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

• Sponsor: Ludwig Institute for Cancer Research (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01838200
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 5
• Location: 1
• Arms: 4
• Actual Duration (Months): 17.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma	Biological: Bacillus Calmette-Guérin (BCG) vaccine; Drug: Ipilimumab; Drug: Isoniazid	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Actual Study Start Date: Mar 1, 2014
• Actual Primary Completion Date: Aug 17, 2015
• Actual Study Completion Date: Aug 17, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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) 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; BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.; Other Names: BCG ; Drug: Ipilimumab; 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.; Other Names: YERVOY ; Drug: Isoniazid; Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.
Experimental: 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) 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; BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.; Other Names: BCG ; Drug: Ipilimumab; 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.; Other Names: YERVOY ; Drug: Isoniazid; Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.
Experimental: Cohort 1, Group 3 (BCG 4.0-16.0 × 10^6 CFU) 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; BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.; Other Names: BCG ; Drug: Ipilimumab; 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.; Other Names: YERVOY ; Drug: Isoniazid; Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.
Experimental: Cohort 2 (BCG 0.16-0.64 × 10^6 CFU) 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; BCG was to be administered as a single intralesional injection (200 µL volume) on Day 1 at varying doses depending on cohort assignment.; Other Names: BCG ; Drug: Ipilimumab; 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.; Other Names: YERVOY ; Drug: Isoniazid; Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

1. 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.

2. Full recovery from surgery. A minimum of 2 weeks should have elapsed since the most recent surgery.

3. Men and women ≥ 18 years of age.

4. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Austin Health, LICR Melbourne Austin Branch	Heidelberg	Victoria	Australia	3084

Sponsors and Collaborators

• Ludwig Institute for Cancer Research
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Jonathan Cebon, MD, PhD, Austin Health

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ludwig Institute for Cancer Research
• ClinicalTrials.gov Identifier: NCT01838200
• Other Study ID Numbers: LUD2012-003
• First Posted: Apr 23, 2013
• Last Update Posted: Mar 28, 2019
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Ludwig Institute for Cancer Research: BCG; Bacillus Calmette-Guérin; Ipilimumab; YERVOY; Advanced Metastatic Melanoma; Metastatic Melanoma
• Additional relevant MeSH terms: Melanoma; Isoniazid; Ipilimumab; BCG Vaccine

Study Results

Participant Flow

Pre-assignment Detail	The study was terminated early due to slow enrollment; thus, Cohort 1 Group 3 and Cohort 2 were not enrolled.

Arm/Group Title	Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU)	Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU)
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	3	2
COMPLETED	0	0
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	3	2	5
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	61.3	53.5	58.2
Sex: Female, Male (Count of Participants)
Female	1 33.3%	1 50%	2 40%
Male	2 66.7%	1 50%	3 60%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	3 100%	2 100%	5 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	3 100%	2 100%	5 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Australia	3 100%	2 100%	5 100%
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) at Baseline (Count of Participants)
0	2 66.7%	0 0%	2 40%
1	1 33.3%	2 100%	3 60%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Treatment-emergent Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set includes all patients who received at least 1 dose of study treatment.

Arm/Group Title	Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU)	Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU)
Arm/Group Description	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.	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.
Measure Participants	3	2
Any TEAE	3 100%	2 100%
Maximum grade 1 TEAE	0 0%	0 0%
Maximum grade 2 TEAE	1 33.3%	0 0%
Maximum grade 3 TEAE	2 66.7%	1 50%
Maximum grade 4 TEAE	0 0%	1 50%
BCG-related TEAE	0 0%	1 50%
Ipilimumab-related TEAE	1 33.3%	2 100%
Isoniazid-related TEAE	0 0%	0 0%
Serious TEAE	2 66.7%	1 50%
TEAE Leading to BCG Discontinuation	0 0%	0 0%
TEAE Leading to Ipilimumab Discontinuation	1 33.3%	2 100%
TEAE Leading to Isoniazid Discontinuation	0 0%	0 0%
TEAE Meeting DLT Criteria	0 0%	2 100%

2. Secondary Outcome

Title	Number of Patients With Best Overall Clinical Tumor Response
Description	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

Outcome Measure Data

Analysis Population Description

The Efficacy Analysis Set includes all patients who received at least 1 dose of study treatment and had response evaluated through Week 17.

