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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

NCT03871348

Description:

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 (Monotherapy): To determine the objective response rate of SAR441000 administered intratumorally as monotherapy in patients with advanced melanoma whose disease has progressed after prior therapy based on anti-PD-1 or anti-PD-L1. - 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 as monotherapy and 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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Lymphoma
  • Malignant Solid Tumor
  • Melanoma
  • Skin Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: TED15297
  • SECONDARY ID: 2017-004766-94
  • SECONDARY ID: U1111-1205-1176
  • NCT ID: NCT03871348

Conditions

  • Metastatic Neoplasm

Interventions

DrugSynonymsArms
SAR441000SAR441000 + cemiplimab - Dose Escalation Phase
Cemiplimab REGN2810SAR441000 + cemiplimab - Dose Escalation Phase

Purpose

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 (Monotherapy): To determine the objective response rate of SAR441000 administered intratumorally as monotherapy in patients with advanced melanoma whose disease has progressed after prior therapy based on anti-PD-1 or anti-PD-L1. - 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 as monotherapy and 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 52 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
SAR441000 Dose Escalation PhaseExperimentalSAR441000 will be administered as intratumoral injection as monotherapy in patients with solid tumors over a 28-day cycle
  • SAR441000
SAR441000 + cemiplimab - Dose Escalation PhaseExperimentalSAR441000 will be administered as intratumoral injection in patients with solid tumors in combination with cemiplimab over a 21-day cycle
  • SAR441000
  • Cemiplimab REGN2810
SAR441000 Expansion Cohort in MelanomaExperimentalSAR441000 will be administered intratumorally at the determined recommended dose to patients with advanced melanoma over a 28-day cycle
  • SAR441000
SAR441000 + cemiplimab Expansion Melanoma, anti-PD-1 failureExperimentalSAR441000 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
  • SAR441000
  • Cemiplimab REGN2810
SAR441000 + cemiplimab Expansion Melanoma, anti-PD-1 naiveExperimentalSAR441000 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
  • SAR441000
  • Cemiplimab REGN2810
SAR441000 + cemiplimab Expansion CSCC, anti-PD-1 naiveExperimentalSAR441000 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
  • SAR441000
  • Cemiplimab REGN2810
SAR441000 + cemiplimab Expansion HNSCC, anti-PD-1 naiveExperimentalSAR441000 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
  • SAR441000
  • Cemiplimab REGN2810

Eligibility Criteria

        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 (patient with 2 lesions is acceptable in selected cases) at
             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).

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:For dose escalation: Incidence of Dose Limiting Toxicities (DLTs) (Monotherapy)
Time Frame:Cycle 1; Cycle = 28 days for monotherapy
Safety Issue:
Description: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

Secondary Outcome Measures

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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sanofi

Last Updated

May 12, 2020