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

Study Overview
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Brief Summary
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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
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This study is designed as a Phase III, multi-center study consisting of three parts: Part 1, known as the Safety Run-in, is an open-label part aimed at determining the recommended Phase III regimen (RP3R) of spartalizumab in combination with dabrafenib and trametinib for previously untreated subjects with BRAF V600 mutant unresectable or metastatic melanoma (Stage IIIC/IV per AJCC edition 7). In Part 1, spartalizumab was administered at a starting dose level (DL1) of 400 mg every 4 weeks (Q4W), along with fixed doses of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily). The RP3R for Part 3 was determined using the Bayesian Logistic Regression Model (BLRM) with escalation with overdose control (EWOC) criteria. Part 2, referred to as the Biomarker Cohort, is an open-label section focused on characterizing the kinetics of immune biomarkers and potential immune resistance mechanisms. Part 2 started when the fourth subject in dose level 1 (DL1) of Part 1 completed approximately 4 weeks of study treatment, and fewer than 3 dose-limiting toxicities (DLTs) were observed. Participants in Part 2 receive PDR001 (spartalizumab) at a dosage of 400 mg Q4W, in combination with dabrafenib (150 mg BID) and trametinib (2 mg QD). Part 3 is a double-blind, randomized, placebo-controlled phase that compares the efficacy and safety of spartalizumab in combination with dabrafenib and trametinib to placebo in combination with dabrafenib and trametinib. Part 3 was initiated after determining the RP3R for the combination of spartalizumab with dabrafenib and trametinib in Part 1. Subjects were randomized in a 1:1 ratio to receive either the RP3R dose of spartalizumab identified in Part 1 or placebo, along with dabrafenib (150 mg BID) and trametinib (2 mg QD). For all parts of the study, the treatment is continued until the subject experiences any of the following events: disease progression according to RECIST 1.1 as determined by the Investigator, unacceptable toxicity, initiation of a new anti-neoplastic therapy, pregnancy, withdrawal of consent, physician's decision, loss to follow-up, death, or termination of the study by the Sponsor. Safety evaluations are conducted for all subjects for up to 150 days after the last dose of spartalizumab/placebo (safety follow-up period). Subjects who discontinue study treatment without disease progression as per RECIST 1.1 continue with tumor assessments according to the protocol until documented disease progression, withdrawal of consent, loss to follow-up, or death, regardless of the initiation of new anti-neoplastic therapy (efficacy follow-up period). Subjects enter the survival follow-up period after completing the safety follow-up period or experiencing disease progression as per RECIST 1.1 or response criteria for immunotherapy, whichever period is longer (survival follow-up period).

Official Title
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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

Conditions
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Melanoma

Intervention / Treatment
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* Biological: Spartalizumab
* Other: Placebo
* Drug: Dabrafenib
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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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 Measurable disease according to RECIST 1.1 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 Measurable disease according to RECIST 1.1 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 Measurable disease according to RECIST 1.1 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 Neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months prior to enrollmen Radiation therapy within 4 weeks prior to start of study treatment Active autoimmune disease, and/or history of autoimmune disease(s) that required treatment Parts 2 & 3: Biomarker cohort & double-blind, randomized, placebo-controlled part Subjects with uveal or mucosal melanoma Prior systemic anti-cancer treatment for unresectable or metastatic melanoma Neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months prior to enrollment Radiation therapy within 4 weeks prior to start of study treatment Clinically active cerebral melanoma metastasis. Active autoimmune disease, and/or history of autoimmune disease(s) that required treatment Other protocol-defined Inclusion/Exclusion may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Safety run-in Cohort<br>In Part 1, participants are treated at different dose levels to determine the recommended Phase 3 regimen of spartalizumab in combination with dabrafenib and trametinib. The starting dose of spartalizumab is 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD). | Biological: Spartalizumab<br>* Spartalizumab powder for solution is used in Part 1 and Part 2, and as concentrate for solution for infusion for Part 3. Spartalizumab is administered via intravenous infusion over 30 minutes once every 4 weeks<br>* Other names: PDR001;Drug: Dabrafenib<br>* Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.<br>Drug: Trametinib<br>* Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions<br>|
| Experimental: Part 2: Biomarker cohort<br>In Part 2, participants are treated with spartalizumab 400 mg Q4W in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD). | Biological: Spartalizumab<br>* Spartalizumab powder for solution is used in Part 1 and Part 2, and as concentrate for solution for infusion for Part 3. Spartalizumab is administered via intravenous infusion over 30 minutes once every 4 weeks<br>* Other names: PDR001;Drug: Dabrafenib<br>* Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.<br>Drug: Trametinib<br>* Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions<br>|
