blinded Phase |
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|
|
CDDP/Epi Gel |
Placebo Gel |
|
|
n = 31 |
n = 15 |
|
Completed six treatments |
7 (23%) |
0 (0%) |
|
Early response with less than six treatments |
2 (6%) |
0 (0%) |
|
Disease progression, local |
3 (10%) |
7 (47%) |
|
Disease progression, systemic |
8 (26%) |
4 (27%) |
|
Adverse event |
4 (13%) |
1 (7%) |
|
Other a |
7 (2%) |
3 (20%) |
|
TOTAL |
31 |
15 |
|
a Delay in scheduled dosing for >2 weeks; need for confounding therapy; patient decision; other. |
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Nine patients (29%) completed all six treatments or stopped early because of a response to CDDP/epi gel. Placebo-treated patients developed local progression more frequently. CDDP/epi gel patients more frequently stopped because of an adverse event.
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Table A4-3: Patient Demographics |
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|
|
CDDP/epi Gel |
Placebo Gel |
Combined |
|
Characteristic |
n=31 |
n= 15 |
n= 46 |
|
Age (years), n |
31 |
15 |
46 |
Mean (SD) |
62 (11) |
63 (16) |
62 (13) |
Median |
61 |
63 |
61 |
Range |
42-88 |
38-91 |
38-91 |
|
Gender, n |
31 |
15 |
46 |
Male |
22 (71%) |
12 (80%) |
34 (74%) |
Female |
9 (29%) |
3 (20%) |
12 (26%) |
|
Ethnicity, n |
31 |
15 |
46 |
White |
25 (81%) |
13 (87%) |
38 (83%) |
Black |
3 (10%) |
0 |
3 (7%) |
Hispanic |
2 (6%) |
1 (7%) |
3 (7%) |
American Indian |
0 |
0 |
0 |
Asian |
1 (3%) |
1 (7%) |
2 (4%) |
|
Weight (kg), n |
31 |
15 |
46 |
Mean (SD) |
62 (13) |
59 (13) |
61 (13) |
Median |
60 |
56 |
60 |
Range |
40-83 |
41-84 |
40-84 |
|
Karnofsky Performance Status, n |
31 |
15 |
46 |
100-90 |
8 |
1 |
9 |
80-70 |
19 |
11 |
30 |
60-50 |
4 |
3 |
7 |
40 |
0 |
0 |
0 |
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Table A4-4: Location of MTT and of All Tumors Treated in Treatment Phase |
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|
Location |
CDDP/epi Gel n=31 |
Placebo Gel n=15 |
Total n=46 |
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|
Tumor(s) Treated |
MTT |
ALL |
MTT |
ALL |
MTT |
ALL |
|
Total n (tumors) |
31 |
38 |
15 |
17 |
46 |
55 |
|
Cervical |
14 |
20 |
7 |
7 |
21 |
27 |
|
Oral cavity |
7 |
7 |
3 |
3 |
10 |
10 |
|
Facial |
6 |
7 |
2 |
4 |
8 |
11 |
|
Laryngopharyngeal |
3 |
3 |
2 |
2 |
5 |
5 |
|
Nasopharyngeal |
0 |
0 |
0 |
0 |
0 |
0 |
|
Cranial |
0 |
0 |
1 |
1 |
1 |
1 |
|
Chest wall |
1 |
1 |
0 |
0 |
1 |
1 |
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Table A4-5: Cancer Treatment History |
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|
|
CDDP/epi Gel |
Placebo Gel n (%) |
Total n (%) |
|
Total n |
31 |
15 |
46 |
|
Surgery |
0 (0%) |
1 (7%) |
1 (2%) |
|
Surgery and radiation |
14 (45%) |
4 (27%) |
18 (39%) |
|
Surgery, radiation, and systemic chemotherapy |
12 (39%) |
9 (60%) |
21 (46%) |
|
Radiation and systemic chemotherapy |
3 (10%) |
1 (7%) |
4 (9%) |
|
Surgery and systemic chemotherapy |
2 (6%) |
(0 (0%) |
2 (4%) |
Patients in Stratum 3 had somewhat lower Karnofsky Performance Status than Stratum 1 and 2 (KPS 90-100: 20% vs. 37%). The MTT was most frequently cervical, oral cavity, and facial as in Stratum 1 and 2. Previous treatment history is similar.
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Table A4-6: Extent of Exposure to Treatment with CDDP/epi gel or Placebo — Stratum 3 |
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|
|
Blinded Period |
Open-Label Period |
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|
CDDP/epi Gel n=31 |
Placebo Gel n=15 |
CDDP/epi Gela n=6 |
Placebo Gela n=16 |
|
|
No. of Rxs |
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1 |
3 (10%) |
1 ( 7%) |
0 ( 0%) |
3 (30%) |
2 |
9 (29 %) |
8 (53%) |
0 ( 0%) |
1(10%) |
3 |
5 (16 %) |
5 (33%) |
0 ( 0%) |
3(30%) |
4 |
3 (10 %) |
1 ( 7%) |
3 (50%) |
1(10%) |
5 |
4 (13 %) |
0 ( 0%) |
3 (50%) |
1(10%) |
6 |
7 (23%) |
0 ( 0%) |
0 ( 0%) |
1(10%) |
7 or more |
0 ( 0%) |
0 ( 0%) |
0 ( 0%) |
0 ( 0%) |
|
Cumulative Dose (mL) |
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mean |
25 |
17 |
33 |
23 |
median |
20 |
14 |
35 |
19 |
SD |
16.6 |
8.5 |
15.4 |
20.9 |
range |
3.8 - 60 |
4 - 30 |
14 - 50 |
2 - 60 |
|
a Original randomization group |
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Table A4-7: Overall Response Rate of MTT – Blinded Phase |
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|
|
CDDP/epi Gel |
Placebo Gel |
|
||||
|
|
Response Rate (%) |
|
|
Response Rate (%) |
|
||
|
Stratum 3 |
31 |
13% c |
(3.6-30%) |
15 |
0% c,d |
(0-22%) |
0.15 |
|
Stratum 1 |
62 |
37% |
(25-50%) |
29 |
3% |
(0.87-18%) |
<0.001 |
|
Stratum 2 |
57 |
21% |
(11-34%) |
30 |
0% |
(0-12%) |
0.015 |
|
Strata 1 & 2 |
119 |
29% |
(21-38%) |
59 |
2% |
(0.043-9.1%) |
<0.001 |
|
a Clopper-Pearson exact 95% confidence intervalb For stratified comparisons, p-values are Cochran-Mantel-Haenszel test p-values, as calculated by SAS procedure MULTTEST. For unstratified active vs. placebo comparisons, p-values are Fisher’s exact test p-values, as calculated by SAS procedure FREQ.c In Stratum 3, 14% of CDDP/epi gel treated patients achieved benefit, but no placebo patients did.d 10 placebo patients crossed over to receive open label CDDP/epi gel. |
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Table A4-8: Patient Benefit Rates – Blinded Phase |
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|
|
CDDP/epi Gel |
Placebo Gel |
||
|
|
Benefit Rate (%) |
|
Benefit Rate (%) |
|
|
Stratum 3 |
31 |
16% |
15 |
0% |
|
Stratum 1 |
62 |
32% |
29 |
17% |
|
Stratum 2 |
57 |
21% |
30 |
7% |
|
Strata 1 & 2 |
119 |
27% |
59 |
12% |
It is likely that the lower response and benefit rate in stratum 3 maybe due to the larger tumor size and the shorter time patients remained in therapy because of progressive distant or local cancers.