A First-in-Human Dose Escalation and Expansion Study to Evaluate Intratumoral Administration of SAR441000 as Monotherapy and in Combination With Cemiplimab in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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Primary Objectives: Dose Escalation: To determine maximum tolerated dose (MTD) or maximum administered dose (MAD) and overall safety and tolerability profile of SAR441000 when administered intratumorally as monotherapy and in combination with cemiplimab in patients who have no alternative standard treatment options. Dose Expansion (Combination): To determine the objective response rate of SAR441000 administered intratumorally in combination with cemiplimab in patients with melanoma, cutaneous squamous cell carcinoma or head and neck squamous cell carcinoma. Secondary Objectives: To characterize the pharmacokinetic (PK) profile of SAR441000 administered as monotherapy and in combination with cemiplimab. To assess the immunogenicity of SAR441000. To characterize the safety of SAR441000 when administered intratumorally in combination with cemiplimab. To determine the disease control rate (DCR), duration of response (DoR) and progression free survival (PFS) of SAR441000. To determine the recommended dose of SAR441000 for the expansion phase.

Detailed Description
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The expected duration of treatment for patients who benefit from study intervention may vary, based on progression date. Median expected duration of study per patient is estimated as 9 months in monotherapy and 12 months in combination therapy. The maximum treatment duration for non-progressive patients is up to 2 years.

Official Title
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A Phase 1 First-in-Human Dose Escalation and Expansion Study for the Evaluation of Safety, Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity of SAR441000 Administered Intratumorally as Monotherapy and in Combination With Cemiplimab in Patients With Advanced Solid Tumors

Conditions
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Metastatic Neoplasm

Intervention / Treatment
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* Drug: SAR441000
* Drug: Cemiplimab REGN2810