| Experimental: Part 3- Arm 1: Spartalizumab in combination with dabrafenib and trametinib<br>In Part 3, participants are randomized to receive spartalizumab at the RP3R identified in Part 1 (400 mg Q4W) in combination with approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD) | Biological: Spartalizumab<br>* Spartalizumab powder for solution is used in Part 1 and Part 2, and as concentrate for solution for infusion for Part 3. Spartalizumab is administered via intravenous infusion over 30 minutes once every 4 weeks<br>* Other names: PDR001;Drug: Dabrafenib<br>* Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.<br>Drug: Trametinib<br>* Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions<br>|
| Placebo Comparator: Part 3- Arm 2: Placebo in combination with dabrafenib and trametinib<br>In Part 3, participants are randomized to receive matching placebo in combination with the approved dose of dabrafenib (150 mg BID) and trametinib (2 mg QD) | Other: Placebo<br>* Placebo is administered via intravenous infusion over 30 minutes once every 4 weeks<br>Drug: Dabrafenib<br>* Dabrafenib 150 mg capsules BID is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions.<br>Drug: Trametinib<br>* Trametinib 2 mg tablets QD is administered orally for Days 1-28 of a 28-day cycle, in fasting conditions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Run-In (Part 1): Number of Participants With Dose Limiting Toxicities (DLTs) | DLT was defined as an adverse event or abnormal laboratory value that was unrelated to disease, disease progression, inter-current illness, or concomitant medications and occured within 8 weeks of treatment with spartalizumab in combination with dabrafenib and trametinib. The DLT criteria included Grade 4 hematological adverse events, Grade 4 bilirubin elevation, specific gastrointestinal adverse events, symptomatic serum amylase or lipase elevation, Grade 3 or higher hypertension, Grade 3 or higher cardiac events, Grade 2 or higher pneumonitis, Grade 3 or higher immune-related toxicities, infusion-related reactions, other clinically significant adverse events, and toxicities leading to a dosing delay of over 12 weeks. NCI CTCAE v4.03 was used for grading DLTs | Up to 8 weeks (Part 1) | 
| Biomarker Cohort (Part 2): Change From Baseline in Programmed Cell Death-ligand 1 (PD-L1) Expression Upon Treatment With Spartalizumab in Combination With Dabrafenib and Trametinib | Change from baseline in PD-L1 expression (as determined by immunohistochemistry in tissue samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2 | Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days | 
| Biomarker Cohort (Part 2): Change From Baseline in CD8+ Cells Upon Treatment With Spartalizumab in Combination With Dabrafenib and Trametinib | Change from baseline in CD8+ cells (as determined by flow cytometry in blood samples) upon treatment with spartalizumab in combination with dabrafenib and trametinib in participants from Part 2 | Baseline, Cycle 1 Day 15 and Cycle 3 Day 1 (Part 2). Each cycle is 28 days | 
| Randomized (Part 3): Progression-Free Survival (PFS) as Per Investigator's Assessment by RECIST 1.1 | Progression-free survival was 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 or death due to any cause. The distribution of PFS was estimated using the Kaplan-Meier (KM) method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment. | Up to disease progression or death due to any cause, whichever occurs first, assessed up to 2.8 years (Part 3) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival is defined as the time from date of randomization to date of death due to any cause | Up to death due to any cause, assessed up to approximately 5 years | 
| Overall Response Rate (ORR) as Per Investigator's Assessment by RECIST 1.1 | ORR was defined as the percentage 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 | Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 years | 
| Duration of Response (DOR) as Per Investigator's Assessment by RECIST 1.1 | DOR was 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. The distribution of DOR was estimated using the KM method. 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 | From first documented response to date of first documented progression or death, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3) | 
| Disease Control Rate (DCR) as Per Investigator's Assessment by RECIST 1.1 | DCR was defined as the percentage of participants 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. | Part 1: Up to 3.3 years. Part 2: Up to 3 years. Part 3: Up to 2.8 year | 
| Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status Scores | The EORTC QLQ-C30 was a 30-item questionnaire that patients complete, consisting of both multi-item scales and single-item measures. It included five functional scales, three symptom scales, six single items, and a Global Health Status/Quality of Life (GHS/QoL) scale. The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life. The change from baseline in GHS/QoL scores was calculated. A positive change from baseline indicated improvement in the patient's quality of life. | From baseline to 60 days post progression, assessed up to 2.8 years (Part 3) | 
| Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Physical Functioning Scale Scores | The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale. The EORTC QLQ-C30 physical functioning scale measured a patient's ability to carry out daily activities and tasks requiring physical exertion. It consisted of five questions asking patients to rate their level of physical functioning, with response options ranging from 1=not at all to 4=very much. The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating better physical functioning. The change from baseline in physical functioning scale scores was calculated. A positive change from baseline indicated improvement in physical functioning. | From baseline to 60 days post progression, assessed up to 2.8 years (Part 3) | 
