This is a phase Ib trial with SAR439459, a TGF-beta inhibitor, in combination with
cemiplimab, a PD-L1 inhibitor, in patients with solid tumors that have spread to other places
in the body (advanced) or cannot be removed by surgery (unresectable). Inhibiting TGF-beta
may interfere with the ability of cancer cells to grow and spread and may sensitize cancers
to immune checkpoint inhibitor therapy. The objective of this study is to determine whether
this drug combination is effective in shrinking cancers, keeping them from growing, helping
patients live longer, and to see if the drug combination is safe.
PRIMARY OBJECTIVE:
I. To assess the anti-tumor activity of the combination of anti-TGF-beta monoclonal antibody
SAR-439459 (SAR439459) and cemiplimab in patients with advanced solid tumors.
SECONDARY OBJECTIVES:
I. To confirm the safety and tolerability of the combination of SAR439459 and cemiplimab in
patients with advanced solid tumors.
II. To evaluate the overall response rate (ORR), progression-free survival (PFS), median
overall survival (OS) and duration of response (DoR).
III. To identify biomarkers of response and resistance to the combination of SAR439459 and
cemiplimab in patients with advanced solid tumors.
OUTLINE:
Patients receive SAR439459 intravenously (IV) over 30 minutes on day 1 and cemiplimab IV over
30 minutes on day 1 starting cycle 2. Cycles repeat every 21 days in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30, 60, and 90 days, then
every 12 weeks until progression of disease is determined or patient receives additional
anti-neoplastic medication.
Inclusion Criteria:
- Patients must have a histologically confirmed, advanced unresectable or metastatic
solid tumor whom in the opinion of the Investigator do not have a suitable alternative
therapy
- Disease must be measurable by Response Evaluation Criteria in Solid Tumors (RECIST
1.1), and safely undergo serial tumor biopsies. For patients with castration-resistant
prostate cancer, evaluable disease by Prostate Cancer Working Group 3 (PCWG3) will be
permitted if serial biopsies (e.g. bone tumor biopsies) are feasible
- Patients must have previously received a PD-1 or PD-L1 inhibitor-based therapy and
must have achieved stable disease (SD) for at least 6 months, or complete
remission/partial remission (CR/PR) prior to disease progression (secondary
resistance) by radiological assessment by the study investigator. The PD-1 or PD-L1
inhibitor-based therapy must be the immediate line of treatment prior to study
enrollment
- Patients must have adequate functional status as defined by Eastern Cooperative
Oncology Group (ECOG) performance status (PS) 0-1
- Absolute neutrophil count (ANC) >= 1,500 /mcL
- Platelets >= 100,000 / mcL
- Hemoglobin >= 9.0 g/dL
- Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
levels > 1.5 x institutional ULN (creatinine clearance should be calculated per
institutional standard)
- Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels >= 1.5 x ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN OR =<
5 x ULN for subjects with liver metastases
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN
- Patients must have discontinued all previous systemic cancer treatments for at least
21 days and recovered from the acute toxic effects of therapy to grade < 1 per Common
Terminology Criteria for Adverse Events (CTCAE) v5.0, excluding persistent grade 2 or
higher toxicities determined to be clinically insignificant per the principal
investigator (PI) (i.e. alopecia or grade 2 neuropathy). Patients must have
discontinued from previous treatments as shown below:
- Cytotoxic therapies or targeted agents that are small-molecule inhibitors >= 3
weeks prior to (study entry/enrollment/first dose of study treatment)
- Mitomycin C or nitrosoureas >= 42 days prior to (study entry/enrollment/first
dose of study treatment)
- Biologic agents (e.g., antibodies) >= 3 weeks prior to (study
entry/enrollment/first dose of study treatment)
- Immunotherapy (e.g., CTLA4, PD-1, PDL1 inhibitors) >= 3 weeks prior to (study
entry/enrollment/first dose of study treatment)
- Radiotherapy >= 4 weeks prior to (study entry/enrollment/first dose of study
treatment)
- Limited field radiotherapy or palliative radiotherapy >= 3 weeks prior to (study
entry/enrollment/first dose of study treatment)
- Major surgery, excluding biopsy: Patients with recent major surgery must have
recovered, in the opinion of the investigator, from the toxicity and/or
complication from the intervention before starting therapy