Arm/Group Title	Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU)	Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU)
Arm/Group Description	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.	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.
Measure Participants	3	2
Best response: SD	2 66.7%	0 0%
Best response: PD	1 33.3%	2 100%

3. Secondary Outcome

Title	Number of Patients With Best Overall Immune-related Tumor Response
Description	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

Outcome Measure Data

Analysis Population Description

The Efficacy Analysis Set includes all patients who received at least 1 dose of study treatment and had response evaluated through Week 17.

Arm/Group Title	Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU)	Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU)
Arm/Group Description	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.	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.
Measure Participants	3	2
Best response: irSD	1 33.3%	1 50%
Best response: irPD	2 66.7%	0 0%
Not evaluable by irRC	0 0%	1 50%

Adverse Events

Time Frame	All adverse events (AEs) occurring between the signing of informed consent and the off-study date were documented, regardless of the causal relationship to study drug. AEs occurring after the first dose of study drug were considered treatment emergent (i.e., TEAEs) and are presented in the summary tabulations. The AE reporting period for this study was up to 5 months.
Adverse Event Reporting Description	AE documentation included onset/resolution dates, severity using the NCI CTCAE (version 4.0), seriousness, relationship to study drug, study drug action taken, treatment, and outcome. In summaries, treatment-related AEs included those with a "possible", "probable", or "definite" relationship to study drug; preferred terms were counted only once per patient at the maximum reported grade.
Arm/Group Title	Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU)		Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU)
Arm/Group Description	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.		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.
All Cause Mortality
	Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU)		Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/2 (0%)
Serious Adverse Events
	Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU)		Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		1/2 (50%)
Blood and lymphatic system disorders
Lymph node pain	1/3 (33.3%)		0/2 (0%)
Gastrointestinal disorders
Colitis	0/3 (0%)		1/2 (50%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/3 (33.3%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1, Group 1 (BCG 0.16-0.64 × 10^6 CFU)		Cohort 1, Group 2 (BCG 0.8-3.2 × 10^6 CFU)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		2/2 (100%)
Gastrointestinal disorders
Constipation	2/3 (66.7%)		1/2 (50%)
Nausea	2/3 (66.7%)		1/2 (50%)
Abdominal pain	0/3 (0%)		1/2 (50%)
Diarrhoea	0/3 (0%)		1/2 (50%)
General disorders
Fatigue	2/3 (66.7%)		2/2 (100%)
Axillary pain	2/3 (66.7%)		0/2 (0%)
Influenza-like illness	1/3 (33.3%)		0/2 (0%)
Injection site ulcer	0/3 (0%)		1/2 (50%)
Non-cardiac chest pain	0/3 (0%)		1/2 (50%)
Infections and infestations
Cellulitis	1/3 (33.3%)		0/2 (0%)
Lower respiratory tract infection	1/3 (33.3%)		0/2 (0%)
Investigations
Hepatic enzyme increased	0/3 (0%)		1/2 (50%)
Metabolism and nutrition disorders
Decreased appetite	1/3 (33.3%)		1/2 (50%)
Musculoskeletal and connective tissue disorders
Back pain	2/3 (66.7%)		0/2 (0%)
Musculoskeletal chest pain	0/3 (0%)		1/2 (50%)
Nervous system disorders
Neuralgia	0/3 (0%)		1/2 (50%)
Psychiatric disorders
Insomnia	1/3 (33.3%)		1/2 (50%)
Respiratory, thoracic and mediastinal disorders
Cough	1/3 (33.3%)		0/2 (0%)
Dyspnoea exertional	1/3 (33.3%)		0/2 (0%)
Skin and subcutaneous tissue disorders
Pruritus	1/3 (33.3%)		2/2 (100%)
Night sweats	2/3 (66.7%)		0/2 (0%)
Rash	0/3 (0%)		1/2 (50%)
Urticaria	0/3 (0%)		1/2 (50%)

Limitations/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.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.