1. Introduction

Studies 403-93-2 and 503-93-2 were multi-center, open-label, single arm, Phase II studies of patients with recurrent or refractory solid tumors of any histology, except Kaposi’s sarcoma and HNSCC. The patients had undergone treatment with at least one previous cancer modality, such as systemic chemotherapy, surgery, or radiation, and presented with relapsed or progressive local tumors at study entry. Tumors were treated at a dose of CDDP/epi gel of 0.5 mL/cm3. The maximum total dose for all tumors treated at one visit was 10 mL. Patients received up to 6 weekly treatments in an 8-week period and were then followed weekly for 4 weeks. Patients who achieved a complete response were followed monthly; patients with partial response or those with recurrence following response or with newly emergent tumors were allowed to receive additional treatments and then followed. During the treatment period, tumors were measured each week using one of the following methods (clinical/physical exam, computed tomography, ultrasound, endoscopy, or colposcopy), and the tumor volume was measured at each visit. Responses were based on reduction in tumor volume using standard definitions of response.

For esophageal cancer patients, a dysphagia assessment was conducted at each visit, and a barium swallow test or esophagoscopy was conducted one week after the patient’s last of the six treatments and when clinically indicated during the studies. Because measurement of esophageal tumors was difficult, the protocol permitted change in ability to swallow to be used as an assessment of tumor response in these patients. For patients with obstructing exophytic esophageal cancer, response was assessed based on three specific criteria:

Progress toward prospectively selected treatment goals was evaluated using the Treatment Goals Questionnaire as it was used in the phase III trials in patients with HNSCC.

2. Results

2.1. Demographics and Baseline Characteristics

Patient demographics are summarized in Table A6-1. Patients with a variety of recurrent or refractory solid tumors were enrolled in these Phase II studies, without restriction as to the original site of the primary cancer or the histologic type of cancer.

The cancer subgroups differed with respect to gender and ethnicity. All patients with breast cancer were female, 75% of patients with esophageal cancer were male, and all patients with melanoma were white. Of patients with "other" cancers, most (82%) were white.

Table A6-1: Demographics and Patient Characteristics by Cancer Subgroup


Characteristic

Breast
(n = 29)

Esophageal
(n = 24)

Melanoma
(n = 28)

Other
(n = 45)

Overall
(n = 126)

Age (years)

N

29

24

28

45

126

Mean (SD)

62 (12.5)

74 (12.0)

61 (12.2)

61 (14.1)

64 (13.7)

Median

63

76

61

63

64

Range

41–87

52–92

39–82

31-88

31–92

Gender

N

29

24

28

45

126

Male

0 (0%)

18 (75%)

13 (46%)

27 (60%)

58 (46%)

Female

29 (100%)

6 (25%)

15 (54%)

18 (40%)

68 (54%)

Ethnicity

N

29

24

28

45

126

White

23 (79%)

21 (88%)

28 (100%)

37 (82%)

109 (87%)

Black

1 (3%)

3 (13%)

0 (0%)

5 (11%)

9 (7%)

Asian

1 (3%)

0 (0%)

0 (0%)

1 (2%)

2 (2%)

Other

4 (14%)

0 (0%)

0 (0%)

2 (4%)

6 (5%)

Weight (kg)

N

28

23

28

44

123

Mean (SD)

67 (19.2)

65 (14.3)

77 (18.2)

70 (17.1)

70 (17.6)

Median

68

66

74

68

69

Range

38–101

44–92

49–121

44-127

38-127

Karnofsky, baseline

N

28

24

27

45

124

Mean (SD)

85 (14.8)

71 (14.8)

84 (11.2)

83 (14.6)

81 (14.7)

Median

90

70

90

90

90

Range

40–100

40–100

60–100

50–100

40–100

2.1.2. Baseline Disease Characteristics

Typical patients with breast cancer had primary adenocarcinoma with local recurrence or metastases, most often to the chest wall, with associated difficulties of pain, wound management, and limb mobility. Patients with malignant melanoma characteristically had metastases to the chest wall or extremities. Patients with esophageal cancer commonly presented with exophytic tumor growing into and obstructing the esophageal lumen. These patients were treated by endoscopic injection of the exophytic or intramural base of the tumors using small needles, such as those designed for sclerotherapy of esophageal varices. Patients with "other" cancer had a variety of recurrent primary cancers and superficial metastases that were amenable to injection of CDDP/epi gel by conventional injection techniques, guided by vision and/or physical palpation of the tumor masses. Tumors were chosen for treatment because of local symptomatology. The advanced state of disease in this patient population is illustrated by their extensive prior cancer therapy.