- Study drug with an investigational product, or non-approved use of a drug or
device >= 3 weeks prior to (study entry/enrollment/first dose of study treatment)
- If the patient was treated with an agent with a short half-life, washout can
be < 3 weeks but no shorter than 5 times the half-life
- Women of child-bearing potential MUST have a negative serum or urine human chorionic
gonadotropin (HCG) test at screening and within 2 days prior to receiving first dose
of study treatment unless prior tubal ligation (>= 1 year before screening), total
hysterectomy or menopause (defined as 12 consecutive months of amenorrhea). Patients
should not become pregnant or breastfeed while on this study. Sexually active patients
must agree to use dual contraception for the duration of study participation and for
at least 6 months for females and 3 months for males after. Males should not donate
sperm during the study and for 3 months after your last dose of study drugs
- Ability to understand and willingness to sign informed consent form prior to
initiation of the study and any study procedures
Exclusion Criteria:
- Patients who are pregnant or breastfeeding
- Patients who have known active Hepatitis B, Hepatitis C, or human immunodeficiency
virus (HIV) infection
- Patients who have active infection requiring intravenous (IV) antibiotics or other
uncontrolled intercurrent illness requiring hospitalization
- Patients unable to comply with the study and follow-up procedures
- Patients with history of cerebrovascular accident (CVA), myocardial infarction,
clinically significant arrhythmia, unstable angina, pulmonary embolism, clinically
significant deep vein thrombosis, gastrointestinal hemorrhage, clinically significant
intestinal obstruction or perforation, or active uncontrolled bleeding within the
previous 6 months before starting therapy
- Patients with a history of valvular heart disease (including valve replacement), known
atrioventricular (A-V) malformation or evidence or history of septal aneurysm, other
heart aneurysm, or any aneurysm of the major vessels
- Patients with a known additional malignancy that is progressing or requires active
treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin that has undergone potentially curative therapy or in situ
cervical cancer
- Patients who have a known psychiatric or substance abuse disorders that would
interfere with cooperation with the requirements of the trial
- Patients who have received a live vaccine within 30 days before the first dose of
study treatment
- Patients who have symptomatic or uncontrolled brain metastases, spinal cord
compression, or leptomeningeal disease requiring concurrent treatment, including but
not limited to surgery, radiation, and/or corticosteroids (patients receiving
anticonvulsants are eligible)
- Patients who have primary central nervous system (CNS) tumors
- Patients with active known or suspected autoimmune disease or any illness that could
compromise the immune system (e.g., prior organ transplant) within the past 2 years,
or a syndrome that requires systemic steroids or immunosuppressive agents. Patients
with vitiligo, alopecia, type I diabetes mellitus, residual hypothyroidism due to
autoimmune condition only requiring hormone replacement, psoriasis not requiring
chronic, and systemic immunosuppressive treatment within the past 2 years, not
expected to recur in the absence of an external trigger, are permitted to enroll.
Patients with inflammatory bowel disease and autoimmune related uveitis are not
eligible
- Patients being treated with therapeutic doses of anticoagulants or antiplatelet agents
(1 mg/kg of enoxaparin, 30 0mg of aspirin daily, 300 mg of clopidogrel daily or
equivalent) within 7 days prior to first dose of SAR439459. Prophylactic use of
anticoagulants or antiplatelets are allowed
- Prior treatment with any anti-transforming growth factor beta (TGFb) inhibitors
- Patients who received prior immunotherapy who developed toxicity leading to a
permanent discontinuation of immunotherapy
- Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within
4 weeks prior to the first dose of SAR349459 and/or cemiplimab (occasional use of
inhaled, intraocular, nasal or topical steroids for symptomatic relief allowed)
- History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing
pneumonia) or active, non-infectious pneumonitis that require immunosuppressive doses
of glucocorticoids to assist with management. A history of radiation pneumonitis in
radiation field is permitted
- Prior history of CTCAE version 5.0 grade >= 1 or ongoing active uveitis
