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

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.