Table A6-2: Previous Cancer Therapy

 

n

%

Any Previous Therapy

115

91%

Single Modality

22

18%

Surgery

12

10%

Radiation

5

4%

Chemotherapy

5

4%

Multiple Modalities

93

73%

Surgery and radiation

17

13%

Surgery and chemotherapy

13

10%

Radiation and chemotherapy

10

8%

Surgery, radiation, and chemotherapy

53

42%

2.1.3. Baseline tumor characteristics

All patients enrolled had histologically confirmed, recurrent or refractory, primary or metastatic tumors that were accessible for injection with CDDP/epi gel and were measurable. The sites of primary cancer were breast, skin, esophagus, and lung, with remaining primary sites varying widely. The predominant histologic type of the primary cancer was adenocarcinoma, followed by squamous cell carcinoma and melanoma. There were also a variety of other histologies, such as soft tissue sarcomas.

The 126 patients in these studies had a total of 488 individual tumors treated at any time during the trials. For the cancer subgroups, the median tumor volumes for the MTT of patients with breast and melanoma were similar (3.2 and 3.5 cm3, respectively), whereas the median tumor volumes for the esophageal and "other" categories of cancers were larger (8.4 cm3and 26.2 cm3, respectively).

Table A6-3: Tumor Characteristics

Cancer Subgroup

Breast

Melanoma

Esophageal

Other

No. of MTT treated

29

28

24

45

Median baseline MTT volume (cm3) (range)

3.2
(0.4–412.5)

3.5
(0.1–200.6)

8.4
(0.7–124.0)

26.2
(0.5–1400)

No. of individual tumors, total

99

254

35

100

Baseline tumor volume (cm3)

median (range)

0.7
(<0.5–412.5)

<0.5
(<0.5–200.6)

3.0
(<0.5–124.0)

1.8
(<0.5–1400)

2.1.4. Dosing

In the overall study sample, the median dose of CDDP/epi gel per treatment visit was 1.39 mL and the median cumulative dose was 6.15 mL for MTTs of median size 6.5 cm3. The median fraction of assigned dose administered to the MTT was 59% per treatment visit and 56% cumulatively.

 

Table A6-4: Summary of Dosing

 

Cancer Subgroup

 

Variable

Breast

(n=29)

Melanoma

(n=28)

Esophageal

(n=24)

Other

(n=45)

Overall

(n=126)

Dose (mL) administered per baseline tumor volume (cm3)

Per treatment visit

median

0.16

0.29

0.23

0.10

0.16

range

0.013-1.80

0.041-1.05

0.020-0.90

0.002-0.72

0.002-1.80

Cumulative

median

0.99

1.33

0.88

0.50

0.92

range

0.075-12.60

0.244-12.00

0.040-4.12

0.012-4.35

0.012-12.60

Dose (mL) administered

Per treatment visit

median

0.90

1.19

1.98

3.00

1.39

range

0.06-5.17

0.05-8.17

0.13-4.20

0.09-10.00

0.05-10.00

Cumulative

median

3.60

5.21

5.45

10.00

6.15

range

0.25-31.00

0.25-49.00

0.40-25.20

0.22-190.2

0.22-190.2

No. of treatments

median

2

3

3

3

3

range

1-7

1-12

1-6

1-21

1-21

2.2. Primary Endpoints

The primary efficacy variable for the uncontrolled trials 403 and 503 was:

The association of Patient Benefit with response of the MTT was a key efficacy analysis and is described following the discussions of MTT response and Patient Benefit.

