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

NCT ID: NCT01838200

Last Updated: 2022-10-12

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-03-31
• Study Completion Date: 2015-08-17

Brief Summary

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

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.

Conditions

Metastatic Melanoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU)

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.

Group Type: EXPERIMENTAL

Bacillus Calmette-Guérin (BCG) vaccine

Intervention Type: BIOLOGICAL

BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.

Ipilimumab

Intervention Type: DRUG

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.

Isoniazid

Intervention Type: DRUG

Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.

Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU)

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.

Group Type: EXPERIMENTAL

Bacillus Calmette-Guérin (BCG) vaccine

Intervention Type: BIOLOGICAL

BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.

Ipilimumab

Intervention Type: DRUG

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.

Isoniazid

Intervention Type: DRUG

Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.

Cohort 1, Group 3 (BCG 4.0-16.0 × 10^6 CFU)

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.

Group Type: EXPERIMENTAL

Bacillus Calmette-Guérin (BCG) vaccine

Intervention Type: BIOLOGICAL

BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.

Ipilimumab

Intervention Type: DRUG

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.

Isoniazid

Intervention Type: DRUG

Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.

Cohort 2 (BCG 0.16-0.64 × 10^6 CFU)

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.

Group Type: EXPERIMENTAL

Bacillus Calmette-Guérin (BCG) vaccine

Intervention Type: BIOLOGICAL

BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.

Ipilimumab

Intervention Type: DRUG

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.

Isoniazid

Intervention Type: DRUG

Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.

Interventions

Bacillus Calmette-Guérin (BCG) vaccine

BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.

Intervention Type: BIOLOGICAL

Ipilimumab

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.

Intervention Type: DRUG

Isoniazid

Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.

Intervention Type: DRUG

Other Intervention Names

BCG; YERVOY

Eligibility Criteria

Inclusion Criteria

1. Histologically confirmed stage III (unresectable) or stage IV melanoma.

2. 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]).

3. Performance status of Eastern Cooperative Oncology Group 0-1.

4. 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

5. 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.

6. Full recovery from surgery. A minimum of 2 weeks should have elapsed since the most recent surgery.

7. Men and women ≥ 18 years of age.

8. Able and willing to give written informed consent.

Exclusion Criteria

1. Active cerebral metastases unless stable after radiation for at least 1 month and not requiring corticosteroid treatment for 30 days prior to enrollment.

2. Other known malignancy within 3 years prior to entry into the study, except for treated non-melanoma skin cancer and cervical carcinoma in situ.

3. History of tuberculosis.

4. History of hypersensitivity to BCG.

5. Any contraindication to the use of isoniazid.

6. Generalized skin disease.

7. 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).

8. 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.

9. Prior immunotherapy or systemic adjuvant therapy for melanoma following most recent relapse and/or resection of melanoma.

10. Prior treatment with a cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitor.

11. 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.

12. Known human immunodeficiency virus positivity, Hepatitis B or Hepatitis C.

13. Chemotherapy or radiation therapy within the preceding 4 weeks (6 weeks for nitrosourea drugs).

14. Lack of availability for immunological and clinical follow-up assessments.

15. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first dosing.

16. Mental impairment that may have compromised the ability to give informed consent and to comply with the requirements of the study.

17. Women who were pregnant (positive pregnancy test at baseline), or breastfeeding.

18. 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.

19. Prisoners or patients who were compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

Ludwig Institute for Cancer Research

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jonathan Cebon, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Austin Health

Locations

Austin Health, LICR Melbourne Austin Branch

Heidelberg, Victoria, Australia

Countries

Australia

References

Da Gama Duarte J, Parakh S, Andrews MC, Woods K, Pasam A, Tutuka C, Ostrouska S, Blackburn JM, Behren A, Cebon J. Autoantibodies May Predict Immune-Related Toxicity: Results from a Phase I Study of Intralesional Bacillus Calmette-Guerin followed by Ipilimumab in Patients with Advanced Metastatic Melanoma. Front Immunol. 2018 Mar 2;9:411. doi: 10.3389/fimmu.2018.00411. eCollection 2018.

Reference Type: DERIVED

PMID: 29552014 (View on PubMed)

Other Identifiers

LUD2012-003

Identifier Type: -

Identifier Source: org_study_id