Clinical trial NCT01838200: Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) Followed by Ipilimumab in Advanced Metastatic Melanoma
Official title: A Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) and Followed by Ipilimumab Therapy in Patients With Advanced Metastatic Melanoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Metastatic Melanoma
Keywords: BCG
Bacillus Calmette-Guérin
Ipilimumab
YERVOY
Advanced Metastatic Melanoma
Metastatic Melanoma
Lead sponsor: Ludwig Institute for Cancer Research
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2013-04-23
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Patients With Treatment-emergent Adverse Events
timeFrame: Continuously for up to 5 months
Secondary outcomes:
measure: Number of Patients With Best Overall Clinical Tumor Response
timeFrame: Up to 5 months
measure: Number of Patients With Best Overall Immune-related Tumor Response
timeFrame: Up to 5 months
Other outcomes:
Locations:
city: Heidelberg
country: Australia
facility: Austin Health, LICR Melbourne Austin Branch
state: Victoria
Study officials:
affiliation: Austin Health
name: Jonathan Cebon, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.