2.2.1. Response of the MTT

Complete or partial response of the MTT of at least 28-day duration occurred in 35% of 124 patients treated with CDDP/epi gel. The response rate was highest in breast cancer (50%) and similar in all other groups (29-33%). The response rate was higher for smaller tumors. For responders, the median time to onset of response was 21 days and the median duration was 85 days (range, 29-637 days).

Of 44 responders to CDDP/epi gel, 35 (80%) continued in local remission at the time of study withdrawal or start of a potentially confounding therapy. Many of these patients who experienced tumor response due to local CDDP/epi gel treatment were not able to extend their participation in the study beyond a few months, due to systemic disease progression, general physical debilitation, or death. The mean time to progression of the MTT for all patients was just over 7 months (214 days, SE 11.0).

 

Table A6-5: Response of the MTT

 

Breast

(n=28)

Esophageal

(n=24)

Melanoma

(n=27)

Other

(n=45)

Total

(n=124)

Response Rate

(CR+PR)

14 (50%)

7 (29%)

9 (8d) (33%)

14 (31%)

44 (43d) (35%)

CR

6 (21%)

0

5 (19%)

8 (18%)

19 (15%)

PR

8 (29%)

7 (29%)

4 (15%)

6 (13%)

25 (20%)

Time to Response (days)

Mean (SD)

48

(75.1)

12

(6.5)

66

(44.2)

45

(42.3)

45

(53.7)

Median (range)

25

(7–294)

8

(7–21)

62

(13–126)

30

(7–122)

21

(7–294)

Duration of Response (days)

Mean (SD)

96

(51.3)

75

(31.9)

163

(213.2)

165

(158.0)

128

(133.3)

Median (range)

82

(29-211)

84

(29-120)

72.5

(30-632)

101

(29-637)

85

(29-637)

2.2.2. Patient Benefit

Attainment of Patient Benefit was based on achievement of prospectively selected Primary Treatment Goals, according to the Treatment Goal Questionnaire and the Patient Benefit Algorithm, as described.

The overall rate of attainment of Patient Benefit for the 124 patients in the uncontrolled studies was 31%. In the esophageal cancer subgroup, investigator-selected Primary Treatment Goals were related to obstruction for all patients: for 22 of 24 patients, the goal was relief of obstruction, and for the remaining two patients, the goal was prevention of obstruction. Likewise in this subgroup, the patient-selected goal for almost all patients was relief of obstructive symptoms (22/24 = 92%); for the remaining two patients, the primary goal was pain relief.

Table A6-6: Percent of Patients who Attained Patient Benefit)

Subgroup

n

Benefit Rate (%)

Breast

28

39%

Esophageal

24

21%

Melanoma

27

30%

Other

45

33%

Total

124

31%

2.2.3. Association of Primary Endpoints

Of the 126 patients treated with CDDP/epi gel in Studies 403 and 503, 35% were responders. Of the responders, 52% attained Patient Benefit, and of the nonresponders, 20% attained Patient Benefit. The association between Patient Benefit and response of the MTT was statistically significant (p < 0.001). For the subgroups of breast cancer and "other" cancers, the association was also statistically significant. In all cancer subgroups, the percentage of patients who attained Patient Benefit was higher in MTT responders than in nonresponders.

Table A6-7: Association of Tumor Response and Patient Benefit

Responder

Nonresponder

p-value

n

(%)

n

(%)

Breast (n=28)

Benefitter

9

64%

2

14%

0.033 a

Non-benefitter

5

36%

12

86%

Esophageal (n=24)

Benefitter

2

29%

3

18%

0.55 a

Non-benefitter

5

71%

14

82%

Melanoma (n=27)

Benefitter

3

33%

5

28%

1 a

Non-benefitter

6

67%

13

72%

Other (n=45)

Benefitter

9

64%

6

19%

0.005 a

Non-benefitter

5

36%

25

81%

Total (n=124)

Benefitter

23

52%

16

20%

0.0001 a

Non-benefitter

21

48%

64

80%

a Exact Cochran-Mantel-Haenszel test

3. Conclusions of Uncontrolled Studies

Treatment with CDDP/epi gel effectively:

The association between Patient Benefit and tumor response was statistically significant (p < 0.001). In all cancer subgroups, the percentage of patients who attained Patient Benefit was higher in responders than in nonresponders.