Metastatic Melanoma
Conditions
Keywords
BCG, Bacillus Calmette-Guérin, Ipilimumab, YERVOY, Advanced Metastatic Melanoma, Metastatic Melanoma
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.
Interventions
BIOLOGICALBacillus Calmette-Guérin (BCG) vaccine
BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.
DRUGIpilimumab
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.
DRUGIsoniazid
Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.
Sponsors
Bristol-Myers Squibb
Ludwig Institute for Cancer Research
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Treatment-emergent Adverse Events | Continuously for up to 5 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Best Overall Clinical Tumor Response | Up to 5 months | Tumor responses were evaluated using computed tomography and clinical photography at Baseline, Weeks 6, 17, 21, and 30 (± 3-day window for each assessment), and at the end of the study. Tumor response was designated according to the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1). Per RECIST, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions (no evaluable disease); Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. |
| Number of Patients With Best Overall Immune-related Tumor Response | Up to 5 months | Immune-related tumor responses were evaluated using computed tomography and clinical photography at Baseline, Weeks 6, 17, 21, and 30 (± 3-day window for each assessment), and at the end of the study. Tumor response was designated according to the immune-related Response Criteria (irRC) (Wolchok et al. Clin Cancer Res 2009;15:7412-20) into the following categories: immune-related complete response (irCR) requires disappearance of all lesions in two consecutive observations not less than 4 weeks apart; immune-related partial response (irPR) requires ≥ 50% decrease in tumor burden compared with baseline in two observations at least 4 weeks apart; immune-related stable disease (irSD) is assigned when neither a 50% decrease from baseline tumor burden nor a 25% increase in tumor burden from nadir can be established; immune-related progressive disease (irPD) requires a ≥ 25% increase from nadir in tumor burden at any single time point in two consecutive observations at least 4 weeks apart. |
Countries
Australia
Participant flow
Pre-assignment details
The study was terminated early due to slow enrollment; thus, Cohort 1 Group 3 and Cohort 2 were not enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) Patients with an induration \<10 mm in diameter after the baseline PPD reactivity test received BCG (IL, 200 µL volume) at a dose of 0.16 - 0.64 × 10\^6 CFU on Day 1. Isoniazid (300 mg) was administered orally every day from Days 29 through 56. Ipilimumab (3 mg/kg) was administered as a 90-minute IV infusion every 3 weeks (± 3 days) on Days 36, 57, 78, and 99. | 3 |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) Patients with an induration \<10 mm in diameter after the baseline PPD reactivity test received BCG (IL, 200 µL volume) at a dose of 0.8 - 3.2 × 10\^6 CFU on Day 1. Isoniazid (300 mg) was administered orally every day from Days 29 through 56. Ipilimumab (3 mg/kg) was administered as a 90-minute IV infusion every 3 weeks (± 3 days) on Days 36, 57, 78, and 99. | 2 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Progressive disease | 3 | 0 |
Baseline characteristics
| Characteristic | Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Total |
|---|---|---|---|
| Age, Continuous | 61.3 years | 53.5 years | 58.2 years |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline 0 | 2 Participants | 0 Participants | 2 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline 1 | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Australia | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 2 / 3 | 1 / 2 |
Outcome results
Primary
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.
Time frame: Continuously for up to 5 months
Population: The Safety Analysis Set includes all patients who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Ipilimumab-related TEAE | 1 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Maximum grade 3 TEAE | 2 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Isoniazid-related TEAE | 0 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Serious TEAE | 2 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Any TEAE | 3 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | TEAE Leading to BCG Discontinuation | 0 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Maximum grade 4 TEAE | 0 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | TEAE Leading to Ipilimumab Discontinuation | 1 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Maximum grade 2 TEAE | 1 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | TEAE Leading to Isoniazid Discontinuation | 0 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | BCG-related TEAE | 0 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | TEAE Meeting DLT Criteria | 0 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Maximum grade 1 TEAE | 0 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | TEAE Meeting DLT Criteria | 2 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Any TEAE | 2 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Maximum grade 1 TEAE | 0 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Maximum grade 2 TEAE | 0 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Maximum grade 3 TEAE | 1 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Maximum grade 4 TEAE | 1 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | BCG-related TEAE | 1 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Ipilimumab-related TEAE | 2 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Serious TEAE | 1 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | TEAE Leading to BCG Discontinuation | 0 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | TEAE Leading to Ipilimumab Discontinuation | 2 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | TEAE Leading to Isoniazid Discontinuation | 0 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Treatment-emergent Adverse Events | Isoniazid-related TEAE | 0 Participants |
Secondary
Number of Patients With Best Overall Clinical Tumor Response
Tumor responses were evaluated using computed tomography and clinical photography at Baseline, Weeks 6, 17, 21, and 30 (± 3-day window for each assessment), and at the end of the study. Tumor response was designated according to the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1). Per RECIST, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions (no evaluable disease); Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria.
Time frame: Up to 5 months
Population: The Efficacy Analysis Set includes all patients who received at least 1 dose of study treatment and had response evaluated through Week 17.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Best Overall Clinical Tumor Response | Best response: SD | 2 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Best Overall Clinical Tumor Response | Best response: PD | 1 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Best Overall Clinical Tumor Response | Best response: SD | 0 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Best Overall Clinical Tumor Response | Best response: PD | 2 Participants |
Secondary
Number of Patients With Best Overall Immune-related Tumor Response
Immune-related tumor responses were evaluated using computed tomography and clinical photography at Baseline, Weeks 6, 17, 21, and 30 (± 3-day window for each assessment), and at the end of the study. Tumor response was designated according to the immune-related Response Criteria (irRC) (Wolchok et al. Clin Cancer Res 2009;15:7412-20) into the following categories: immune-related complete response (irCR) requires disappearance of all lesions in two consecutive observations not less than 4 weeks apart; immune-related partial response (irPR) requires ≥ 50% decrease in tumor burden compared with baseline in two observations at least 4 weeks apart; immune-related stable disease (irSD) is assigned when neither a 50% decrease from baseline tumor burden nor a 25% increase in tumor burden from nadir can be established; immune-related progressive disease (irPD) requires a ≥ 25% increase from nadir in tumor burden at any single time point in two consecutive observations at least 4 weeks apart.
Time frame: Up to 5 months
Population: The Efficacy Analysis Set includes all patients who received at least 1 dose of study treatment and had response evaluated through Week 17.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Best Overall Immune-related Tumor Response | Best response: irSD | 1 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Best Overall Immune-related Tumor Response | Best response: irPD | 2 Participants |
| Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU) | Number of Patients With Best Overall Immune-related Tumor Response | Not evaluable by irRC | 0 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Best Overall Immune-related Tumor Response | Best response: irSD | 1 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Best Overall Immune-related Tumor Response | Best response: irPD | 0 Participants |
| Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU) | Number of Patients With Best Overall Immune-related Tumor Response | Not evaluable by irRC | 1 Participants |