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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

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ClinicalTrials.gov Identifier: NCT03192345
Recruitment Status : Recruiting
First Posted : June 20, 2017
Last Update Posted : August 13, 2019
Sponsor:
Information provided by (Responsible Party):
Sanofi

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 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.

Condition or disease Intervention/treatment Phase
Malignant Solid Tumor Biological: SAR439459 Drug: Cemiplimab REGN2810 Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 225 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Escalation monotherapy and escalation combination followed by expansion monotherapy and expansion combination. Escalation phases will not be randomized while expansion phases will be randomized.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 9, 2017
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : August 2022

Arm Intervention/treatment
Experimental: Dose Escalation SAR439459 monotherapy
SAR439459 administered intravenously every 2 weeks in a 14-day cycle with escalating doses
Biological: SAR439459

Pharmaceutical form: powder for solution for infusion

Route of administration: intravenous infusion


Experimental: Dose Expansion SAR439459 monotherapy
SAR439459 administered intravenously every 2 weeks in a 14-day cycle with the previously determined recommended dose
Biological: SAR439459

Pharmaceutical form: powder for solution for infusion

Route of administration: intravenous infusion


Experimental: Dose Escalation SAR439459 + cemiplimab combination
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 at a standard dose
Biological: SAR439459

Pharmaceutical form: powder for solution for infusion

Route of administration: intravenous infusion


Drug: Cemiplimab REGN2810

Pharmaceutical form: solution

Route of administration: intravenous infusion


Experimental: Dose Expansion SAR439459 + cemiplimab combination
SAR439459 + cemiplimab combination administered intravenously every 3 weeks in a 21-day cycle with a previously determined SAR439459 dose and cemiplimab at a standard dose
Biological: SAR439459

Pharmaceutical form: powder for solution for infusion

Route of administration: intravenous infusion


Drug: Cemiplimab REGN2810

Pharmaceutical form: solution

Route of administration: intravenous infusion





Primary Outcome Measures :
  1. 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) ]
    Incidence of DLTs at Cycle 1 and 2 in Parts 1A and 1B.

  2. Objective Response Rate (ORR) for Part 2B [ Time Frame: Continuous throughout study assessment (up to approximately 1 year) ]
    Efficacy as documented by ORR will be assessed by evaluation of antitumor response information according to RECIST 1.1 (Part 2B).


Secondary Outcome Measures :
  1. Overall safety profile [ Time Frame: Continuous throughout study assessment (up to approximately 1 year) ]
    The overall safety profile of SAR439459 administered in monotherapy (Part 1A and Part 2A) or in combination with cemiplimab (Part 1B and Part 2B).

  2. Progression free survival (PFS) [ Time Frame: Continuous throughout study assessment (up to approximately 1 year) ]
    The time from first investigational medicinal product (IMP) administration until objective tumor progression or death (Part 2A and Part 2B).

  3. Time to progression (TTP) [ Time Frame: Continuous throughout study assessment (up to approximately 1 year) ]
    The time from first IMP administration until objective tumor progression (Part 2A and 2B).

  4. Objective Response Rate (ORR) Part 2A [ Time Frame: Continuous throughout study assessment (up to approximately 1 year) ]
    Efficacy as documented by ORR will be assessed by evaluation of antitumor response information according to RECIST 1.1 (Part 2A).

  5. Duration of response Part 2B (urothelial cancer cohort only) [ Time Frame: Continuous throughout study assessment (up to approximately 1 year) ]
    Time from initial response to the first documented tumor progression.

  6. Immunogenicity evaluation [ Time Frame: Up to approximately 1 year ]
    Blood samples will be assessed for human anti-SAR439459 antibodies (all cohorts) and for human anti-cemiplimab antibodies (Parts 1B and 2B).

  7. Cmax for SAR439459 and for cemiplimab [ Time Frame: Cycle 1, Day 1 to Day 15 or to Day 22 ]
    Maximum plasma concentration observed.

  8. AUC for SAR439459 [ Time Frame: Cycle 1, Day 1 to Day 15 or to Day 22 ]
    Area under the serum concentration versus time curve extrapolated to infinity.

  9. AUC0-tau for SAR439459 and for cemiplimab [ Time Frame: Cycle 1, Day 1 to Day 15 or to Day 22 ]
    Area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to 14 or 21 days post-dose.

  10. t1/2z for SAR439459 [ Time Frame: Cycle 1, Day 1 to Day 15 or to Day 22 ]
    Terminal half-life associated with the terminal slope (λz).

  11. CL for SAR439459 [ Time Frame: Cycle 1, Day 1 to Day 15 or to Day 22 ]
    Total body clearance of a drug from plasma calculated using the following equation from AUC: CL= Dose/AUC on cycle 1.

  12. Vss for SAR439459 [ Time Frame: Cycle 1, Day 1 to Day 15 or to Day 22 ]
    Estimate of Volume of distribution at the steady state after single intravenous dose.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03192345


Contacts
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Contact: Trial Transparency email recommended (Toll free number for US & Canada) 800-633-1610 ext 1 then # Contact-Us@sanofi.com

Locations
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United States, California
Investigational Site Number 8400007 Recruiting
Duarte, California, United States, 91010
United States, Kansas
Investigational Site Number 8400004 Recruiting
Fairway, Kansas, United States, 66205
United States, Massachusetts
Investigational Site Number 8400001 Recruiting
Boston, Massachusetts, United States, 02114
Investigational Site Number 8400101 Recruiting
Boston, Massachusetts, United States, 02115
United States, Tennessee
Investigational Site Number 8400006 Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
Investigational Site Number 8400003 Recruiting
Dallas, Texas, United States, 75230
Netherlands
Investigational Site Number 5280001 Recruiting
Rotterdam, Netherlands, 3015 GD
Sponsors and Collaborators
Sanofi
Investigators
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Study Director: Clinical Sciences & Operations Sanofi

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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT03192345     History of Changes
Other Study ID Numbers: TCD14678
2018-001113-32 ( EudraCT Number )
First Posted: June 20, 2017    Key Record Dates
Last Update Posted: August 13, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data (IPD) and supporting clinical documents are available for request at clinicalstudydatarequest.com. While making information available Sanofi continues to protect the privacy of the participants in clinical trials and to remove commercially confidential information (CCI). Details on Data Sharing criteria and process for requesting access can be found at this web address: clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Cemiplimab
Antineoplastic Agents, Immunological
Antineoplastic Agents