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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

Description:

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 and safety in combination with cemiplimab in adult patients with advanced melanoma who have failed a prior therapy based on anti-PD-1 or anti-PD-L1 and patients with mesenchymal Colorectal cancer. - PFS, duration of response (DOR) and safety in adult patients with metastatic urothelial cancer. - To confirm the optimal dose of SAR439459 administered in combination with cemiplimab.

Related Conditions:
  • Colorectal Adenocarcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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 IDs

  • ORG STUDY ID: TCD14678
  • SECONDARY ID: 2018-001113-32
  • NCT ID: NCT03192345

Conditions

  • Malignant Solid Tumor

Interventions

DrugSynonymsArms
SAR439459Dose Escalation SAR439459 monotherapy
Cemiplimab REGN2810Dose Escalation SAR439459 + cemiplimab combination

Purpose

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 and safety in combination with cemiplimab in adult patients with advanced melanoma who have failed a prior therapy based on anti-PD-1 or anti-PD-L1 and patients with mesenchymal Colorectal cancer. - PFS, duration of response (DOR) and safety in adult patients with metastatic urothelial cancer. - To confirm the optimal dose of SAR439459 administered in combination with cemiplimab.

Detailed 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 2 cycles (14 or 21 days per cycle), 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 or the cutoff date 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.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation SAR439459 monotherapyExperimentalSAR439459 administered intravenously every 2 weeks in a 14-day cycle with escalating doses
  • SAR439459
Dose Expansion SAR439459 monotherapyExperimentalSAR439459 administered intravenously every 2 weeks in a 14-day cycle with the previously determined recommended dose
  • SAR439459
Dose Escalation SAR439459 + cemiplimab combinationExperimentalSAR439459 + 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 at a standard dose
  • SAR439459
  • Cemiplimab REGN2810
Dose Expansion SAR439459 + cemiplimab combinationExperimentalSAR439459 + cemiplimab combination administered intravenously every 3 weeks in a 21-day cycle with a previously determined SAR439459 dose and cemiplimab at a standard dose
  • SAR439459
  • Cemiplimab REGN2810

Eligibility Criteria

        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 a prior therapy based on anti-PD-1 or anti-PD-L1 as defined
             by disease progression confirmed radiologically within 12 weeks of commencing
             treatment without any evidence of a response.

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

        Dose expansion (Part 2B)

          -  Patients with histologically confirmed advanced unresectable or metastatic melanoma or
             colorectal adenocarcinoma or patients with urothelial cancer.

          -  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
             prior lines therapy. Patients must not have received prior treatment with anti-PD1 or
             anti-PDL1.

          -  Patients with histologically confirmed, advanced unresectable or metastatic melanoma,
             colorectal cancer or metastatic urothelial cancer whom in the opinion of the
             Investigator does 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.

          -  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 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), unresolved viral hepatitis.

          -  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 that are untreated.

          -  History of severe, 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 β (anti-TGFβ) 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).

        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:Incidence of Dose Limiting Toxicities (DLTs)
Time Frame:Through the end of two 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)
Safety Issue:
Description:Incidence of DLTs at Cycle 1 and 2 in Parts 1A and 1B.

Secondary Outcome Measures

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

Details

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

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