Clinical trial NCT03871348: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Metastatic Neoplasm
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: BioNTech RNA Pharmaceuticals GmbH
First posted: 2019-03-12
Enrollment: 77
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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.

Primary outcomes:
measure: For dose escalation: Incidence of Dose Limiting Toxicities (DLTs) (Monotherapy)
timeFrame: Cycle 1; Cycle = 28 days for monotherapy
measure: For dose escalation: Incidence of Dose Limiting Toxicities (DLTs) (Combination therapy)
timeFrame: Cycle 1 Day 1 to Cycle 2 Day 8; Cycle = 21 days for combination therapy; overall assessment = 28 days
measure: For dose escalation: Maximum tolerated dose (MTD) of SAR441000 (Monotherapy)
timeFrame: End of Dose Escalation phase (ie, End of Cycle 1 for last patient); Cycle = 28 days for monotherapy
measure: For dose escalation: Maximum tolerated dose (MTD) of SAR441000 (Combination therapy)
timeFrame: 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
measure: Adverse Events
timeFrame: Up to end of treatment (Estimated median duration=12 months)
measure: For Expansion: Objective Response Rate (ORR)
timeFrame: Estimated median duration = 12 months
Secondary outcomes:
measure: Assessment of Pharmacokinetic (PK) parameter for SAR441000 (Cmax) (Monotherapy)
timeFrame: Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 28 days for monotherapy
measure: Assessment of Pharmacokinetic (PK) parameter for SAR441000 (Cmax) (Combination therapy)
timeFrame: Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 21 days for combination therapy
measure: Assessment of PK parameter for SAR441000 (AUC) (Monotherapy)
timeFrame: Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 28 days for monotherapy
measure: Assessment of PK parameter for SAR441000 (AUC) (Combination therapy)
timeFrame: Cycle 1 Week 1 and Cycle 3 Week 1 (in all patients); Cycle duration is 21 days for combination therapy
measure: Assessment of PK parameter (Ctrough) for SAR441000
timeFrame: Baseline to End of Treatment (Estimated median duration of 12 months)
measure: Assessment of PK parameter for cemiplimab (Cmax)
timeFrame: Cycle 1; Cycle duration is 21 days
measure: Assessment of PK parameter of cemiplimab (AUC)
timeFrame: Cycle 1; Cycle duration is 21 days
measure: Assessment of PK parameter for cemiplimab (Ctrough)
timeFrame: Baseline to End of Treatment (Estimated median duration of 12 months)
measure: Immunogenicity of SAR441000 and cemiplimab
timeFrame: Baseline to End of Study (Estimated median duration of 12 months)
measure: DCR
timeFrame: Baseline to End of Study (Estimated median duration of 12 months)
measure: DoR
timeFrame: Baseline to End of Study (Estimated median duration of 12 months)
measure: Progression Free Survival (PFS)
timeFrame: Baseline to End of Study (Estimated median duration of 12 months)
measure: Incidence of Treatment Emergent Adverse Events (TEAE) during dose expansion phase
timeFrame: Baseline to End of Treatment (Estimated median duration of 12 months)
measure: Recommended dose of SAR441000 for expansion phase (Combination therapy)
timeFrame: 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
measure: For Dose Expansion: Objective Response Rate (ORR)
timeFrame: Estimated median duration of 12 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute Site Number : 8400003
state: Massachusetts
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation Site Number : 8400007
state: Ohio
city: Houston
country: United States
facility: ~University of Texas - MD Anderson Cancer Center Site Number : 8400002
state: Texas
city: Gent
country: Belgium
facility: Investigational Site Number : 0560003
city: Leuven
country: Belgium
facility: Investigational Site Number : 0560002
city: Sint-Lambrechts-Woluwe
country: Belgium
facility: Investigational Site Number : 0560001
city: Marseille
country: France
facility: Investigational Site Number : 2500004
city: Paris
country: France
facility: Investigational Site Number : 2500002
city: Villejuif
country: France
facility: Investigational Site Number : 2500001
city: Hamburg
country: Germany
facility: Investigational Site Number : 2760005
city: Heidelberg
country: Germany
facility: Investigational Site Number : 2760004
city: Mainz
country: Germany
facility: Investigational Site Number : 2760001
city: Mannheim
country: Germany
facility: Investigational Site Number : 2760003
city: Tübingen
country: Germany
facility: Investigational Site Number : 2760006
city: Nijmegen
country: Netherlands
facility: Investigational Site Number : 5280002
city: Rotterdam
country: Netherlands
facility: Investigational Site Number : 5280001
city: Barcelona
country: Spain
facility: Investigational Site Number : 7240004
state: Barcelona [Barcelona]
city: Pamplona
country: Spain
facility: Investigational Site Number : 7240001
state: Navarra
city: Pamplona
country: Spain
facility: Investigational Site Number : 7240005
state: Navarra
city: Valencia
country: Spain
facility: Investigational Site Number : 7240002
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: