Primary Objective* To compare the objective response rate and overall survival of BMS-936558 to investigator*s choice in subjects with advanced melanoma.Secondary Objectives* To compare the progression-free survival (PFS) of BMS-936558 to…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective will be measured by the primary endpoints of OS and ORR
in all randomized subjects. OS is defined as the time between the date of
randomization and the date of death. For subjects without documentation of
death, OS will be censored on the last date the subject was known to be alive.
OS will be followed continuously while subjects are on the study drug and every
3 months via in-person or phone contact after subjects discontinue the study
drug.
The ORR is defined as the number of subjects with a best overall response (BOR)
of complete response (CR) or partial response (PR) divided by the number of
randomized subjects. BOR is defined as the best response designation, as
determined by the IRC, recorded between the date of randomization and the date
of objectively documented progression per RECIST 1.1 or the date of subsequent
therapy, whichever occurs first. For subjects without documented progression or
subsequent therapy, all available response designations will contribute to the
BOR assessment.
Secondary outcome
The first secondary objective (to compare PFS) will be measured by the endpoint
PFS in all randomized subjects. It is defined as the time from randomization to
the date of the first documented progression, as determined by the IRC, or
death due to any cause, whichever occurs first. Subjects who die without a
reported progression will be considered to have progressed on the date of their
death. Subjects who did not progress or die will be censored on the date of
their last evaluable tumor assessment. Subjects who did not have any on study
tumor assessments and did not die will be censored on the date they were
randomized. Subjects who started any subsequent anti-cancer therapy without a
prior reported progression will be censored at the last evaluable tumor
assessment prior to initiation of the subsequent anti-cancer therapy.
The second secondary objective will be measured by the same primary endpoints.
I.e. ORR and OS in subjects within PD-L1 positive and PD-L1 negative subgroups.
The third secondary objective (to evaluate HRQoL) will be measured by mean
changes from screening/baseline in the EORTC QLQ-C30 global health status/QoL
composite scale and by mean changes from screening/baseline in the remaining
EORTC QLQ-C30 scales in all randomized subjects.
Background summary
The lifetime risk of developing invasive melanoma has been dramatically
increasing and the overall mortality from melanoma continues to rise. Although
in 2011, two new agents, ipilimumab and vemurafenib, were approved for advanced
melanoma there is still a large unmet need for patients who have progressed
post ipilimumab and vemurafenib therapy. Ipilimumab monotherapy at 3 mg/kg has
been shown to increase 2-year survival compared to a vaccine control (26% vs.
14%) in previously treated subjects with metastatic melanoma. Ipilimumab 3
mg/kg was approved for treatment of advanced melanoma without restriction to
BRAF status in both the EU and US. In the US, ipilimumab was approved without
restriction to line of therapy, while in the EU, ipilimumab was indicated in
advanced melanoma patients who had received prior therapy.
Approximately 50% of cutaneous melanoma is BRAF mutation positive, and
vemurafenib is indicated for the treatment of BRAF V600E mutation positive
advanced melanoma. Vemurafenib is a potent inhibitor of mutation positive BRAF
and has demonstrated an increased overall survival benefit compared to
dacarbazine with a hazard ratio for death of 0.62 with a median overall
survival of 13.2 months versus 9.6 months for vemurafenib and dacarbazine,
respectively.
Besides these two agents, no other agent has demonstrated an overall survival
benefit in a Phase 3 randomized study. Dacarbazine is approved for treatment of
metastatic melanoma with a reported objective response rate of 5% to 20% by the
US FDA and the EMA, but these responses are short-lived. Other drugs such as
temozolomide have not resulted in significant improvement in survival when
compared to dacarbazine, with a median overall survival of 7.7 months compared
to 6.4 respectively. Fotemustine is approved and used in the EU and
demonstrates a response rate of 15% and a median survival of 7.3 months.
Finally, carboplatin and paclitaxel is another commonly used cytotoxic
treatment regimen recommended by the NCCN and ESMO clinical guidelines with
response rates around 11% and median overall survival around 10.5 months. The
cytotoxic treatments are fairly well tolerated primarily with hematological
adverse events.
