Metastatic Neoplasm
Conditions
Brief summary
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
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.
Interventions
DRUGSAR441000
Pharmaceutical form: concentrate for solution for injection Route of administration: intratumoral
Pharmaceutical form: solution for injection Route of administration: intravenous
Sponsors
BioNTech RNA Pharmaceuticals GmbH
Sanofi
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| For dose escalation: Incidence of Dose Limiting Toxicities (DLTs) (Monotherapy) | Cycle 1; Cycle = 28 days for 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 |
| For dose escalation: Incidence of Dose Limiting Toxicities (DLTs) (Combination therapy) | Cycle 1 Day 1 to Cycle 2 Day 8; Cycle = 21 days for combination therapy; overall assessment = 28 days | 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 |
| For dose escalation: Maximum tolerated dose (MTD) of SAR441000 (Monotherapy) | End of Dose Escalation phase (ie, End of Cycle 1 for last patient); Cycle = 28 days for monotherapy | MTD of SAR441000 as monotherapy, determined during Cycle 1 of dose escalation phase |
| For dose escalation: Maximum tolerated dose (MTD) of SAR441000 (Combination therapy) | 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 | MTD of SAR441000, in combination with cemiplimab, determined during period from Cycle 1 Day 1 to Cycle 2 Day 8 in dose escalation phase |
| Adverse Events | Up to end of treatment (Estimated median duration=12 months) | Incidence of Treatment Emergent Adverse Events (TEAE) during dose escalation phase |
| For Expansion: Objective Response Rate (ORR) | Estimated median duration = 12 months | Assessment of overall response rate using standard imaging and RECIST 1.1 criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of PK parameter of cemiplimab (AUC) | Cycle 1; Cycle duration is 21 days | Area under the plasma concentration versus time curve of cemiplimab in combination with SAR441000 over the dosing interval |
| Assessment of PK parameter for cemiplimab (Ctrough) | Baseline to End of Treatment (Estimated median duration of 12 months) | Trough plasma concentration of cemiplimab in combination with SAR441000, observed just before treatment administration during repeated dosing |
| Immunogenicity of SAR441000 and cemiplimab | Baseline to End of Study (Estimated median duration of 12 months) | Incidence of anti-drug antibody (ADA) positive patients for immunogenicity |
| DCR | Baseline to End of Study (Estimated median duration of 12 months) | Disease Control Rate (DCR) with SAR441000 in combination with cemiplimab. DCR is sum of Complete Response + Partial Response + Stable Disease |
| Assessment of Pharmacokinetic (PK) parameter for SAR441000 (Cmax) (Monotherapy) | Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 28 days for monotherapy | Maximum plasma concentration (Cmax) of SAR4410000 as monotherapy observed over the dosing interval |
| Progression Free Survival (PFS) | Baseline to End of Study (Estimated median duration of 12 months) | Time from first drug administration to the first documented tumor progression or death from any cause, whichever comes first |
| Incidence of Treatment Emergent Adverse Events (TEAE) during dose expansion phase | Baseline to End of Treatment (Estimated median duration of 12 months) | Incidence of Adverse Events (AE)/ Serious AE (SAE) / Laboratory abnormalities considered to be adverse events |
| Recommended dose of SAR441000 for expansion phase (Combination therapy) | 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 | 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 |
| For Dose Expansion: Objective Response Rate (ORR) | Estimated median duration of 12 months | Assessment of overall response rate using standard imaging by RECIST 1.1 and iRECIST criteria |
| DoR | Baseline to End of Study (Estimated median duration of 12 months) | Duration of Response (DoR) with SAR441000 in combination with cemiplimab. DoR is time from initial response to the first documented tumor progression |
| Assessment of Pharmacokinetic (PK) parameter for SAR441000 (Cmax) (Combination therapy) | Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 21 days for combination therapy | Maximum plasma concentration (Cmax) of SAR4410000 in combination with cemiplimab observed over the dosing interval |
| Assessment of PK parameter for SAR441000 (AUC) (Monotherapy) | Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 28 days for monotherapy | Area under the plasma concentration versus time curve (AUC) of SAR441000 as monotherapy over the dosing interval |
| Assessment of PK parameter for SAR441000 (AUC) (Combination therapy) | Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 21 days for combination therapy | Area under the plasma concentration versus time curve (AUC) of SAR441000 in combination with cemiplimab over the dosing interval |
| Assessment of PK parameter (Ctrough) for SAR441000 | Baseline to End of Treatment (Estimated median duration of 12 months) | 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 |
| Assessment of PK parameter for cemiplimab (Cmax) | Cycle 1; Cycle duration is 21 days | Maximum plasma concentration of cemiplimab in combination with SAR441000, observed over the dosing interval |
Countries
Belgium, France, Germany, Netherlands, Spain, United States
Outcome results
None listed