| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable or metastatic melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Unresectable or metastatic melanoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of each combination arm, as measured by objective response rate (ORR) |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary:
To evaluate the efficacy of each combination arm in terms of duration of response (DoR)
Other secondary objectives :
- To evaluate the efficacy of each combination arm in terms of progression-free survival (PFS) and disease control rate (DCR)
-To evaluate the overall survival (OS) of each combination arm
-To characterize the safety and tolerability of each combination arm
-To characterize the prevalence and incidence of immunogenicity of spartalizumab, LAG525 and canakinumab in each combination arm
-To evaluate changes in levels and phenotype of T cell populations in the tumor and tumor microenvironment after treatment with combination therapies |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 systemictherapy 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
Other inclusion criteria may apply. |
|
| E.4 | Principal exclusion criteria |
• 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 médications 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/PDL1 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
Other exclusion criteria may apply. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Response Rate (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) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- 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)
- Overall Survival (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
- Progression Free Survival (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)
- Disease Control Rate (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)
- Prevalence of anti-drug antibodies (ADA) at baseline: number of patients with presence of ADA
- Incidence of anti-drug antibodies (ADA): number of patients developing new ADA
- Percentage of subjects with a favorable biomarker profile (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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- DOR: Up to disease progression or death due to any cause, whichever occurs first (3 years)
- OS: Up to death due to any cause (3 years)
- PFS: Up to disease progression or death due to any cause, whichever occurs first (3 years)
- DCR: Up to disease progression or death due to any cause, whichever occurs first (3 years)
- Prevalence of ADA prevalence at baseline: at baseline
- Incidence of ADA: Throughout study until 150 day after last drug administration
- pFBP: Baseline and after 3-4 weeks on treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| United States |
| France |
| Germany |
| Italy |
| United Kingdom |
| Netherlands |
| Spain |
| Switzerland |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of study is defined as the earliest occurrence of one of the
following:
- All subjects have died or discontinued from the study
- Another clinical study becomes available that can continue to provide the appropriate combination treatment in this subject population and all subjects ongoing are eligible to be transferred to that clinical study
- All subjects randomized/enrolled in the study have at least 15 months of follow-up (i.e. 15 months after last subject is randomized/enrolled). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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