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A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma (COMBI-i)

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ClinicalTrials.gov Identifier: NCT02967692
Recruitment Status : Recruiting
First Posted : November 18, 2016
Last Update Posted : August 27, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE November 16, 2016
First Posted Date  ICMJE November 18, 2016
Last Update Posted Date August 27, 2019
Actual Study Start Date  ICMJE February 17, 2017
Estimated Primary Completion Date September 9, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 20, 2018)
  • Safety Run-In (Part 1): Incidence of dose limiting toxicities (DLTs) [ Time Frame: 8 weeks ]
    Incidence of DLTs during the first 8 weeks of treatment with Spartalizumab (PDR001) in combination of dabrafenib and trametinib
  • Biomarker cohort (Part 2): Immune microenvironment and biomarker modulation [ Time Frame: 2 years ]
    Changes in PD-L1 levels and CD8+ cells upon treatment with Spartalizumab (PDR001) in combination with dabrafenib and trametinib
  • Randomized (Part 3): Progression-Free Survival (PFS), investigator assessed by RECIST 1.1 [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    Progression-free survival is defined as the time from the date of first dose to the date of the first documented radiological progression using RECIST 1.1 response criteria
Original Primary Outcome Measures  ICMJE
 (submitted: November 16, 2016)
  • Safety Run-In (Part 1): Incidence of dose limiting toxicities (DLTs) [ Time Frame: 8 weeks ]
    Incidence of DLTs during the first 8 weeks of treatment with PDR001 in combination of dabrafenib and trametinib
  • Biomarker cohort (Part 2): Immune microenvironment and biomarker modulation [ Time Frame: 2 years ]
    Changes in immune microenvironment and biomarker modulation and changes from baseline by visit
  • Randomized (Part 3): Progression-Free Survival (PFS), investigator assessed by RECIST 1.1 [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    Progression-free survival is defined as the time from the date of first dose to the date of the first documented radiological progression using RECIST 1.1 response criteria
Change History Complete list of historical versions of study NCT02967692 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2017)
  • Overall survival [ Time Frame: Up to death due to any cause (5 years) ]
    Overall survival is defined as the time from date of randomization to date of death due to any cause
  • Overall response rate [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    ORR is defined as the proportion of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1
  • Duration of response [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death, according to RECIST 1.1 criteria
  • Disease control rate [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    Disease control rate is defined as the proportion of patients with CR or PR or subjects with SD lasting for a duration of at least 24 weeks as per local review according to RECIST 1.1 criteria
  • Global health status/quality of life score of the EORTC QLQ-C30 [ Time Frame: Up to 60 days post progression (5 years) ]
    Patient's health-related quality of life
  • Global health status/quality of life score of the FACT-M subscale [ Time Frame: Up to 60 days post progression (5 years) ]
    Patient's health-related quality of life
  • Global health status/quality of life score of the EQ-5D-5L [ Time Frame: Up to 60 days post progression (5 years) ]
    Patient's health-related quality of life
  • Time to 10 point definitive deterioration in overall quality of life score from EORTC QLQ-C30 [ Time Frame: Up to 60 days post progression (5 years) ]
    Patient's health-related quality of life
  • PFS by PD-L1 expression [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    PFS analysis will be performed by PD-L1 subgroup (positive, negative) where a positive status is defined as having ≥ 1% expression and a negative status is defined as having < 1% expression. Additionally PD-L1 subgroups will also be assessed using defined by a PD-L1 expression level cut-off of 10%, where a positive status is defined as having ≥ 10% expression and a negative status is defined as having < 10% expression.
  • OS by PD-L1 expression [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    OS analysis will be performed by PD-L1 subgroup (positive, negative) where a positive status is defined as having ≥ 1% expression and a negative status is defined as having < 1% expression. Additionally PD-L1 subgroups will also be assessed using defined by a PD-L1 expression level cut-off of 10%, where a positive status is defined as having ≥ 10% expression and a negative status is defined as having < 10% expression.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 16, 2016)
  • Overall survival [ Time Frame: Up to death due to any cause (5 years) ]
    Overall survival is defined as the time from date of randomization to date of death due to any cause
  • Overall response rate [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    ORR is defined as the proportion of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1
  • Duration of response [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death, according to RECIST 1.1 criteria.
  • Disease control rate [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    Disease Control is defined as the proportion of patients with best overall response of CR, PR or SD according to RECIST 1.1 criteria
  • Global health status/quality of life score of the EORTC QLQ-C30 [ Time Frame: Up to 60 days post progression (5 years) ]
    Patient's health-related quality of life
  • Global health status/quality of life score of the FACT-M subscale [ Time Frame: Up to 60 days post progression (5 years) ]
    Patient's health-related quality of life
  • Global health status/quality of life score of the EQ-5D-5L [ Time Frame: Up to 60 days post progression (5 years) ]
    Patient's health-related quality of life
  • Time to 10 point definitive deterioration in overall quality of life score from EORTC QLQ-C30 [ Time Frame: Up to 60 days post progression (5 years) ]
    Patient's health-related quality of life
  • PFS by PD-L1 expression [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    PFS will be performed by PD-L1 subgroup (positive, negative) where a positive status is defined as having ≥ 1% expression and a negative status is defined as having < 1% expression
  • OS by PD-L1 expression [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]
    OS analyses will be performed by PD-L1 subgroup (positive, negative) where a positive status is defined as having ≥ 1% expression and a negative status is defined as having < 1% expression.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma
Official Title  ICMJE A Randomized, Double-blind, Placebo-controlled, Phase III Study Comparing the Combination of PDR001, Dabrafenib and Trametinib Versus Placebo, Dabrafenib and Trametinib in Previously Untreated Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma
Brief Summary To evaluate the safety and efficacy of the combination of an anti-PD-1 antibody (Spartalizumab (PDR001)), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in unresectable or metastatic BRAF V600 mutant melanoma
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Melanoma
Intervention  ICMJE
  • Biological: Spartalizumab (PDR001)
    Spartalizumab (PDR001) will be supplied in vial in liquid or lyophilized pharmaceutical form. Spartalizumab (PDR001) will be administered via intravenous infusion over 30 minutes (up to 2 hours) once every 4 or 8 weeks.
  • Other: Placebo
    Placebo will be a Dextrose 5% in water (D5W) infusion supplied by the site.
    Other Name: Placebo control
  • Drug: Dabrafenib
    Dabrafenib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Dabrafenib will be administered orally twice daily (150 mg BID) for Days 1-28 of a 28-day cycle.
    Other Name: Tafinlar®
  • Drug: Trametinib
    Trametinib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Trametinib will be administered orally once daily (2 mg QD) for Days 1-28 of a 28-day cycle.
    Other Name: Mekinist®
Study Arms  ICMJE
  • Experimental: Investigational treatment arm

