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

NCT01838200 | Terminated Phase 1 Results

• 1 other identifier: LUD2012-003
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Melanoma

Keywords

BCG; Bacillus Calmette-Guérin; Ipilimumab; YERVOY; Advanced Metastatic Melanoma; Metastatic Melanoma

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Number of Patients With Best Overall Clinical Tumor Response

  Up to 5 months

• Number of Patients With Best Overall Immune-related Tumor Response

  Up to 5 months

Study Arms (4)

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

EXPERIMENTAL

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; Drug: Ipilimumab; Drug: Isoniazid

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

EXPERIMENTAL

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; Drug: Ipilimumab; Drug: Isoniazid

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

EXPERIMENTAL

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; Drug: Ipilimumab; Drug: Isoniazid

Cohort 2 (BCG 0.16-0.64 × 10^6 CFU)

EXPERIMENTAL

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; Drug: Ipilimumab; Drug: Isoniazid

Interventions

Bacillus Calmette-Guérin (BCG) vaccine BIOLOGICAL

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

Also known as: BCG

Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU); Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU); Cohort 1, Group 3 (BCG 4.0-16.0 × 10^6 CFU); Cohort 2 (BCG 0.16-0.64 × 10^6 CFU)

Ipilimumab 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.

Also known as: YERVOY

Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU); Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU); Cohort 1, Group 3 (BCG 4.0-16.0 × 10^6 CFU); Cohort 2 (BCG 0.16-0.64 × 10^6 CFU)

Isoniazid 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 1 (BCG 0.16-0.64 × 10^6 CFU); Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU); Cohort 1, Group 3 (BCG 4.0-16.0 × 10^6 CFU); Cohort 2 (BCG 0.16-0.64 × 10^6 CFU)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Ludwig Institute for Cancer Research: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Austin Health, LICR Melbourne Austin Branch

Heidelberg, Victoria, 3084, Australia

Location

Related Publications (1)

• 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.

  PMID: 29552014 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

BCG Vaccine; Ipilimumab; Isoniazid

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Tuberculosis Vaccines; Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Limitations and Caveats

As the study was terminated early due to slow enrollment, immune response (cellular, humoral, in situ) analyses were not performed as outlined in the protocol due to small sample sizes within each arm.

Results Point of Contact

• Title: Jonathan Skipper PhD
• Organization: Ludwig Institute for Cancer Research

jskipper@lcr.org

(212) 450-1539

Study Officials

• Jonathan Cebon, MD, PhD

  Austin Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 17, 2013
• First Posted: April 23, 2013
• Study Start: March 1, 2014
• Primary Completion: August 17, 2015
• Study Completion: August 17, 2015
• Last Updated: October 12, 2022
• Results First Posted: March 28, 2019

Record last verified: 2022-10

Locations

AU (1)