Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) Followed by Ipilimumab in Advanced Metastatic Melanoma

Study Overview
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Brief Summary
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This was a Phase 1, open-label, dose-escalation, single-center study in patients with histologically confirmed Stage III or IV melanoma and at least 3 metastatic cutaneous or subcutaneous lesions that were suitable and accessible for intralesional (IL) injection (1 lesion), biopsy (1 lesion), and response evaluation (1 lesion). The primary objective was to determine the safety of IL administration of bacillus Calmette-Guerin (BCG) followed by oral dosing with an antibiotic (isoniazid) and intravenous (IV) infusions of ipilimumab. Secondary objectives were to evaluate the clinical efficacy (induction of tumor response) and immunogenicity (induction of immune response against the tumors) of the combination regimen.

Detailed Description
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Patients were enrolled into one of two study cohorts depending on the induration noted after a baseline purified protein derivative (PPD) skin test to determine tuberculin reactivity. Cohort 1 comprised patients with an induration of <10mm in diameter, and Cohort 2 comprised patients with an induration of ≥10mm. Enrollment was staggered by 3 weeks for each of the first 3 patients in Cohort 1, Group 1 to enable safety monitoring of each patient prior to exposure of additional patients. In all cohorts, study treatment included BCG (200 µL volume) given IL on Day 1, isoniazid (300 mg) given orally daily from Days 29 to 56, and ipilimumab (3 mg/kg) given IV every 3 weeks (± 3 days) on Days 36, 57, 78, and 99. The dose of BCG varied by assigned treatment group: Cohort 1, Group 1 received 0.16 - 0.64 × 10^6 colony-forming units (CFU); Cohort 1, Group 2 received 0.8 - 3.2 x 10^6 CFU; Cohort 1, Group 3 was to receive 4.0 - 16.0 x 10^6 CFU; and Cohort 2 was to receive 0.16 - 0.64 × 10^6 CFU. Enrollment into Cohort 2 was to be initiated after the final patient in Cohort 1, Group 1 reached Week 7. Enrollment was then to proceed in parallel for Cohort 2 and Cohort 1, Groups 2 and 3. Patients were monitored for safety, tumor response, and immunogenicity (cellular, humoral, and in situ immunity) for the duration of study participation.

Official Title
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A Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) and Followed by Ipilimumab Therapy in Patients With Advanced Metastatic Melanoma

Conditions
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Metastatic Melanoma

