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

NCT03192345 | Completed Phase 1 DMC FDA Drug

• 3 other identifiers: TCD14678U1111-1187-54252018-001113-32
• Study Type: interventional
• Target: 161
• Locations: 12 countries
• Sites: 33

Brief 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.

Conditions

Malignant Solid Tumor

Outcome Measures

Primary Outcomes (2)

• 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)

• 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 Outcomes (13)

• Overall safety profile

  Continuous throughout study assessment (up to approximately 1 year)

• Progression free survival (PFS)

  Continuous throughout study assessment (up to approximately 1 year)

• Time to progression (TTP)

  Continuous throughout study assessment (up to approximately 1 year)

• Objective Response Rate (ORR) Part 2A

  Continuous throughout study assessment (up to approximately 1 year)

• Duration of response Part 2B

  Continuous throughout study assessment (up to approximately 1 year)

Study Arms (4)

Dose Escalation SAR439459 monotherapy

EXPERIMENTAL

SAR439459 administered intravenously every 2 weeks in a 14-day cycle with escalating doses

Biological: SAR439459

Dose Expansion SAR439459 monotherapy

EXPERIMENTAL

SAR439459 administered intravenously every 3 weeks in a 21-day cycle with the previously determined recommended doses as the patients will be randomized to 2 different doses

Biological: SAR439459

Dose Escalation SAR439459 + cemiplimab combination

EXPERIMENTAL

SAR439459 + cemiplimab combination administered intravenously every 2 weeks in a 14-day cycle or every 3 weeks in a 21-day cycle with escalating SAR439459 doses and cemiplimab

Biological: SAR439459; Drug: Cemiplimab REGN2810

Dose Expansion SAR439459 + cemiplimab combination

EXPERIMENTAL

SAR439459 + cemiplimab combination administered intravenously every 3 weeks in a 21-day cycle with previously determined SAR439459 doses and cemiplimab

Biological: SAR439459; Drug: Cemiplimab REGN2810

Interventions

SAR439459 BIOLOGICAL

Pharmaceutical form: powder for solution for infusion Route of administration: intravenous infusion

Dose Escalation SAR439459 + cemiplimab combination; Dose Escalation SAR439459 monotherapy; Dose Expansion SAR439459 + cemiplimab combination; Dose Expansion SAR439459 monotherapy

Cemiplimab REGN2810 DRUG

Pharmaceutical form: solution for infusion Route of administration: intravenous infusion

Dose Escalation SAR439459 + cemiplimab combination; Dose Expansion SAR439459 + cemiplimab combination

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sanofi: lead

Study Sites (34)

The University of Kansas Clinical Research Center Site Number : 8400004

Fairway, Kansas, 66205, United States

Location

Massachusetts General Hospital Site Number : 8400001

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute Site Number : 8400101

Boston, Massachusetts, 02115, United States

Location

Duke University Medical Center Site Number : 8400008

Durham, North Carolina, 27710, United States

Location

Tennessee Oncology, PLLC Site Number : 8400006

Nashville, Tennessee, 37203, United States

Location

Mary Crowley Cancer Research Center Site Number : 8400003

Dallas, Texas, 75230, United States

Location

Investigational Site Number : 0360002

Heidelberg West, Victoria, 3081, Australia

Location

Investigational Site Number : 0360001

Melbourne, Victoria, 3000, Australia

Location

Investigational Site Number : 0560001

Leuven, 3000, Belgium

Location

Investigational Site Number : 1240003

Calgary, Alberta, T2N 4N2, Canada

Location

Investigational Site Number : 1240001

Toronto, Ontario, M5G 2M9, Canada

Location

Investigational Site Number : 1240002

Montreal, Quebec, H3T 1E2, Canada

Location

Investigational Site Number : 2330001

Tallinn, 13419, Estonia

Location

Investigational Site Number : 2500002

Marseille, 13385, France

Location

Investigational Site Number : 2500003

Nantes, 44093, France

Location

Investigational Site Number : 2500005

Nantes, 44093, France

Location

Investigational Site Number : 2500001

Villejuif, 94800, France

Location

Investigational Site Number : 2760001

Essen, 45122, Germany

Location

Investigational Site Number : 2760003

Hanover, 30625, Germany

Location

Investigational Site Number : 3800003

Rozzano, Milano, 20089, Italy

Location

Investigational Site Number : 3800001

Milan, 20133, Italy

Location

Investigational Site Number : 3800002

Milan, 20141, Italy

Location

Investigational Site Number : 5280001

Rotterdam, 3015 GD, Netherlands

Location

Investigational Site Number : 5280002

Utrecht, 3584 CX, Netherlands

Location

Investigational Site Number : 4100001

Seoul, Seoul-teukbyeolsi, 03080, South Korea

Location

Investigational Site Number : 4100002

Seoul, Seoul-teukbyeolsi, 138-736, South Korea

Location

Investigational Site Number : 7240002

Barcelona, Barcelona [Barcelona], 08003, Spain

Location

Investigational Site Number : 7240001

Barcelona, Barcelona [Barcelona], 08035, Spain

Location

Investigational Site Number : 7240003

Madrid / Madrid, Madrid, Comunidad de, 28040, Spain

Location

Investigational Site Number : 7240004

Madrid / Madrid, Madrid, Comunidad de, 28050, Spain

Location

Investigational Site Number : 7240005

Pamplona, Navarre, 31008, Spain

Location

Investigational Site Number : 1580002

Tainan, 704, Taiwan

Location

Investigational Site Number : 8260001

Glasgow, Central Bedfordshire, G12 0YN, United Kingdom

Location

Investigational Site Number : 8260002

Cardiff, Vale of Glamorgan, the, CF14 2TL, United Kingdom

Location

Related Publications (2)

• Baranda JC, Robbrecht D, Sullivan R, Doger B, Santoro A, Barve M, Grob JJ, Bechter O, Vieito M, de Miguel MJ, Schadendorf D, Johnson M, Pouzin C, Cantalloube C, Wang R, Lee J, Chen X, Demers B, Amrate A, Abbadessa G, Hodi FS. Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of SAR439459, a TGFbeta inhibitor, as monotherapy and in combination with cemiplimab in patients with advanced solid tumors: Findings from a phase 1/1b study. Clin Transl Sci. 2024 Jun;17(6):e13854. doi: 10.1111/cts.13854.

  PMID: 38898592 RESULT

• Greco R, Qu H, Qu H, Theilhaber J, Shapiro G, Gregory R, Winter C, Malkova N, Sun F, Jaworski J, Best A, Pao L, Hebert A, Levit M, Protopopov A, Pollard J, Bahjat K, Wiederschain D, Sharma S. Pan-TGFbeta inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade. Oncoimmunology. 2020 Sep 13;9(1):1811605. doi: 10.1080/2162402X.2020.1811605.

  PMID: 33224628 DERIVED

MeSH Terms

Interventions

cemiplimab

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Escalation monotherapy and escalation combination followed by expansion monotherapy and expansion combination. Escalation phases will not be randomized while expansion phases will be randomized.

Study Record Dates

• First Submitted: June 16, 2017
• First Posted: June 20, 2017
• Study Start: June 9, 2017
• Primary Completion: December 21, 2021
• Study Completion: January 17, 2022
• Last Updated: August 7, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share

Locations

TW (1); DE (2); ES (5); GB (2); IT (3); CA (3); BE (1); AU (2); US (6); NL (2); FR (4); KR (2)