Clinical trial NCT03192345: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Solid Tumor
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2017-06-20
Enrollment: 161
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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 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.

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 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 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).
* 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.

Primary outcomes:
measure: Incidence of Dose Limiting Toxicities (DLTs)
timeFrame: 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)
measure: Objective Response Rate (ORR) for Part 2B
timeFrame: Continuous throughout study assessment (up to approximately 1 year)
Secondary outcomes:
measure: Overall safety profile
timeFrame: Continuous throughout study assessment (up to approximately 1 year)
measure: Progression free survival (PFS)
timeFrame: Continuous throughout study assessment (up to approximately 1 year)
measure: Time to progression (TTP)
timeFrame: Continuous throughout study assessment (up to approximately 1 year)
measure: Objective Response Rate (ORR) Part 2A
timeFrame: Continuous throughout study assessment (up to approximately 1 year)
measure: Duration of response Part 2B
timeFrame: Continuous throughout study assessment (up to approximately 1 year)
measure: Disease Control Rate Part 2B
timeFrame: Continuous throughout study assessment (up to approximately 1 year)
measure: Immunogenicity evaluation
timeFrame: Up to approximately 1 year
measure: Cmax for SAR439459 and for cemiplimab
timeFrame: Cycle 1, Day 1 to Day 15 or to Day 22
measure: AUC for SAR439459
timeFrame: Cycle 1, Day 1 to Day 15 or to Day 22
measure: AUC0-tau for SAR439459 and for cemiplimab
timeFrame: Cycle 1, Day 1 to Day 15 or to Day 22
measure: t1/2z for SAR439459
timeFrame: Cycle 1, Day 1 to Day 15 or to Day 22
measure: CL for SAR439459
timeFrame: Cycle 1, Day 1 to Day 15 or to Day 22
measure: Vss for SAR439459
timeFrame: Cycle 1, Day 1 to Day 15 or to Day 22
Other outcomes:
Locations:
city: Fairway
country: United States
facility: The University of Kansas Clinical Research Center Site Number : 8400004
state: Kansas
city: Boston
country: United States
facility: Massachusetts General Hospital Site Number : 8400001
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute Site Number : 8400101
state: Massachusetts
city: Durham
country: United States
facility: Duke University Medical Center Site Number : 8400008
state: North Carolina
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC Site Number : 8400006
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Center Site Number : 8400003
state: Texas
city: Heidelberg West
country: Australia
facility: Investigational Site Number : 0360002
state: Victoria
city: Melbourne
country: Australia
facility: Investigational Site Number : 0360001
state: Victoria
city: Leuven
country: Belgium
facility: Investigational Site Number : 0560001
city: Calgary
country: Canada
facility: Investigational Site Number : 1240003
state: Alberta
city: Toronto
country: Canada
facility: Investigational Site Number : 1240001
state: Ontario
city: Montreal
country: Canada
facility: Investigational Site Number : 1240002
state: Quebec
city: Tallinn
country: Estonia
facility: Investigational Site Number : 2330001
city: Marseille
country: France
facility: Investigational Site Number : 2500002
city: Nantes
country: France
facility: Investigational Site Number : 2500003
city: Nantes
country: France
facility: Investigational Site Number : 2500005
city: Villejuif
country: France
facility: Investigational Site Number : 2500001
city: Essen
country: Germany
facility: Investigational Site Number : 2760001
city: Hannover
country: Germany
facility: Investigational Site Number : 2760003
city: Rozzano
country: Italy
facility: Investigational Site Number : 3800003
state: Milano
city: Milano
country: Italy
facility: Investigational Site Number : 3800001
city: Milano
country: Italy
facility: Investigational Site Number : 3800002
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100001
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100002
state: Seoul-teukbyeolsi
city: Rotterdam
country: Netherlands
facility: Investigational Site Number : 5280001
city: Utrecht
country: Netherlands
facility: Investigational Site Number : 5280002
city: Barcelona
country: Spain
facility: Investigational Site Number : 7240002
state: Barcelona [Barcelona]
city: Barcelona
country: Spain
facility: Investigational Site Number : 7240001
state: Barcelona [Barcelona]
city: Madrid / Madrid
country: Spain
facility: Investigational Site Number : 7240003
state: Madrid, Comunidad De
city: Madrid / Madrid
country: Spain
facility: Investigational Site Number : 7240004
state: Madrid, Comunidad De
city: Pamplona
country: Spain
facility: Investigational Site Number : 7240005
state: Navarra
city: Tainan
country: Taiwan
facility: Investigational Site Number : 1580002
city: Glasgow
country: United Kingdom
facility: Investigational Site Number : 8260001
state: Central Bedfordshire
city: Cardiff
country: United Kingdom
facility: Investigational Site Number : 8260002
state: Vale Of Glamorgan, The
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.