Intervention / Treatment
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* Biological: Bacillus Calmette-Guérin (BCG) vaccine
* Drug: Ipilimumab
* Drug: Isoniazid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed stage III (unresectable) or stage IV melanoma. Minimum 1 metastatic lesion, cutaneous or subcutaneous, but ideally 3 or more lesions, to accommodate intralesional injection (1 lesion), accessibility for biopsy (1 lesion), and evaluability for response by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (1 lesion) and modified RECIST (immune-related response criteria [irRC]). Performance status of Eastern Cooperative Oncology Group 0-1. Within the last 2 weeks prior to study Day 1, vital laboratory parameters must have been within normal ranges, except for the following laboratory parameters, which must have been within the ranges specified: Hemoglobin: ≥ 100 g/L Platelets: ≥ 100 x 10^9/L International normalized ratio: ≤ 2.0 Creatinine: ≤ 120 µmol/L Bilirubin: ≤ 30 µmol/L Estimated glomerular filtration rate: > 0.75 x lower limit of normal Aspartate and alanine aminotransferase: ≤ 2.0 x upper limit of normal Albumin: > 28 g/L Neutrophils: > 1.5 x 10^9/L Lymphocytes: > 0.5 x 10^9/L Estimated life expectancy of at least 4 to 6 months. Because of the slow onset of action of ipilimumab and the protocol requirement for a 5-week delay post-BCG, patients with rapidly progressive disease may not have been suitable for the protocol. Full recovery from surgery. A minimum of 2 weeks should have elapsed since the most recent surgery. Men and women ≥ 18 years of age. Able and willing to give written informed consent. Exclusion Criteria: Active cerebral metastases unless stable after radiation for at least 1 month and not requiring corticosteroid treatment for 30 days prior to enrollment. Other known malignancy within 3 years prior to entry into the study, except for treated non-melanoma skin cancer and cervical carcinoma in situ. History of tuberculosis. History of hypersensitivity to BCG. Any contraindication to the use of isoniazid. Generalized skin disease. Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, were excluded from this study, as were patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis). Exceptions: vitiligo, type I diabetes, pernicious anemia (treated). Any underlying medical or psychiatric condition, which in the opinion of the Investigator would have made the administration of ipilimumab hazardous or obscured the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea. Prior immunotherapy or systemic adjuvant therapy for melanoma following most recent relapse and/or resection of melanoma. Prior treatment with a cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitor. Concomitant therapy with any of the following: interleukin 2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids. Known human immunodeficiency virus positivity, Hepatitis B or Hepatitis C. Chemotherapy or radiation therapy within the preceding 4 weeks (6 weeks for nitrosourea drugs). Lack of availability for immunological and clinical follow-up assessments. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first dosing. Mental impairment that may have compromised the ability to give informed consent and to comply with the requirements of the study. Women who were pregnant (positive pregnancy test at baseline), or breastfeeding. Men and women unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 8 weeks after cessation of study drug. Prisoners or patients who were compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU)<br>Patients with an induration <10 mm in diameter after the baseline PPD reactivity test received BCG (IL) on Day 1, followed by isoniazid (orally, daily) starting 28 days after the BCG injection and continuing for 4 weeks, and ipilimumab (IV) administered every 3 weeks starting 5 weeks after the BCG injection and continuing for a total of 4 doses. | Biological: Bacillus Calmette-Guérin (BCG) vaccine<br>* BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.<br>* Other names: BCG;Drug: Ipilimumab<br>* Ipilimumab was to be administered as a 90-minute IV infusion at a dose of 3 mg/kg every 3 weeks (± 3 days) on Days 36, 57, 78, and 99.<br>* Other names: YERVOY;Drug: Isoniazid<br>* Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.<br>|
| Experimental: Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU)<br>Patients with an induration <10 mm in diameter after the baseline PPD reactivity test received BCG (IL) on Day 1, followed by isoniazid (orally, daily) starting 28 days after the BCG injection and continuing for 4 weeks, and ipilimumab (IV) administered every 3 weeks starting 5 weeks after the BCG injection and continuing for a total of 4 doses. | Biological: Bacillus Calmette-Guérin (BCG) vaccine<br>* BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.<br>* Other names: BCG;Drug: Ipilimumab<br>* Ipilimumab was to be administered as a 90-minute IV infusion at a dose of 3 mg/kg every 3 weeks (± 3 days) on Days 36, 57, 78, and 99.<br>* Other names: YERVOY;Drug: Isoniazid<br>* Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.<br>|
| Experimental: Cohort 1, Group 3 (BCG 4.0-16.0 × 10^6 CFU)<br>Patients with an induration <10 mm in diameter after the baseline PPD reactivity test were to receive BCG (IL) on Day 1, followed by isoniazid (orally, daily) starting 28 days after the BCG injection and continuing for 4 weeks, and ipilimumab (IV) administered every 3 weeks starting 5 weeks after the BCG injection and continuing for a total of 4 doses. | Biological: Bacillus Calmette-Guérin (BCG) vaccine<br>* BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.<br>* Other names: BCG;Drug: Ipilimumab<br>* Ipilimumab was to be administered as a 90-minute IV infusion at a dose of 3 mg/kg every 3 weeks (± 3 days) on Days 36, 57, 78, and 99.<br>* Other names: YERVOY;Drug: Isoniazid<br>* Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.<br>|
| Experimental: Cohort 2 (BCG 0.16-0.64 × 10^6 CFU)<br>Patients with an induration ≥10 mm in diameter after the baseline PPD reactivity test were to receive BCG (IL) on Day 1, followed by isoniazid (orally, daily) starting 28 days after the BCG injection and continuing for 4 weeks, and ipilimumab (IV) administered every 3 weeks starting 5 weeks after the BCG injection and continuing for a total of 4 doses. | Biological: Bacillus Calmette-Guérin (BCG) vaccine<br>* BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.<br>* Other names: BCG;Drug: Ipilimumab<br>* Ipilimumab was to be administered as a 90-minute IV infusion at a dose of 3 mg/kg every 3 weeks (± 3 days) on Days 36, 57, 78, and 99.<br>* Other names: YERVOY;Drug: Isoniazid<br>* Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Treatment-emergent Adverse Events | Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Treatment-emergent adverse events (TEAEs) were reported based on clinical laboratory tests, physical examinations, and vital signs from pre-treatment through the study period. Dose-limiting toxicity (DLT) for BCG was defined as any ≥ Grade 3 local injection site reaction (ulceration or necrosis requiring operative intervention), and DLT for ipilimumab was defined as any toxicity that required dosing modifications in accordance with the recommendations in the local product labelling, or any ≥ Grade 3 hematologic or nonhematologic toxicity that was definitely, probably, or possibly related to the administration of ipilimumab. | Continuously for up to 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Best Overall Clinical Tumor Response | Tumor responses were evaluated using computed tomography and clinical photography at Baseline, Weeks 6, 17, 21, and 30 (± 3-day window for each assessment), and at the end of the study. Tumor response was designated according to the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1). Per RECIST, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions (no evaluable disease); Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. | Up to 5 months | 
| Number of Patients With Best Overall Immune-related Tumor Response | Immune-related tumor responses were evaluated using computed tomography and clinical photography at Baseline, Weeks 6, 17, 21, and 30 (± 3-day window for each assessment), and at the end of the study. Tumor response was designated according to the immune-related Response Criteria (irRC) (Wolchok et al. Clin Cancer Res 2009;15:7412-20) into the following categories: immune-related complete response (irCR) requires disappearance of all lesions in two consecutive observations not less than 4 weeks apart; immune-related partial response (irPR) requires ≥ 50% decrease in tumor burden compared with baseline in two observations at least 4 weeks apart; immune-related stable disease (irSD) is assigned when neither a 50% decrease from baseline tumor burden nor a 25% increase in tumor burden from nadir can be established; immune-related progressive disease (irPD) requires a ≥ 25% increase from nadir in tumor burden at any single time point in two consecutive observations at least 4 weeks apart. | Up to 5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ipilimumab, YERVOY, Advanced Metastatic Melanoma, Metastatic Melanoma, BCG, Bacillus Calmette-Guérin