    Part 1: Safety run-in Up to 18 evaluable patients with previously untreated unresectable or metastatic BRAF V600 mutated melanoma will be enrolled and treated at different dose levels to determine the recommended Phase 3 regimen of PDR001 in combination with dabrafenib and trametinib.

    Part 2: Biomarker cohort Approximately 20 patients with previously unresectable or metastatic BRAF V600 mutated melanoma will be enrolled to describe changes in the immune microenvironment and biomarker modulations

    Part 3: Randomized double blind Approximately 500 patients with previously untreated unresectable and metastatic BRAF V600 mutated melanoma will be enrolled to compare the anti-tumor activity of PDR001 in combination with dabrafenib and trametinib versus placebo plus dabrafenib and trametinib.

    Interventions:
    • Biological: Spartalizumab (PDR001)
    • Drug: Dabrafenib
    • Drug: Trametinib
  • Placebo Comparator: Placebo comparator arm
    Matching placebo in combination with dabrafenib and trametinib
    Interventions:
    • Other: Placebo
    • Drug: Dabrafenib
    • Drug: Trametinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 16, 2016)
538
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 11, 2023
Estimated Primary Completion Date September 9, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria Part 1: Safety run-in

  • Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
  • Aspartate transaminase (AST) < 2.5× ULN and Alanine transaminase (ALT) < 2.5× ULN
  • ECOG performance status ≤ 1

Part 2: Biomarker cohort

  • Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
  • At least two cutaneous or subcutaneous or nodal lesions for tumor sample collection
  • ECOG performance status ≤ 2

Part 3: Double-blind, randomized, placebo-controlled part

  • Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
  • ECOG performance status ≤ 2

Exclusion Criteria:

Part 1: Safety run-in

  • Subjects with uveal or mucosal melanoma
  • Any history of CNS metastases
  • Prior systemic anti-cancer treatment for unresectable or metastatic melanoma
  • Prior loco-regional treatment for unresectable or metastatic melanoma in the last 6 month
  • Prior neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months
  • Radiation therapy within 4 weeks prior to start of study treatment
  • Active, known, suspected or a documented history of autoimmune disease

Parts 2 & 3: Biomarker cohort & double-blind, randomized, placebo-controlled part

  • Subjects with uveal or mucosal melanoma
  • Clinically active cerebral melanoma metastasis
  • Prior systemic anti-cancer treatment for unresectable or metastatic melanoma
  • Prior loco-regional treatment for unresectable or metastatic melanoma in the last 6 month
  • Prior neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months
  • Radiation therapy within 4 weeks prior to start of study treatment
  • Active, known, suspected or a documented history of autoimmune disease

Other protocol-defined Inclusion/Exclusion may apply.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Bulgaria,   Canada,   Chile,   Czechia,   Denmark,   France,   Germany,   Greece,   Hungary,   Israel,   Italy,   Japan,   Mexico,   Netherlands,   Norway,   Poland,   Portugal,   Russian Federation,   Spain,   Sweden,   Switzerland,   Thailand,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02967692
Other Study ID Numbers  ICMJE CPDR001F2301
2016-002794-35 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP