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

Metastatic Neoplasm Clinical Trial

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 Details — Status: Terminated

Administrative data

• NCT number: NCT03871348
• Other study ID #: TED15297
• Secondary ID: U1111-1205-11762
• Status: Terminated
• Phase: Phase 1
• Start date: January 3, 2019
• Est. completion date: February 21, 2024

Study information

• Verified date: March 2024
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 77
• Est. completion date: February 21, 2024
• Est. primary completion date: July 25, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Metastatic Neoplasm
• Neoplasm Metastasis

Intervention

Drug:
• SAR441000
Pharmaceutical form: concentrate for solution for injection Route of administration: intratumoral
• Cemiplimab REGN2810
Pharmaceutical form: solution for injection Route of administration: intravenous

Locations

Country	Name	City	State
Belgium	Investigational Site Number : 0560003	Gent
Belgium	Investigational Site Number : 0560002	Leuven
Belgium	Investigational Site Number : 0560001	Sint-Lambrechts-Woluwe
France	Investigational Site Number : 2500004	Marseille
France	Investigational Site Number : 2500002	Paris
France	Investigational Site Number : 2500001	Villejuif
Germany	Investigational Site Number : 2760005	Hamburg
Germany	Investigational Site Number : 2760004	Heidelberg
Germany	Investigational Site Number : 2760001	Mainz
Germany	Investigational Site Number : 2760003	Mannheim
Germany	Investigational Site Number : 2760006	Tübingen
Netherlands	Investigational Site Number : 5280002	Nijmegen
Netherlands	Investigational Site Number : 5280001	Rotterdam
Spain	Investigational Site Number : 7240004	Barcelona	Barcelona [Barcelona]
Spain	Investigational Site Number : 7240001	Pamplona	Navarra
Spain	Investigational Site Number : 7240005	Pamplona	Navarra
Spain	Investigational Site Number : 7240002	Valencia
United States	Dana Farber Cancer Institute Site Number : 8400003	Boston	Massachusetts
United States	Cleveland Clinic Foundation Site Number : 8400007	Cleveland	Ohio
United States	~University of Texas - MD Anderson Cancer Center Site Number : 8400002	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	BioNTech RNA Pharmaceuticals GmbH

Countries where clinical trial is conducted

United States,  Belgium,  France,  Germany,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Adverse Events	Incidence of Treatment Emergent Adverse Events (TEAE) during dose escalation phase	Up to end of treatment (Estimated median duration=12 months)
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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