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.

Table A4-1: Patients enrolled in Stratum 3

Study

CDDP/epi Gel

Placebo Gel

TOTAL

414

14

9

23

514

17

6

23

TOTAL

31

15

46

 

Table A4-2: Treatment Termination Status – Stratum 3, Blinded Phase

 

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.

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.

 

Table A4-3: Patient Demographics

 

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

Table A4-4: Location of MTT and of All Tumors Treated in Treatment Phase

Location

CDDP/epi Gel

n=31

Placebo Gel

n=15

Total

n=46

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

 

Table A4-5: Cancer Treatment History

 

CDDP/epi Gel
n (%)

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.

Table A4-6: Extent of Exposure to Treatment with CDDP/epi gel or Placebo — Stratum 3

 

Blinded Period

Open-Label Period

CDDP/epi Gel

n=31

Placebo Gel

n=15

CDDP/epi Gela

n=6

Placebo Gela

n=16

No. of Rxs

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)

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

 

 

Table A4-7: Overall Response Rate of MTT – Blinded Phase



Stratum

CDDP/epi Gel

Placebo Gel



Exact p b


n

Response Rate (%)


95% CI a


n

Response Rate (%)


95% CI a

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 interval

b 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.

 

Table A4-8: Patient Benefit Rates – Blinded Phase



Stratum

CDDP/epi Gel

Placebo Gel


n

Benefit Rate

(%)


n

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.