Study of Efficacy and Safety of Novel Spartalizumab Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the efficacy of novel spartalizumab (PDR001) combinations in previously treated unresectable or metastatic melanoma

Official Title
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A Randomized, Open-label, Phase II Open Platform Study Evaluating the Efficacy and Safety of Novel Spartalizumab (PDR001) Combinations in Previously Treated Unresectable or Metastatic Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Spartalizumab
* Drug: LAG525
* Drug: Capmatinib
* Drug: Canakinumab
* Drug: Ribociclib


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria for Arm 1,2,3,4: Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma using AJCC edition 8 Previously treated for unresectable or metastatic melanoma: Subjects with V600BRAF wild-type disease must have received prior systemic therapy for unresectable or metastatic melanoma with anti-PD-1/PD-L1. Additionally, subjects may have received anti-CTLA-4 as a single agent or in combination with anti-PD-1/PD-L1, irrespective of the sequence. No additional systemic treatment is allowed for advanced or metastatic melanoma. A maximum of two prior lines of systemic therapies for unresectable or metastatic melanoma are allowed. The last dose of prior therapy (anti-PD-1, anti-PD-L1 or anti-CTLA-4) must have been received more than four weeks before randomization. Subjects with V600BRAF mutant disease must have received prior systemic therapy for unresectable or metastatic melanoma with anti-PD-1/PD-L1, and V600BRAF inhibitor. Additionally, subjects may have received anti-CTLA-4 as a single agent or in combination with anti-PD-1/PD-L1, or MEK inhibitor (in combination with V600BRAF inhibitor or as a single agent), irrespective of the sequence. No additional systemic treatment is allowed for advanced or metastatic melanoma . A maximum of three prior lines of systemic therapies for unresectable or metastatic melanoma are allowed. The last dose of prior therapy must have been received more than 4 weeks (for anti-PD-1, anti-PD-L1 or anti-CTLA-4) or more than 2 weeks (for V600BRAF or MEK inhibitor) prior to randomization. All subjects (with V600BRAF wild-type disease and with V600BRAF mutant disease) must have documented disease progression as per RECIST v1.1 while on/after the last therapy received prior to study entry and while on/after treatment with anti-PD1/PD-L1. The last progression must have occured within 12 weeks prior to randomization in the study. ECOG performance status 0-2 At least one measurable lesion per RECIST v1.1 At least one lesion, suitable for sequential mandatory tumor biopsies (screening and on-treatment) in accordance with the biopsy guidelines specified in protocol. The same lesion must be biopsied sequentially. Screening tumor biopsy must fulfill the tissue quality criteria outlined in the protocol, as assessed by a local pathologist Key inclusion criteria for Arm 1A: Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma according to AJCC Edition 8 Previously treated for unresectable or metastatic melanoma: All subjects must have received anti-PD-1 checkpoint inhibitor therapy (ie. pembrolizumab or nivolumab) either as monotherapy or in combination with ipilimumab as the last systemic therapy prior to enrollment and must have confirmed disease progression as per RECIST v1.1 (confirmed on a subsequent scan, which can be the scan performed during screening) while on or after this therapy prior to enrollment. Subjects with V600BRAF wild-type disease must have received no more than 2 prior systemic therapies including prior anti-PD-1/PD-L1 (as monotherapy or in combination with ipilimumab) Subjects with V600BRAF mutant disease must have received no more than 3 prior systemic therapies including anti-PD-1/PD-L1 (as monotherapy or in combination with ipilimumab), and V600BRAF inhibitor (as monotherapy or in combination with a MEK inhibitor) The last dose of anti-PD-1 based therapy must have been received more than four weeks prior to first dose of study treatment. The last documented disease progression must have occurred within 12 weeks prior to first dose of study treatment No additional systemic treatment is allowed for advanced or metastatic melanoma (this includes for example tumor infiltrating lymphocyte therapy) ECOG performance status 0-1 At least one measurable lesion per RECIST v1.1 Subjects must have baseline tumor sample that is positive for LAG-3 per central assessment Key exclusion criteria common to all combination arms: Subjects with uveal or mucosal melanoma Presence of clinically active or unstable brain metastasis at time of screening. Use of any live vaccines against infectious diseases within 3 months before randomization/enrolment. Active infection requiring systemic antibiotic therapy at time of randomization/enrolment. Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization/enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Active, known or suspected autoimmune disease or a documented history of autoimmune disease. Prior allogenic bone marrow or solid organ transplant History of known hypersensitivity to any of the investigational drugs used in this study Prior systemic therapy for unresectable or metastatic melanoma with any investigational agent, or with any other agent except anti-PD-1/PD-L1 and anti-CTLA-4 (and V600BRAF and MEK inhibitors if subject has V600BRAF mutant disease). Prior neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months before the start of the study treatment Medical history or current diagnosis of myocarditis Cardiac Troponin T (or Troponin I) level > 2 x ULN at screening

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
Interventional Model Description: 4 arms are included in the randomized part of the study. One arm is included in the non-randomized part of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: LAG525 + Spartalizumab in unselected patients<br>Spartalizumab and LAG525 will be administered intravenously | Drug: Spartalizumab<br>* 400 mg every 4 weeks intravenously (i.v)<br>* Other names: PDR001;Drug: LAG525<br>* Taken intravenously (i.v)<br>|
| Experimental: Arm 2: Capmatinib+Spartalizumab in unselected patients<br>Spartalizumab will be administered intravenously. Capmatinib will be administered orally. | Drug: Spartalizumab<br>* 400 mg every 4 weeks intravenously (i.v)<br>* Other names: PDR001;Drug: Capmatinib<br>* Taken orally<br>* Other names: INC280;|
| Experimental: Arm 3: Canakinumab+Spartalizumab in unselected patients<br>Spartalizumab will be administered intravenously. Canakinumab will be administered subcutaneously. | Drug: Spartalizumab<br>* 400 mg every 4 weeks intravenously (i.v)<br>* Other names: PDR001;Drug: Canakinumab<br>* Taken subcutaneusly (s.c)<br>* Other names: ACZ885;|
| Experimental: Arm 4: Ribociclib+Spartalizumab in unselected patients<br>Spartalizumab will be administered intravenously. Ribociclib will be administered orally. | Drug: Spartalizumab<br>* 400 mg every 4 weeks intravenously (i.v)<br>* Other names: PDR001;Drug: Ribociclib<br>* Taken orally<br>* Other names: LEE011;|
| Experimental: Arm 1A: LAG525 + Spartalizumab in LAG-3 positive patients<br>Spartalizumab and LAG525 will be administered intravenously | Drug: Spartalizumab<br>* 400 mg every 4 weeks intravenously (i.v)<br>* Other names: PDR001;Drug: LAG525<br>* Taken intravenously (i.v)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR defined as the proportion of patients with a best overall response of either confirmed complete response or confirmed partial response (as per local review and according to RECIST v1.1) | 38 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | DOR defined as the time from date of first documented complete response or partial response to date of first documented disease progression or death due to any cause (as per local review and according to RECIST v1.1) | Up to disease progression or death due to any cause, whichever occurs first (3 years) | 
| Overall Survival (OS) | OS defined as time from date of randomization (or date of first dose of study treatment in arm 1A) to date of death due to any cause | Up to death due to any cause (3 years) | 
| Progression Free Survival (PFS) | PFS defined as the interval of time between the date of randomization (or date of first dose of study treatment in arm 1A) to the date of event defined as the first documented disease progression or death due to any cause (as per local review and according to RECIST v1.1) | Up to disease progression or death due to any cause, whichever occurs first (3 years) | 
| Disease Control Rate (DCR) | DCR defined as the proportion of patients with best overall response of complete response, partial response, or stable disease (as per local review and according to RECIST v1.1) | Up to disease progression or death due to any cause, whichever occurs first (3 years) | 
| Prevalence of anti-drug antibodies (ADA) prevalence at baseline | Number of patients with presence of anti-drug antibodies (ADA) | At Baseline | 
| Incidence of anti-drug antibodies (ADA) | Number of patients developing new anti-drug antibodies (ADA) | Throughout study until 150 day after last drug administration | 
| Percentage of subjects with a favorable biomarker profile (pFBP) | pFBP defined by changes in number of cells expressing the CD8+ T cell marker and/or T cell activation marker(s), T cell clonality and/or gene expression tumor biosy samples. | Baseline and after 3-4 weeks on treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Unresectable, melanoma, metastatic melanoma, advanced melanoma, spartalizumab, PDR001, LAG525, capmatinib, INC280, canakinumab, ACZ885, ribociclib, LEE011, immunotherapy, platform study, LAG-3