Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) Followed by Ipilimumab in Advanced Metastatic Melanoma
Condition: Metastatic Melanoma
MeSH terms: Melanoma
Intervention: Bacillus Calmette-Guérin (BCG) vaccine; Ipilimumab; Isoniazid
Intervention description: BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.; 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 was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.
Intervention MeSH terms: Isoniazid; Ipilimumab; BCG Vaccine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: BCG; Bacillus Calmette-Guérin; Ipilimumab; YERVOY; Advanced Metastatic Melanoma; Metastatic Melanoma

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.
    

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.