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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 : December 14, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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

Condition or disease Intervention/treatment Phase
Melanoma Biological: Spartalizumab (PDR001) Other: Placebo Drug: Dabrafenib Drug: Trametinib Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 538 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 17, 2017
Estimated Primary Completion Date : July 19, 2019
Estimated Study Completion Date : February 13, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
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.

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.

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®

Placebo Comparator: Placebo comparator arm
Matching placebo in combination with dabrafenib and trametinib
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®




Primary Outcome Measures :
  1. 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

  2. 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

  3. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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.


  10. 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.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02967692


Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com

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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02967692     History of Changes
Other Study ID Numbers: CPDR001F2301
2016-002794-35 ( EudraCT Number )
First Posted: November 18, 2016    Key Record Dates
Last Update Posted: December 14, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
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


Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Spartalizumab (PDR001)
melanoma
unresectable BRAF V600 mutated melanoma
metastatic BRAF V600 mutated melanoma
dabrafenib
trametinib
immunotherapy
PD 1 inhibitor
anti PD1
PD-1
anti-PD-1
combination treatment
malignant skin cancer
skin cancer
BRAF V600

Additional relevant MeSH terms:
Melanoma
Nevi and Melanomas
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Trametinib
Dabrafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action