The highest unmet need for advanced melanoma subject is currently for those who
have progressed post ipilimumab regardless of BRAF status in addition to
vemurafenib if BRAF V600 mutation positive given these are the only two agents
to have demonstrated overall survival benefit in a Phase 3 study. In an effort
to include a homogenous population in this study, subjects will be required to
have progressed post anti-CTLA-4 treatment and if BRAF V600 mutation positive,
to have also progressed on a BRAF inhibitor.
Study objective
Primary Objective
* To compare the objective response rate and overall survival of BMS-936558 to
investigator*s choice in subjects with advanced melanoma.
Secondary Objectives
* To compare the progression-free survival (PFS) of BMS-936558 to
investigator*s choice in subjects with advanced melanoma.
* To evaluate whether PD-L1 expression is a predictive biomarker for ORR and OS.
* To evaluate Health Related Quality of Life (HRQoL) as assessed by European
Organisation for Research and Treatment of Care (EORTC) QLQ-C30.
Exploratory Objectives
* To evaluate duration of and time to objective response in BMS-936558 and
investigator*s choice in subjects with advanced melanoma.
* To assess the overall safety and tolerability of BMS-936558 and
investigator*s choice.
* To characterize the pharmacokinetics of BMS-936558 and explore
exposure-response relationships with respect to safety and efficacy.
* To characterize the immunogenicity of BMS-936558.
* To explore potential biomarkers associated with clinical response to
BMS-936558 by analyzing tumor tissue specimens and serum for proteins,
including but not limited to PD-1, PD-L1 and PD-L2 and lymphocytic cell
populations involved in regulating immune responses in comparison to clinical
outcomes.
* To assess the effects of natural genetic variation (SNPs) in select genes
including but not limited to PD-1, PD-L1, PD-L2, CTLA-4 on clinical endpoints
and/or on the occurrence of adverse events.
* To assess changes in health status in treatment groups by the EuroQoL EQ-5D
both on treatment and during the survival follow-up period.
Study design
This is an open-label, randomized, phase 3 study in adult (* 18 years old) male
and female subjects with unresectable or metastatic (advanced) melanoma who
have received one and at most two prior treatment regimens in the advanced
setting. Subjects will undergo screening evaluations to determine eligibility
within 28 days prior to randomization. Subjects will be assigned to one of two
treatment arms, BMS-936558 (3 mg/kg every 2 weeks) or investigator*s choice
(dacarbazine 1000 mg/m2 or carboplatin AUC6/paclitaxel 175 mg/m2 every 3
weeks). Randomization will be stratified and balanced according to the
following factors: PD-L1 expression (PD-L1 positive vs. PD-L1 negative), BRAF
status (Wild type vs. Mutation positive) and prior best response to anti-CTLA-4
therapy (Prior anti-CTLA-4 therapy clinical benefit vs. No prior anti-CTLA-4
therapy clinical benefit). Treatment should be initiated within 3 days of
randomization. BMS-936558 or investigator*s choice will be administered as an
IV infusion on Treatment Day 1. A treatment cycle is defined as 2 weeks for
BMS-936558 and 3 weeks for Investigator*s Choice. This study will consist of 3
phases: screening (up to 28 days), treatment and follow-up. Treatment will
continue until documented disease progression, there is discontinuation due to
toxicity, withdrawal of consent or the study ends. Subjects will be followed
every 3 months for survival after completion of the follow-up visits.
Intervention
The medical interventions for this trial include both BMS-936558 and
Investigator*s choice (dacarbazine and carboplatin/paclitaxel). All compounds
will be supplied by the Sponsor company. BMS-936558 or Investigator*s choice
will be administered as an IV infusion on Treatment Day 1. A treatment cycle is
defined as 2 weeks for BMS-936558 and 3 weeks for Investigator*s choice.
BMS-936558 will be administered as an IV infusion over 60 minutes, dacarbazine
over 30-60 minutes. Paclitxel wil be given as an IV infusion over 180 minutes
followed by carboplatin over 30 minutes.
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examinations, vital sign measurements
including oxygen saturation levels, blood tests for safety assessment,
pregnancy testing (for females of child bearing potential) and monitoring for
adverse events. In addition, every 6 weeks (from week 9 onwards) patients will
undergo radiographic assessment of their tumour(s) (by CT or MRI) until disease
progression or treatment discontinuation whichever occurs later. For those
patients randomized to BMS-936558, blood samples will be collected at certain
visits for research purposes (PK and immunogenicity). The frequency of visits
and number of procedures carried out during this trial would typically be
considered over and above standard over care. These procedures are carried out
by trained medical professionals and every effort will be made to minimize any
risks or discomfort to the patient. Treatment for cancer often have side
effects, including some that are life-threatening. An independent Data
Monitoring Committee (DMC) will be utilized to monitor the activity and safety
of BMS-936558 versus Investigator*s choice (dacarbazine and
carboplatin/paclitaxel).
Vijzelmolenlaan 9
Woerden 3447 GX
NL
Vijzelmolenlaan 9
Woerden 3447 GX
NL
Listed location countries
Age
Inclusion criteria
1. Signed Written Informed Consent
2. Eastern Cooperative Oncology Group (ECOG) performance status of * 1
3. Histologically confirmed Stage III (unresectable) or Stage IV melanoma.
4. Measurable disease by CT or MRI per RECIST 1.1 criteria.
5. A pre-treatment recent core, excision or punch biopsy must be provided for PD-L1 status determination prior to randomization and for exploratory biomarker analyses. The biopsy must be from a unresectable or metastatic site, and the subject must have had no intervening systemic therapy between the time of biopsy and randomization. In order to be randomized, a subject must be classified as PD-L1 positive, PD-L1 negative or PD-L1 indeterminate. If an insufficient amount of recently acquired tumor tissue from an unresectable or metastatic site is available prior to the start of the screening phase, subjects must consent o allow the acquisition of tumor biopsy by study personnel for performance of biomarker analyses.
6. Subjects must consent to allow the acquisition of existing formalin-fixed paraffin embedded (FFPE) material (*archival*) (block or a minimum of 10 unstained slides) if available, for performance of correlative studies.
7. Subjects must have objective evidence of disease progression (eg. clinical or radiological) during or after at least 1 (V600 wildtype) or at least 2 (V600 mutation positive) prior treatment regimens for advanced melanoma.
* Subjects BRAF wildtype:
- Must have objective evidence of progression of disease (PD) post (during or following) treatment with anti-CTLA-4 containing therapy for advanced melanoma.
AND
- In addition to progression post anti-CTLA-4 therapy, subjects that have received another treatment regimen must have objective evidence of progression of disease (PD) during or following at least 1 cycle of treatment for advanced melanoma.
* Subjects BRAF V600 mutation positive:
- Must have objective evidence of progression of disease (PD) post treatment with anti-CTLA-4 containing therapy for advanced melanoma.
AND
- In addition to progressing post anti-CTLA-4 therapy, subjects must have objective evidence of progression of disease (PD) post treatment with a BRAF inhibitor.
- Subjects may have received prior anti-CTLA-4 therapy and a BRAF inhibitor in any sequence or in combination.
8. Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) must have been completed at least 4 weeks before study drug administration, and all adverse events have either returned to baseline or stabilized.
9. Prior anti-CTLA-4 therapy must have been completed at least 6 weeks before study drug administration.
10. Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration.
11. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization:
i. WBC * 2000/uL
ii. Neutrophils * 1500/uL
iii. Platelets * 100x10*3/uL
iv. Hemoglobin * 9.0 g/dL
v. Creatinine Serum creatinine * 1.5 x ULN or CrCl > 40 mL/min (using the Cockcroft-Gault formula)
vi. AST/ALT * 3 x ULN
vii. Bilirubin * 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL).
12. Men and women aged * 18 years of age.
13. Women of childbearing potential (WOCBP) must use method(s) of contraception based on the tables in Appendix 1. Dacarbazine, carboplatin and paclitaxel are teratogenic. There is an insufficient amount of information to assess teratogenicity for BMS-936558. For a teratogenic study drug and/or when there is sufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP must follow instructions for birth control when the half life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half lives. The half-life of BMS-936558 is up to 25 days; therefore, WOCBP who received BMS-936558 should use an adequate method to avoid pregnancy for 23 weeks after the last dose of BMS-936558. WOCBP must follow instructions for birth control when the half life of the investigational drug is less than 24 hours, contraception should be continued for a period of 30 days after the last dose of investigational product. The half-life of dacarbazine, carboplatin and paclitaxel is less than 24 hours, therefore WOCBP who received either dacarbazine, carboplatin or paclitaxel should use an adequate method to avoid pregnancy for 30 days after the last dose of either dacarbazine, carboplatin or paclitaxel.
14. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.
15. Women must not be breastfeeding
16. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year (See Appendix 1). The investigator shall review contraception methods and the time period that contraception must be followed. Men that are sexually active with WOCBP must follow instructions for birth control when the half life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half lives. The half-life of BMS-936558 is up to 25 days; therefore, men who received BMS-936558 and are sexually active with WOCBP must continue contraception for 31 weeks after the last dose of BMS-936558. The half-life of dacarbazine, carboplatin and paclitaxel is less than 24 hours. However, the dacarbazine product label requires men who received dacarbazine and are sexually active with WOCBP to use an effective method of contraception for at least 6 months after the last dose of dacarbazine.
Exclusion criteria
1. Active brain metastasis or leptomeningeal metastasis. Subjects with brain metastases are eligible if these have been treated, and must be without magnetic resonance imaging (MRI) evidence of progression for at least 8 weeks and not require immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone or equivalent) for at least 2 weeks prior to study drug administration.
2. Ocular melanoma.
3. Subjects whose melanoma is BRAF status unknown.
4. Any treatment in a BMS-936558 trial.
5. Prior systemic melanoma therapy with both dacarbazine and carboplatin and paclitaxel. Prior systemic therapy with one of the treatments is permitted.
6. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive protocol therapy.
7. Subjects with previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric or colon cancers, cervical cancers/dysplasia, or breast carcinoma in situ) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
8. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
9. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
10. Subjects who received prior therapy with an anti-PD-1, anti-PD-L1 or anti PD L2, (or any other antibody or drug specifically targeting T-cell co stimulation or checkpoint pathways except for anti-CTLA-4 therapy as described above).
11. Known drug or alcohol abuse.
12. Any positive test result for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
13. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
14. Subjects with a known history of the following anti-CTLA-4 therapy related adverse reactions based on the CTCAE v4.0 criteria:
i) Grade * 4 anti-CTLA-4 therapy related adverse reaction except resolved nausea, fatigue, infusion reactions or endocrinopathies where clinical symptoms were able to be controlled with appropriate hormone replacement therapy. Grade 3 anti-CTLA-4 therapy related adverse reactions must have resolved or been controlled within 12 weeks.
ii) Any * Grade 2 eye pain or reduction of visual acuity that did not respond to topical therapy and did not improve to * Grade 1 severity within 2 weeks of starting topical therapy or required systemic treatment.
iii) Any * Grade 3 sensory neurologic toxicity.
iv) Any Grade 4 laboratory abnormalities, except AST, ALT or T. bilirubin;
- AST or ALT > 10 x ULN
- T. bilirubin > 5 x ULN
v) Subjects who required infliximab or other immune suppressants including mycophenolic acid for management of drug related toxicities.
vi) Any other anti-CTLA-4 therapy related adverse event requiring permanent discontinuation of anti-CTLA-4 therapy.
15. History of Grade * 3 neurologic toxicity.
16. History of Grade * 3 allergy to study drug components.
17. WOCBP who are pregnant or breastfeeding.
18. Women with a positive pregnancy test at enrollment or prior to administration of study medication.
19. Prisoners or subjects who are involuntarily incarcerated.
20. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
21. Current participation in another clinical study involving treatment with medications, radiation or surgery.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-001828-35-NL |
| ClinicalTrials.gov | NCT01721746 |
| CCMO | NL41284.031.12 |