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: At least 18 years of age Advanced solid tumors including lymphomas for which no standard alternative therapy is available (escalation phase). Advanced melanoma (Stage IIIB-C or Stage IV, anti-PD-1/PD-L1 treated or not) or anti-PD-1/PD-L1 not treated advanced Head and Neck Squamous Cell Cancer or anti-PD-1/PD-L1 not treated Advanced Cutaneous Squamous Cell Cancer where no other alternative treatment option exists (expansion phases). Minimum 3 lesions enrollment. Injectable disease (i.e., suitable for direct intratumoral injection based on the dose level volume of each cohort and cumulative lesion size; according to the investigator's judgement). A lesion amenable for additional tumor biopsy. Patients with measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Life expectancy more than 3 months. Willingness to provide mandatory tumor biopsy. Male and female patients who agree to use effective contraceptive methods. Signed informed consent. Exclusion criteria: Eastern Cooperative Oncology Group (ECOG) performance score >1. Significant and uncontrolled concomitant illness that would adversely affect the patient's participation in the study. Any prior organ transplantation. History within the last 5 years of an invasive malignancy other than the one treated in this study, with the exception of resected basal or squamous-cell skin cancer or carcinoma, in situ of cervix or other local tumors considered cured by local treatment. History of unresolved viral hepatitis; systemic immune suppression including acquired immunodeficiency syndrome (AIDS) related illnesses or human immunodeficiency virus (HIV) disease requiring antiretroviral treatment. Prior splenectomy. New and progressive brain lesions. Poor bone marrow reserve resulting in low blood cell count. Poor liver and kidney functions, abnormal coagulation tests. Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. Maintenance therapy with prednisolone >7.5 mg/day orally or equivalent during the study. Non-resolution of any prior treatment related toxicity to Grade <2, except alopecia, vitiligo, fatigue and hypothyroidism controlled with replacement therapies. Moderate to severe immune related adverse event to prior immune-modulating agents within 90 days prior to the first study treatment. Central nervous system lymphoma. Prior allogeneic hematopoietic stem cell transplantation (HSCT) for patients with lymphoma. Autologous HSCT less than 90 days prior to initiation of study intervention. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR441000 Dose Escalation Phase<br>SAR441000 will be administered as intratumoral injection as monotherapy in patients with solid tumors over a 28-day cycle | Drug: SAR441000<br>* Pharmaceutical form: concentrate for solution for injection Route of administration: intratumoral<br>|
| Experimental: SAR441000 + cemiplimab - Dose Escalation Phase<br>SAR441000 will be administered as intratumoral injection in patients with solid tumors in combination with cemiplimab over a 21-day cycle | Drug: SAR441000<br>* Pharmaceutical form: concentrate for solution for injection Route of administration: intratumoral<br>Drug: Cemiplimab REGN2810<br>* Pharmaceutical form: solution for injection Route of administration: intravenous<br>|
| Experimental: SAR441000 + cemiplimab Expansion Melanoma, anti-PD-1 failure<br>SAR441000 will be administered intratumorally at the determined recommended dose in combination with cemiplimab to patients with advanced melanoma who have failed anti-PD-1/PD-L1 therapy. Treatment is administered over a 21-day cycle | Drug: SAR441000<br>* Pharmaceutical form: concentrate for solution for injection Route of administration: intratumoral<br>Drug: Cemiplimab REGN2810<br>* Pharmaceutical form: solution for injection Route of administration: intravenous<br>|
| Experimental: SAR441000 + cemiplimab Expansion Melanoma, anti-PD-1 naive<br>SAR441000 will be administered intratumorally at the determined recommended dose in combination with cemiplimab to patients with advanced anti-PD-1/PD-L1 naïve melanoma over a 21-day cycle | Drug: SAR441000<br>* Pharmaceutical form: concentrate for solution for injection Route of administration: intratumoral<br>Drug: Cemiplimab REGN2810<br>* Pharmaceutical form: solution for injection Route of administration: intravenous<br>|
| Experimental: SAR441000 + cemiplimab Expansion CSCC, anti-PD-1 naive<br>SAR441000 will be administered intratumorally at the determined recommended dose in combination with cemiplimab to patients with advanced anti-PD-1/PD-L1 naïve Cutaneous Squamous Cell Carcinoma (CSCC) over a 21-day cycle | Drug: SAR441000<br>* Pharmaceutical form: concentrate for solution for injection Route of administration: intratumoral<br>Drug: Cemiplimab REGN2810<br>* Pharmaceutical form: solution for injection Route of administration: intravenous<br>|
| Experimental: SAR441000 + cemiplimab Expansion HNSCC, anti-PD-1 naive<br>SAR441000 will be administered intratumorally at the determined recommended dose in combination with cemiplimab to patients with advanced anti-PD-1/PD-L1 naïve Head and Neck Squamous Cell Cancer (HNSCC) over a 21-day cycle | Drug: SAR441000<br>* Pharmaceutical form: concentrate for solution for injection Route of administration: intratumoral<br>Drug: Cemiplimab REGN2810<br>* Pharmaceutical form: solution for injection Route of administration: intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For dose escalation: Incidence of Dose Limiting Toxicities (DLTs) (Monotherapy) | Incidence of DLTs at Cycle 1 (SAR441000 monotherapy), assessed as the occurrence of AE, satisfying protocol defined DLT criteria, using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 whether related or not to the study treatment in the absence of clear evidence to the contrary, and if not related to a disease progression | Cycle 1; Cycle = 28 days for monotherapy | 
