A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma (COMBI-i)
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT02967692 |
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Recruitment Status :
Active, not recruiting
First Posted : November 18, 2016
Last Update Posted : April 4, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Melanoma | Biological: Spartalizumab Other: Placebo Drug: Dabrafenib Drug: Trametinib | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 569 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 |
| Actual Primary Completion Date : | August 11, 2020 |
| Estimated Study Completion Date : | December 29, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Part 1: Safety run-in Cohort
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.
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Biological: Spartalizumab
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 Name: PDR001 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. 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. |
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Experimental: Part 2: Biomarker cohort
Patients with previously unresectable or metastatic BRAF V600 mutated melanoma will be enrolled to describe changes in the immune microenvironment and biomarker modulations
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Biological: Spartalizumab
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 Name: PDR001 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. 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. |
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Experimental: Part 3: Randomized double blind cohort
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.
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Biological: Spartalizumab
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 Name: PDR001 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. 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. |
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Placebo Comparator: Part 3: Placebo Cohort
Matching placebo in combination with dabrafenib and trametinib
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Other: Placebo
Placebo will be a Dextrose 5% in water (D5W) infusion supplied by the site. 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. 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. |
- Safety Run-In (Part 1): Percentage of participants with of dose limiting toxicities (DLTs) [ Time Frame: 8 weeks ]Percentage of participants with DLTs during the first 8 weeks of treatment with spartalizumab in combination of dabrafenib and trametinib
- Biomarker cohort (Part 2): Changes from baseline in programmed cell death-ligand 1 (PD-L1) levels upon treatment with spartalizumab in combination with dabrafenib and trametinib [ Time Frame: 2 years ]Changes in PD-L1 levels upon treatment with spartalizumab in combination with dabrafenib and trametinib
- Biomarker cohort (Part 2): Changes from baseline in CD8+ cells upon treatment with spartalizumab in combination with dabrafenib and trametinib [ Time Frame: 2 years ]Changes in CD8+ cells upon treatment with spartalizumab 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, assessed up to approximately 3 years ]Progression-free survival is defined as the time from the date of first dose to the date of the first documented radiological progression per investigator's assessment according to RECIST 1.1
- Overall survival (OS) [ Time Frame: Up to death due to any cause, assessed up to approximately 5 years ]Overall survival is defined as the time from date of randomization to date of death due to any cause
- Overall response rate (ORR) as per investigator's assessment by RECIST 1.1 [ Time Frame: Up to approximately 3 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.
CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters
- Duration of response (DOR) by investigator's assessment according to RECIST 1.1 [ Time Frame: From first documented response to date of first documented progression or death, up to approximately 3 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.
CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters
- Disease control rate (DCR) by investigator's assessment according to RECIST 1.1 [ Time Frame: Up to approximately 3 years ]
Disease control rate is defined as the proportion of patients with CR or PR or subjects with stable disease (SD) lasting for a duration of at least 24 weeks as per local review according to RECIST 1.1 criteria.
CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
- Change from baseline in EORTC QLQ-C30 score [ Time Frame: From baseline to 60 days post progression, assessed up to approximately 3 years ]The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. Global health status/QoL response options are 1 to 4. Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning.
- Change from baseline in FACT-M melanoma subscale score [ Time Frame: From baseline to 60 days post progression, assessed up to approximately 3 years ]The Function Assessment Cancer Therapy-melanoma (FACT-M) ncludes melanoma-specific subscale consists of 16 questions for Melanoma Subscale Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M total score ranges from 0 to 172. Higher scores on all the FACT-M scales indicate a higher quality of life.
- Change from baseline in EQ-5D-5L score [ Time Frame: From baseline to 60 days post progression, up to approximately 3 years ]The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).Overall scores range from 0 to 1 with lower scores representing a higher level of dysfunction.
- Time to 10 point definitive deterioration in overall quality of life score from EORTC QLQ-C30 [ Time Frame: From baseline to date of at least 10 points relative to baseline worsening of the EORTC QLQ-C30 score or death due to any cause, up to approximately 3 years ]
The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. Global health status/QoL response options are 1 to 4. Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning.
The time to definitive 10 point deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the EORTC QLQ-C30 score or death due to any cause
- PFS by PD-L1 expression [ Time Frame: Up to disease progression or death due to any cause, up to approximately 3 years ]
PFS 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.
PFS analysis will be performed by PD-L1 status (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 death due to any cause, up to 5 years ]
OS is defined as the time from date of randomization to date of death due to any cause.
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.
- Anti-drug Antibody (ADA) prevalence at baseline [ Time Frame: Baseline ]Immunogenicity to PDR001 prior to PDR001 exposure
- ADA incidence on treatment [ Time Frame: Throughout study until 150 day safety follow-up, up to 3 years ]Immunogenicity to PDR001 on treatment and after treatment
- Trough serum concentration for PDR001 [ Time Frame: Pre-dose on Day 1 of each cycle (from Cycle 2), up to 3 years. Cycle=28 days ]Pre-dose concentrations of PDR001 collected before dose administration
- Trough serum concentration for dabrafenib [ Time Frame: Pre-dose on Day 15 of each cycle (from Cycle 1), up to 3 years. Cycle=28 days ]Pre-dose concentrations of dabrafenib collected before dose administration
- Trough serum concentration for trametinib [ Time Frame: Pre-dose on Day 15 of each cycle (from Cycle 1), up to 3 years. Cycle=28 days ]Pre-dose concentrations of trametinib collected before dose administration
- Number of patients with dose interruptions [ Time Frame: From baseline to end of treatment, up to 5 years ]Number of patients with dose interruptions for PDR001, dabrafenib and trametinib
- Number of patients with dose reductions [ Time Frame: From baseline to end of treatment, up to 5 years ]Number of patients with dose reductions for PDR001, dabrafenib and trametinib
- Relative dose intensity [ Time Frame: From baseline to end of treatment, up to 5 years ]Relative dose intensity for PDR001, dabrafenib and trametinib computed as computed as the ratio of dose intensity and planned dose intensity
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
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
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| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT02967692 |
| Other Study ID Numbers: |
CPDR001F2301 2016-002794-35 ( EudraCT Number ) |
| First Posted: | November 18, 2016 Key Record Dates |
| Last Update Posted: | April 4, 2023 |
| Last Verified: | March 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| 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 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Spartalizumab (PDR001) dabrafenib trametinib melanoma immunotherapy PD 1 inhibitor anti PD1 PD-1 |
anti-PD-1 combination treatment malignant skin cancer skin cancer BRAF V600 unresectable BRAF V600 mutated melanoma metastatic BRAF V600 mutated melanoma |
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Melanoma Neuroendocrine Tumors Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Nerve Tissue Nevi and Melanomas Trametinib |
Dabrafenib Spartalizumab Antineoplastic Agents Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Immune Checkpoint Inhibitors Antineoplastic Agents, Immunological |