A Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) and Followed by Ipilimumab Therapy in Patients With Advanced Metastatic Melanoma

This study is currently recruiting participants.
Verified May 2013 by Ludwig Institute for Cancer Research
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Ludwig Institute for Cancer Research
ClinicalTrials.gov Identifier:
NCT01838200
First received: April 17, 2013
Last updated: May 28, 2013
Last verified: May 2013
  Purpose

This is an open-label, dose-escalation, non-randomized, phase I study in patients with histologically confirmed Stage III or IV melanoma and at least three metastatic cutaneous or subcutaneous lesions suitable for: intralesional (IL) injection (1 lesion), accessible for biopsy (1 lesion), and response evaluation by RECIST (v1.1) and modified RECIST (irRC) (1 lesion). The primary objective is to determine whether IL administration of BCG followed by intravenous (IV) infusion of ipilimumab is safe. Ipilimumab (YERVOY®) is the monoclonal anti-CTLA-4 antibody approved by the FDA and TGA as anticancer therapy for melanoma. Secondary objectives of the study are: a) clinical efficacy, to document whether this combination therapy induces tumour responses; and b) immunogenicity, to identify if the combination induces immune responses against the tumours. All patients will be included in the analysis of efficacy and immunogenicity.

Cohort 1 (9 patients with <10mm induration after tuberculin Purified Protein Derivative [PPD] test): Group 1 (3 patients) will receive one IL injection of 200 µl BCG containing 0.16 - 0.64 x 106 cfu followed by four IV infusions of 3 mg/kg ipilimumab every 3 weeks, starting on day 36. Group 2 (3 patients) and 3 (n=3) will receive 200 µl BCG containing 0.8 - 3.2 x 106 cfu and 4.0 -16.0 x 106 cfu, respectively, followed by the same ipilimumab regimen. Safety will be evaluated in this cohort.

Cohort 2 (up to 9 patients with ≥10mm induration after PPD test): Enrolment will start after the final patient in Cohort 1, Group 1 has reached study week 7. Then enrolment can proceed in parallel for Cohort 2 and Cohort 1 Groups 2 and 3. Patients will receive 0.16 -0.64 x 106 cfu BCG followed by four IV infusions of 3 mg/kg ipilimumab every 3 weeks, starting on day 36. Evaluation of safety in this cohort will be observational.


Condition Intervention Phase
Metastatic Melanoma
Biological: Bacillus Calmette-Guérin (BCG) vaccine
Drug: Ipilimumab
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) and Followed by Ipilimumab Therapy in Patients With Advanced Metastatic Melanoma

Resource links provided by NLM:


Further study details as provided by Ludwig Institute for Cancer Research:

Primary Outcome Measures:
  • Safety [ Time Frame: 30 weeks ] [ Designated as safety issue: Yes ]
    Adverse events as defined by CTCAE Version 4.0


Secondary Outcome Measures:
  • Clinical Efficacy as measured by tumor response [ Time Frame: 30 weeks ] [ Designated as safety issue: No ]
    Tumor response as accessed by RECIST v1.1 and immune-related response criteria (irRC)

  • Immunogenicity: Humoral Immunity [ Time Frame: Day 1, 36, 78, 113, 141, 204 ] [ Designated as safety issue: No ]
    Induced antibodies from peripheral blood will analyzed by ELISA for NY-ESO-1 and Melan-A, and by proteomics chips for other tumor antigens.

  • Immunogenicty: Cellular Immunity [ Time Frame: Day 1, 36, 43, 57, 78, 113, 141, 204 ] [ Designated as safety issue: No ]
    Antigens for cellular immunity will be selected on the basis of serological responses identified through ELISA and proteomic chips.

  • Immunogencity; In situ Immunity [ Time Frame: Screening, Day 36, 43, 204 ] [ Designated as safety issue: No ]
    Optional Tumor samples will be collect for exploratory analyses


Estimated Enrollment: 18
Study Start Date: April 2013
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1

Cohort 1 will include patients with an induration <10 mm in diameter after the pre-study PPD reactivity test. These patients will be enrolled into 3 groups sequentially, each given a single dose IL dose of BCG vaccine into a single selected melanoma lesion on Study Day 1. Each group will include 3 patients to be given a BCG at 16 - 0.64 x 106 cfu BCG (200 µl volume), 0.8 - 3.2 x 106 cfu BCG (200 µl volume), and 4.0 - 16.0 x 106 cfu BCG (200 µl volume)for groups 1, 2, and 3 respectively

All patients in these 3 groups will receive 300 mg daily doses of Isoniazid, commencing 28 days following the BCG injection and continuing for 4 weeks, and Ipilimumab administered intravenously starting 5 weeks after BCG, on Day 36. Four doses of 3 mg/kg ipilimumab are to be given every 3 weeks.

Biological: Bacillus Calmette-Guérin (BCG) vaccine
Bacillus Calmette-Guérin (BCG) is a living attenuated strain of Mycobacterium bovis that stimulates cell-mediated immunity by producing a localized and self-limiting infection. BCG is used worldwide for vaccination against tuberculosis. BCG is an immunostimulating agent that has been also shown to have anti-tumour activity in several clinical studies. The exact mechanism of action is not well known, but study data suggest that active non-specific immune responses are induced. It is probable that BCG invokes a local inflammatory response involving a variety of immune cells, such as macrophages, natural killer cells and T cells
Other Name: BCG
Drug: Ipilimumab
Ipilimumab is a human CTLA-4-blocking antibody, designed to suppress the CTLA-4 inhibition of T cells. Ipilimumab is marketed by Bristol-Myers-Squibb under the name Yervoy® and was first approved by the FDA and TGA in 2011 for the treatment of unresectable or metastatic melanoma
Other Name: YERVOY
Experimental: Cohort 2
Cohort 2 will include maximum 9 patients with a pre-study PPD reactivity to tuberculin that is ≥10 mm. Patients will receive 0.16 - 0.64 x 106 cfu BCG (200 µl volume) followed by administration of 300 mg daily doses of Isoniazid, commencing 28 days after the BCG and continuing for 4 weeks. Ipilimumab is administered intravenously starting 5 weeks after BCG, on Day 36. Four doses of (3 mg/kg) ipilimumab are to be given every 3 weeks.
Biological: Bacillus Calmette-Guérin (BCG) vaccine
Bacillus Calmette-Guérin (BCG) is a living attenuated strain of Mycobacterium bovis that stimulates cell-mediated immunity by producing a localized and self-limiting infection. BCG is used worldwide for vaccination against tuberculosis. BCG is an immunostimulating agent that has been also shown to have anti-tumour activity in several clinical studies. The exact mechanism of action is not well known, but study data suggest that active non-specific immune responses are induced. It is probable that BCG invokes a local inflammatory response involving a variety of immune cells, such as macrophages, natural killer cells and T cells
Other Name: BCG
Drug: Ipilimumab
Ipilimumab is a human CTLA-4-blocking antibody, designed to suppress the CTLA-4 inhibition of T cells. Ipilimumab is marketed by Bristol-Myers-Squibb under the name Yervoy® and was first approved by the FDA and TGA in 2011 for the treatment of unresectable or metastatic melanoma
Other Name: YERVOY

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed stage III (unresectable) or stage IV melanoma
  • Minimum one metastatic lesion, cutaneous or subcutaneous, but ideally three or more lesions, to accommodate IL injection (1 lesion), accessibility for biopsy (1 lesion), and evaluability for response by RECIST v.1.1 (1 lesion) and modified RECIST (irRC).
  • Performance status of ECOG 0-1
  • Within the last 2 weeks prior to study day 1, vital laboratory parameters should be within normal range, except for the following laboratory parameters, which should be within the ranges specified:

Haemoglobin: ≥ 100 g/L, Platelets: ≥ 100 x 10^9/L, INR: ≤ 2.0, Creatinine: ≤ 120 µmol/L, Bilirubin: ≤ 30 µmol/L, eGFR: > 0.75 x LLN, ALT/AST: ≤ 2.0 x ULN, Albumin: > 28 g/L, Neutrophils: > 1.5 x 10^9/L, Lymphocytes: > 0.9 x 10^9/L,

Exclusion Criteria:

  • Active cerebral metastases unless stable after radiation for at least one month and not requiring corticosteroid treatment for 30 days prior to enrolment
  • 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, are excluded from this study, as are patients with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia Gravis). Exceptions: vitiligo, type I diabetes, pernicious anaemia (treated).
  • Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of 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 CTLA4 inhibitor
  • Concomitant therapy with any of the following: IL-2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids
  • Known HIV 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.
  • articipation in any other clinical trial involving another investigational agent within 4 weeks prior to first dosing.
  • Mental impairment that may compromise the ability to give informed consent and to comply with the requirements of the study.
  • Women who are pregnant (positive pregnancy test at baseline), or breastfeeding
  • 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.
  • Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01838200

Contacts
Contact: Linda Pan, PharmD 212-450-1581 lpan@licr.org

Locations
Australia, Victoria
Austin Health, LICR Melbourne Austin Branch Recruiting
Heidelberg, Victoria, Australia, 2084
Contact: Noel Micallef    +61 3 9496 3088    Noel.MICALLEF@austin.org.au   
Principal Investigator: Jonathan Cebon, MBBS, FRACP, PhD         
Sponsors and Collaborators
Ludwig Institute for Cancer Research
Bristol-Myers Squibb
Investigators
Principal Investigator: Jonathan Cebon, MBBS, FRACP, PhD Austin Health
  More Information

No publications provided

Responsible Party: Ludwig Institute for Cancer Research
ClinicalTrials.gov Identifier: NCT01838200     History of Changes
Other Study ID Numbers: LUD2012-003
Study First Received: April 17, 2013
Last Updated: May 28, 2013
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by Ludwig Institute for Cancer Research:
BCG
Bacillus Calmette-Guérin
Ipilimumab
YERVOY
Advanced Metastatic Melanoma
Metastatic Melanoma

Additional relevant MeSH terms:
Nevi and Melanomas
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
BCG Vaccine
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 14, 2014