| Randomized (Part 3): Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Pain Symptom Scale Scores | The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale. The EORTC QLQ-C30 pain symptom scale was one of the symptom scales in the questionnaire, which measured the severity of pain experienced by the patient. The pain symptom scale consisted of two items, one measuring the severity of pain and the other measuring the use of painkillers. The items were rated on a 4-point scale ranging from 1=not at all to 4=very much. The scores for each item were summed and transformed to a 0 to 100 scale, with higher scores indicating more severe pain. The change from baseline in pain symptom scale scores was calculated. A negative change from baseline indicated improvement. | From baseline to 60 days post progression, assessed up to 2.8 years (Part 3) | 
| Randomized (Part 3): Time to 10 Point Definitive Deterioration in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30- Global Health Status | The EORTC QLQ-C30 was a patient completed 30 item questionnaire that was composed of both multi-item scales and single-item measures. These included five functional scales, three symptom scales, six single items and a global health status/QoL scale. The GHS/QoL scale had seven possible response scores ranging from 1 (very poor) to 7 (excellent), which were averaged and transformed to a 0-100 scale. A higher score on this scale indicated a better quality of life. 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 GHS/QoL score or death due to any cause. If a subject had not had an event, the time to deterioration was censored at the date of the last adequate assessment. The distribution was estimated using KM method. | From baseline to date of at least 10 points relative to baseline worsening of the global health status score or death due to any cause, up to 2.8 years (Part 3) | 
| Randomized (Part 3): Change From Baseline in Function Assessment Cancer Therapy-melanoma (FACT-M) Melanoma Subscale Score | The Functional Assessment of Cancer Therapy-Melanoma (FACT-M) quality of life questionnaire was composed of the FACT-General (FACT-G) plus the Melanoma Subscale and the Melanoma Surgery Subscale, which complemented the general scale with items specific to quality of life (QoL) in melanoma. The Melanoma Subscale of FACT-M included 16 questions, with response options of 0= Not at all, 1= a little bit, 2= somewhat, 3= quite a bit and 4= very much. The FACT-M melanoma subscale score ranged from 0 to 64, with higher scores indicating a higher quality of life in relation to melanoma. The change from baseline in melanoma subscale scores was calculated. A positive change from baseline indicated improvement. | From baseline to 60 days post progression, assessed up to 2.8 years (Part 3) | 
| Randomized (Part 3): Change From Baseline in EuroQoL 5-level Instrument (EQ-5D-5L)- Visual Analog Scale (VAS) Score | The EQ-5D-5L is a standardized questionnaire used to assess health-related quality of life, and it includes a Visual Analog Scale (VAS). The VAS score is obtained by asking the individual to rate their current health status on a scale from 0 to 100, where 0 represents the worst possible health state and 100 represents the best possible health state. The change from baseline in EQ-5D-5L VAS score was calculated. A positive change from baseline indicates improvement in the health status. | From baseline to 60 days post progression, assessed up to 2.8 years (Part 3) | 
| Randomized (Part 3): PFS as Per Investigator's Assessment by RECIST 1.1 by PD-L1 Expression | PFS was defined as the time from the date of first dose to the date of the first documented radiological progression as per investigator's assessment using RECIST 1.1 response criteria or death due to any cause. The distribution of PFS was estimated using the KM method. If a patient had not had an event at the time of data cut-off, progression-free survival was censored at the date of last adequate tumor assessment. PFS analysis was performed by PD-L1 status (positive, negative) where a positive status was defined as having ≥ 1% expression and a negative status was defined as having < 1% expression. | Up to disease progression or death due to any cause, up to 2.8 years (Part 3) | 
| Randomized (Part 3): OS by PD-L1 Expression | 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. | Up to death due to any cause, up to 5 years | 
| Spartalizumab Anti-drug Antibody (ADA) Prevalence at Baseline | Spartalizumab ADA prevalence at baseline was calculated as the percentage of participants who had an spartalizumab ADA positive result at baseline. | Baseline | 
| Spartalizumab ADA Incidence | Spartalizumab ADA incidence was calculated as the percentage of participants who were treatment-induced spartalizumab ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted spartalizumab ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer) | Throughout study until 150 days after the last dose of spartalizumab, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). | 
| Trough Concentration (Ctrough) for Spartalizumab | Ctrough for spartalizumab refers to the serum concentration of spartalizumab immediately prior to the administration of a dose of spartalizumab on Day 1 of Cycle 2 and later cycles. | Pre-infusion on Day 1 of each Cycle starting from Cycle 2, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days | 
| Pre-dose Plasma Concentration for Dabrafenib | Plasma concentration of dabrafenib immediately prior to the administration of a dose of dabrafenib. | Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days | 
| Pre-dose Plasma Concentration for Trametinib | Plasma concentration of trametinib immediately prior to the administration of a dose of trametinib. | Pre-infusion on Day 1 of every cycle from Cycle 2 to 12, and then every 6 cycles from Cycle 18 to 36, up to 3.3 years (Part 1), 3 years (Part 2) and 2.8 years (Part 3). Cycle=28 days | 
| Number of Participants With Dose Interruptions | Number of participants with dose interruptions for spartalizumab, dabrafenib and trametinib | From baseline to end of treatment, up to 5 years | 
| Number of Participants With Dose Reductions | Number of patients with dose reductions for spartalizumab, dabrafenib and trametinib | From baseline to end of treatment, up to 5 years | 
| Relative Dose Intensity | Relative dose intensity for spartalizumab, dabrafenib and trametinib computed as the ratio of dose intensity and planned dose intensity | From baseline to end of treatment, up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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