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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01838200




Registration number
NCT01838200
Ethics application status
Date submitted
17/04/2013
Date registered
23/04/2013

Titles & IDs
Public title
Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) Followed by Ipilimumab in Advanced Metastatic Melanoma
Scientific title
A Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) and Followed by Ipilimumab Therapy in Patients With Advanced Metastatic Melanoma
Secondary ID [1] 0 0
LUD2012-003
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic Melanoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Other - Bacillus Calmette-Guérin (BCG) vaccine
Treatment: Drugs - Ipilimumab
Treatment: Drugs - Isoniazid

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.

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.

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.

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.


Treatment: Other: 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.

Treatment: Drugs: 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.

Treatment: Drugs: Isoniazid
Isoniazid was to be administered orally at a dose of 300 mg (3 × 100 mg tablets) every day from Days 29 through 56.
Intervention code [1] 0 0
Treatment: Other
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Patients With Treatment-emergent Adverse Events
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Continuously for up to 5 months
Secondary outcome [1] 0 0
Number of Patients With Best Overall Clinical Tumor Response
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Up to 5 months
Secondary outcome [2] 0 0
Number of Patients With Best Overall Immune-related Tumor Response
Assessment method [2] 0 0
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.
Timepoint [2] 0 0
Up to 5 months

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/03/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
17/08/2015
Sample size
Target
Accrual to date
Final
5
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Austin Health, LICR Melbourne Austin Branch - Heidelberg
Recruitment postcode(s) [1] 0 0
3084 - Heidelberg

Funding & Sponsors
Primary sponsor type
Other
Name
Ludwig Institute for Cancer Research
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Bristol-Myers Squibb
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Jonathan Cebon, MD, PhD
Address 0 0
Austin Health
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT01838200