A First-in-human Study of the Safety, Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity of SAR439459 Monotherapy and Combination of SAR439459 and Cemiplimab in Patients With Advanced Solid Tumors

Malignant Solid Tumor Clinical Trial

Official title:

A Phase 1/1b First-in-human Dose Escalation and Expansion Study for the Evaluation of Safety, Pharmacokinetics, Pharmacodynamics, and Anti-tumor Activity of SAR439459 Administered Intravenously as Monotherapy and in Combination With Cemiplimab in Adult Patients With Advanced Solid Tumors

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03192345
• Other study ID #: TCD14678
• Secondary ID: 2018-001113-32
• Status: Terminated
• Phase: Phase 1
• Start date: June 9, 2017
• Est. completion date: January 17, 2022

Study information

• Verified date: February 4, 2022
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary Objectives:

Dose escalation (Part 1)

Part 1A (SAR439459 monotherapy)

• To determine the maximum tolerated dose (MTD) and/or maximum administered dose (MAD) of SAR439459 when administered intravenously as monotherapy in adult patients with advanced solid tumors.

Part 1B (SAR439459 and cemiplimab combination therapy)

• To determine the MTD and/or MAD of SAR439459 administered intravenously in combination with cemiplimab administered intravenously in adult patients with advanced solid tumors.

Dose expansion (Part 2)

Part 2A (SAR439459 monotherapy)

• To determine optimal dose of SAR439459 administered intravenously in adult patients with advanced melanoma who have failed a prior therapy based on anti-PD-1 (programmed cell death-1) or anti-PD-L1.

Part 2B (SAR439459 and cemiplimab combination therapy)

• To determine the objective response rate (ORR) of SAR439459 in combination with cemiplimab in adult patients with selected advanced solid tumors by evaluation of antitumor response according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1).

Secondary Objectives:

• Pharmacokinetic (PK) profile SAR439459 monotherapy and combined with cemiplimab, PK profile of cemiplimab combined with SAR439459.

• Immunogenicity of SAR439459 monotherapy and combined with cemiplimab.

Dose escalation (Part 1)

• Overall safety/tolerability profile of SAR439459 monotherapy and combined with cemiplimab.

• Preliminary recommended phase 2 dose (pRP2D) of SAR439459 as monotherapy or combined with cemiplimab.

Dose expansion (Part 2)

• Progression free survival (PFS), time to progression (TTP), ORR, and safety of SAR439459 as monotherapy and PFS, TTP, duration of response (DOR), disease control rate (DCR) and safety in combination with cemiplimab.

• To confirm the optimal dose of SAR439459 administered in combination with cemiplimab.

Description:

The duration of the study for an individual patient will start from the signature of the main informed consent and include a screening period of up to 4 weeks (28 days), a treatment period of at least 1 or 2 cycles (21 or 14 days per cycle, respectively), an end-of-treatment visit at least 30 days following the last administration of study drug (or until the patient receives another anticancer therapy, whichever is earlier), and a follow-up visit 3 months after treatment discontinuation and every 3 months following, until disease progression, or initiation of another antitumor treatment, or death, whichever is earlier. For the urothelial cancer cohort in Part 2B, follow-up visits will occur every 3 months until death, study cut-off date, or upon cancellation of Survival follow-up at the discretion of the Sponsor at any prior timepoint. For the overall survival analysis (approximately 12 months after last patient first dose), whichever comes first.

Patients who have no disease progression, and continue to benefit from the study drug(s), will be allowed to continue treatment beyond the common study end-date at their assigned dose unless the study is terminated by the Sponsor. The expected enrollment period is approximately 42 months.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 161
• Est. completion date: January 17, 2022
• Est. primary completion date: December 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

Dose escalation (Part 1A and Part 1B)

• Patients with histologically confirmed, advanced unresectable or metastatic solid tumor whom in the opinion of the Investigator does not have a suitable alternative therapy.

Dose expansion (Part 2A)

• Patients with histologically confirmed, advanced unresectable or metastatic melanoma whom in the opinion of the Investigator does not have a suitable alternative therapy.

• Patients must have failed after any prior therapy based on anti-PD-1 or anti-PD-L1 as defined by disease progression within 26 weeks of initiating anti-PD-1 or anti-PD-L1 based therapy without any evidence of a response (primary resistance to anti-PD-1 or anti-PD-L1).

• Patients must have a site of disease amenable to biopsy and be a candidate for tumor biopsy. Patients must be able and willing to provide mandatory tumor biopsies prior to and during study treatment.

Dose expansion (Part 2B)

• Patients with disease location amenable to mandatory tumor biopsy at baseline with histologically confirmed advanced unresectable or metastatic melanoma, colorectal adenocarcinoma, urothelial cancer, hepatocellular carcinoma (HCC), or non-small cell lung cancer (NSCLC).

• Melanoma patients must have failed one prior therapy based on anti-PD-1 or anti-PD-L1.

• Patients with colorectal cancer must have progressed after last line of therapy.