| For dose escalation: Incidence of Dose Limiting Toxicities (DLTs) (Combination therapy) | Incidence of DLTs during period from Cycle 1 Day 1 to Cycle 2 Day 8 (SAR441000 + cemiplimab combination therapy), assessed as the occurrence of AE, satisfying protocol defined DLT criteria, using NCI-CTCAE version 5.0 whether related or not to the study treatment in the absence of clear evidence to the contrary, and if not related to a disease progression | Cycle 1 Day 1 to Cycle 2 Day 8; Cycle = 21 days for combination therapy; overall assessment = 28 days | 
| For dose escalation: Maximum tolerated dose (MTD) of SAR441000 (Monotherapy) | MTD of SAR441000 as monotherapy, determined during Cycle 1 of dose escalation phase | End of Dose Escalation phase (ie, End of Cycle 1 for last patient); Cycle = 28 days for monotherapy | 
| For dose escalation: Maximum tolerated dose (MTD) of SAR441000 (Combination therapy) | MTD of SAR441000, in combination with cemiplimab, determined during period from Cycle 1 Day 1 to Cycle 2 Day 8 in dose escalation phase | End of Dose Escalation Phase (ie, End of Cycle 1 Day 1 to Cycle 2 Day 8 for last patient); Cycle = 21 days for combination; overall assesment = 28 days | 
| Adverse Events | Incidence of Treatment Emergent Adverse Events (TEAE) during dose escalation phase | Up to end of treatment (Estimated median duration=12 months) | 
| For Expansion: Objective Response Rate (ORR) | Assessment of overall response rate using standard imaging and RECIST 1.1 criteria | Estimated median duration = 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Pharmacokinetic (PK) parameter for SAR441000 (Cmax) (Monotherapy) | Maximum plasma concentration (Cmax) of SAR4410000 as monotherapy observed over the dosing interval | Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 28 days for monotherapy | 
| Assessment of Pharmacokinetic (PK) parameter for SAR441000 (Cmax) (Combination therapy) | Maximum plasma concentration (Cmax) of SAR4410000 in combination with cemiplimab observed over the dosing interval | Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 21 days for combination therapy | 
| Assessment of PK parameter for SAR441000 (AUC) (Monotherapy) | Area under the plasma concentration versus time curve (AUC) of SAR441000 as monotherapy over the dosing interval | Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 28 days for monotherapy | 
| Assessment of PK parameter for SAR441000 (AUC) (Combination therapy) | Area under the plasma concentration versus time curve (AUC) of SAR441000 in combination with cemiplimab over the dosing interval | Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 21 days for combination therapy | 
| Assessment of PK parameter (Ctrough) for SAR441000 | Trough Plasma Concentration (Ctrough) of SAR441000 as monotherapy and in combination with cemiplimab. It is defined as plasma concentration observed just before treatment administration during repeated dosing | Baseline to End of Treatment (Estimated median duration of 12 months) | 
| Assessment of PK parameter for cemiplimab (Cmax) | Maximum plasma concentration of cemiplimab in combination with SAR441000, observed over the dosing interval | Cycle 1; Cycle duration is 21 days | 
| Assessment of PK parameter of cemiplimab (AUC) | Area under the plasma concentration versus time curve of cemiplimab in combination with SAR441000 over the dosing interval | Cycle 1; Cycle duration is 21 days | 
| Assessment of PK parameter for cemiplimab (Ctrough) | Trough plasma concentration of cemiplimab in combination with SAR441000, observed just before treatment administration during repeated dosing | Baseline to End of Treatment (Estimated median duration of 12 months) | 
| Immunogenicity of SAR441000 and cemiplimab | Incidence of anti-drug antibody (ADA) positive patients for immunogenicity | Baseline to End of Study (Estimated median duration of 12 months) | 
| DCR | Disease Control Rate (DCR) with SAR441000 in combination with cemiplimab. DCR is sum of Complete Response + Partial Response + Stable Disease | Baseline to End of Study (Estimated median duration of 12 months) | 
| DoR | Duration of Response (DoR) with SAR441000 in combination with cemiplimab. DoR is time from initial response to the first documented tumor progression | Baseline to End of Study (Estimated median duration of 12 months) | 
| Progression Free Survival (PFS) | Time from first drug administration to the first documented tumor progression or death from any cause, whichever comes first | Baseline to End of Study (Estimated median duration of 12 months) | 
| Incidence of Treatment Emergent Adverse Events (TEAE) during dose expansion phase | Incidence of Adverse Events (AE)/ Serious AE (SAE) / Laboratory abnormalities considered to be adverse events | Baseline to End of Treatment (Estimated median duration of 12 months) | 
| Recommended dose of SAR441000 for expansion phase (Combination therapy) | SAR441000 dose for administration in combination with cemiplimab selected for expansion phase based on MTD/MAD by the Bayesian model, the overall safety, activity and PK/PDy data | End of Dose Escalation Phase (ie, End of Cycle 1 Day 1 to Cycle 2 Day 8 for last patient); Cycle = 21 days for combination; overall assesment = 28 days | 
| For Dose Expansion: Objective Response Rate (ORR) | Assessment of overall response rate using standard imaging by RECIST 1.1 and iRECIST criteria | Estimated median duration of 12 months |