• Patients with urothelial cancer must have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Patients must not have received >2 lines of therapy for advanced disease. Patients must not have received prior treatment with anti-PD-1 or anti-PD-L1.

• Patients with HCC must have failed after 1 prior therapy based on anti-PD-1 or anti-PD-L1.

• Patients with NSCLC must have failed during or after 1 prior therapy based on anti-PD-1 or anti-PD-L1.

• Patients with histologically confirmed, advanced unresectable or metastatic melanoma, or colorectal cancer or NSCLC whom in the opinion of the Investigator do not have a suitable alternative therapy.

Dose expansion parts 2A and 2B

• At least 1 measurable lesion by RECIST v1.1.

All cohorts

• Patient understands and has signed Informed Consent form and is willing and able to comply with the requirements of the trial.

Exclusion criteria:

• Age <18 years or < the country's legal age of majority if the legal age is more than 18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status >1.

• Concurrent treatment with any other anticancer therapy (including radiotherapy or investigational agents) or participation in another clinical study.

• Washout period of less than 3 weeks to prior anticancer therapy.

• Women of reproductive potential and male subjects with female partners of childbearing potential who are not willing to avoid pregnancy by using highly effective contraceptive.

• Pregnant or breast-feeding women.

• Unwillingness and inability to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

• Significant and uncontrolled concomitant illness, including any psychiatric condition.

• Active infections, including unexplained fever (temperature >38.1ºC), or antibiotic therapy within 1 week prior to enrollment.

• Any prior organ transplant including allogeneic bone marrow transplant.

• History within the last 5 years of an invasive malignancy other than the one treated in this study, with the exception of resected/ablated basal or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix, or other local tumors considered cured by local treatment.

• History of known human immunodeficiency virus (HIV), HIV serology at screening will be conducted only for patients in German study sites.

• Known uncontrolled hepatitis B virus (HBV) infection.

• Known untreated current hepatitis C virus (HCV) infection.

• Any major surgery within the last 28 days.

• Patients with primary central nervous system (CNS) tumors and/or CNS metastases of non-CNS primary tumors.

• History of congestive heart failure, myocardial infarction with reduced ejection fraction, symptomatic coronary artery disease, documented uncontrolled hypertension, major clinically significant Electrocardiography (ECG) and echocardiogram abnormalities, significant ventricular arrhythmias, significant valvular heart disease (including valve replacement), vascular malformation, aneurysm, significant pulmonary conditions such as idiopathic pulmonary hypertension, uncontrolled chronic lung disease.

• History of severe, acute or chronic renal diseases.

• Any of the following within 6 months prior to study enrollment: pulmonary embolism, deep vein thrombosis, active uncontrolled bleeding, infectious or inflammatory bowel disease, diverticulitis, intestinal obstruction or perforation and gastrointestinal hemorrhage.

• Inadequate hematological, renal or liver function.

• Non-resolution of any prior treatment related toxicity to Grade <2.

• Prior treatment with any anti-transforming growth factor ß (anti-TGFß) inhibitors.

• Known allergies to any component of SAR439459 and/or cemiplimab.

• Patients with uveal melanoma and patients with prior or ongoing uveitis.

• Patients who received prior immunotherapy who developed toxicity leading to a permanent discontinuation of immunotherapy.

• Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments.

• Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 4 weeks prior to the first dose of SAR439459 and/or cemiplimab (occasional use of inhaled, intraocular, nasal or topical steroids for symptomatic relief allowed).

• History of interstitial lung disease or active non-infectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management.

• Patients with underlying cancer predisposition syndromes.

• Receipt of a live vaccine within 30 days of planned start of study medication.

• Therapeutic doses of anticoagulants or antiplatelet agents within 7 days prior the first dose of SAR439459.

• Prothrombin time (PT) or international normalized ratio (INR) > 1.5 × upper limit of normal (ULN).

• Patients accommodated in an institution because of regulatory or legal order; prisoners or patients who are legally institutionalized.

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

• Malignant Solid Tumor
• Neoplasms

Intervention

Biological:
• SAR439459
Pharmaceutical form: powder for solution for infusion Route of administration: intravenous infusion

Drug:
• Cemiplimab REGN2810
Pharmaceutical form: solution for infusion Route of administration: intravenous infusion

Locations

Country	Name	City	State
Australia	Investigational Site Number :0360002	Heidelberg West	Victoria
Australia	Investigational Site Number :0360001	Melbourne	Victoria
Belgium	Investigational Site Number :0560002	Bruxelles
Belgium	Investigational Site Number :0560001	Leuven
Canada	Investigational Site Number :1240003	Calgary	Alberta
Canada	Investigational Site Number :1240002	Montreal	Quebec
Canada	Investigational Site Number :1240001	Toronto	Ontario
Estonia	Investigational Site Number :2330001	Tallinn
France	Investigational Site Number :2500006	Lille
France	Investigational Site Number :2500002	Marseille
France	Investigational Site Number :2500003	Nantes
France	Investigational Site Number :2500005	Nantes
France	Investigational Site Number :2500004	Paris
France	Investigational Site Number :2500001	Villejuif
Germany	Investigational Site Number :2760001	Essen
Germany	Investigational Site Number :2760003	Hannover
Italy	Investigational Site Number :3800001	Milano
Italy	Investigational Site Number :3800002	Milano
Italy	Investigational Site Number :3800003	Rozzano	Milano
Korea, Republic of	Investigational Site Number :4100001	Seoul	Seoul-teukbyeolsi
Korea, Republic of	Investigational Site Number :4100002	Seoul	Seoul-teukbyeolsi
Netherlands	Investigational Site Number :5280005	Nijmegen
Netherlands	Investigational Site Number :5280001	Rotterdam
Netherlands	Investigational Site Number :5280002	Utrecht
Spain	Investigational Site Number :7240001	Barcelona	Barcelona [Barcelona]
Spain	Investigational Site Number :7240002	Barcelona	Barcelona [Barcelona]
Spain	Investigational Site Number :7240006	Barcelona	Barcelona [Barcelona]
Spain	Investigational Site Number :7240003	Madrid / Madrid	Madrid, Comunidad De
Spain	Investigational Site Number :7240004	Madrid / Madrid	Madrid, Comunidad De
Spain	Investigational Site Number :7240005	Pamplona	Navarra
Taiwan	Investigational Site Number :1580003	Kaohsiung
Taiwan	Investigational Site Number :1580002	Tainan
Taiwan	Investigational Site Number :1580001	Taipei 100
United Kingdom	Investigational Site Number :8260002	Cardiff	Vale Of Glamorgan, The
United Kingdom	Investigational Site Number :8260001	Glasgow	Central Bedfordshire
United States	Investigational Site Number :8400001	Boston	Massachusetts
United States	Investigational Site Number :8400101	Boston	Massachusetts
United States	Investigational Site Number :8400003	Dallas	Texas
United States	Investigational Site Number :8400007	Duarte	California
United States	Investigational Site Number :8400008	Durham	North Carolina
United States	Investigational Site Number :8400004	Fairway	Kansas
United States	Investigational Site Number :8400006	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Estonia,  France,  Germany,  Italy,  Korea, Republic of,  Netherlands,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Dose Limiting Toxicities (DLTs)	Incidence of DLTs at Cycle 1 and/or 2 in Parts 1A and 1B.	Through the end of 1 or 2 cycles, total duration up to 6 weeks (for Part 1A each cycle is 2 weeks; for Part 1B each cycle is 2 or 3 weeks)
Primary	Objective Response Rate (ORR) for Part 2B	Efficacy as documented by ORR will be assessed by evaluation of antitumor response information according to RECIST 1.1 (Part 2B).	Continuous throughout study assessment (up to approximately 1 year)
Secondary	Overall safety profile	The overall safety profile of SAR439459 administered in monotherapy (Part 1A and Part 2A) or in combination with cemiplimab (Part 1B and Part 2B).	Continuous throughout study assessment (up to approximately 1 year)
Secondary	Progression free survival (PFS)	The time from first investigational medicinal product (IMP) administration until objective tumor progression or death (Part 2A and Part 2B).	Continuous throughout study assessment (up to approximately 1 year)
Secondary	Time to progression (TTP)	The time from first IMP administration until objective tumor progression (Part 2A and 2B).	Continuous throughout study assessment (up to approximately 1 year)
Secondary	Objective Response Rate (ORR) Part 2A	Efficacy as documented by ORR will be assessed by evaluation of antitumor response information according to RECIST 1.1 (Part 2A).	Continuous throughout study assessment (up to approximately 1 year)
Secondary	Duration of response Part 2B	Time from initial response to the first documented tumor progression.	Continuous throughout study assessment (up to approximately 1 year)
Secondary	Disease Control Rate Part 2B	Sum of complete response, partial response and stable disease rates	Continuous throughout study assessment (up to approximately 1 year)
Secondary	Immunogenicity evaluation	Blood samples will be assessed for human anti-SAR439459 antibodies (all cohorts) and for human anti-cemiplimab antibodies (Parts 1B and 2B).	Up to approximately 1 year
Secondary	Cmax for SAR439459 and for cemiplimab	Maximum plasma concentration observed.	Cycle 1, Day 1 to Day 15 or to Day 22
Secondary	AUC for SAR439459	Area under the serum concentration versus time curve extrapolated to infinity.	Cycle 1, Day 1 to Day 15 or to Day 22
Secondary	AUC0-tau for SAR439459 and for cemiplimab	Area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to 14 or 21 days post-dose.	Cycle 1, Day 1 to Day 15 or to Day 22
Secondary	t1/2z for SAR439459	Terminal half-life associated with the terminal slope (?z).	Cycle 1, Day 1 to Day 15 or to Day 22
Secondary	CL for SAR439459	Total body clearance of a drug from plasma calculated using the following equation from AUC: CL= Dose/AUC on cycle 1.	Cycle 1, Day 1 to Day 15 or to Day 22
Secondary	Vss for SAR439459	Estimate of Volume of distribution at the steady state after single intravenous dose.	Cycle 1, Day 1 to Day 15 or to Day 22