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…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Incidence of DLTs at Cycle 1 and 2 (Day 1 to Day 28) in Parts 1A and 1B.
- Objective Response Rate (ORR) for Part 2B: Efficacy as documented by ORR will
be assessed by evaluation of anti-tumor response information according to
RECIST 1.1 (Part 2A and 2B).
Secondary outcome
- Overall safety profile: The overall safety profile of SAR439459 administered
in monotherapy (Part 1A and Part 2A) or in combination
with cemplimab (Part 1B and Part 2B).
- Immunogenicity evaluation: Blood samples will be assessed for human
anti-SAR439459 antibodies (all cohorts) and for human anti- cemiplimab
antibodies (Parts 1B and 2B).
- Progression free survival (PFS): The time from first IMP administration until
objective tumor progression or death (Part 2A and Part 2B).
- Time to progression (TTP): The time from first IMP administration until
objective tumor progression (Part 2A and 2B).
- Objective Response Rate (ORR) for Part 2A: Efficacy as documented by ORR will
be assessed by evaluation of antitumor response information
according to RECIST 1.1 (Part 2A).
- Cmax for SAR439459 and for cemiplimab: Maximum plasma concentration observed.
- AUC for SAR439459: Area under the serum concentration versus time curve
extrapolated to infinity.
- AUClast for SAR439459 and for cemiplimab: Area under the plasma concentration
versus time curve calculated using the trapezoidal method from time zero to
last post-dose corresponding to the last concentration above the limit of
quantification.
- AUC0-14d for SAR439459 and for cemiplimab: Area under the plasma
concentration versus time curve calculated using the trapezoidal method
from time zero to 14 days post-dose.
- t1/2z for SAR439459: Terminal half-life associated with the terminal slope
(*z).
- CL for SAR439459: Total body clearance of a drug from plasmacalculated using
the following equation from AUC: CL= Dose/AUC on cycle 1.
- Vss for SAR439459: Estimate of Volume of distribution at the steady state
after single IV dose.
Background summary
Although immunotherapies, particularly anti-PD-1 treatment have transformed the
treatment landscape of melanoma, there are currently no effective treatment
options for patients after failure of anti-PD-1 therapeutics.
TGFβ regulates several biologic processes including cell proliferation,
angiogenesis, and immune suppression. Importantly, each of these contributes to
tumor progression, and thus the overall role of TGF-β in oncology is likely an
integrated combination of these functions.
It is hypothesized that inhibition of TGF-β will alleviate the suppressive
tumor microenvironment and allow checkpoint modulators, such as PD-1 (or
programmed cell death-ligand 1 [PD-L1]) inhibitors to better induce immune
responses and thus increase the proportion of patients benefitting from
anti-PD-1 treatment.
The TCD14678 study will be conducted in patients with advanced cancer. This
study is a Phase 1/1b first-in-human, dose escalation, and dose expansion study
for the evaluation of safety, PK, PD, and anti-tumor activity of SAR439459
administered intravenously as monotherapy and in combination with cemiplimab in
adult patients with advanced solid tumors.
Study objective
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 REGN2810 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 REGN2810 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 RECIST1.1
Secondary Objectives:
-To characterize the PK profile of SAR439459 administered as monotherapy (Part
1A/2A) and in combination with cemiplimab (Part 1B/2B) and PK profile of
cemiplimab in combination with SAR439459 (Part 1B/2B).
-To assess the immunogenicity of SAR439459 monotherapy (Part 1A/2A) and
SAR439459 and cemiplimab combination (Part 1B/2B).
Dose escalation (Part 1)
-To characterize the overall safety and tolerability profile of SAR439459
administered as monotherapy and in combination with cemiplimab.
-To identify the preliminary recommended phase 2 dose (pRP2D) of SAR439459 as
monotherapy or in combination with cemiplimab.
Dose expansion (Part 2)
-To determine the 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 selected advanced solid
tumors.
-To confirm the optimal dose of SAR439459 administered in combination with
cemiplimab.
Study design
- Phase 1, open-label, parallel sutudy.
- Escalation monotherapy (Part 1A) and escalation combination (Part 1B)
followed by expansion monotherapy (Part 2A) and expansion combination (Part 2B).
- Escalation phases will not be randomized while expansion phases will be
randomized.
Intervention
Part 1A:
SAR439459 administered intravenously every 2 weeks in a 14-day cycle with
escalating doses between 0.05 - 15 mg/kg
Part 1B:
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
Part 2A:
SAR439459 administered intravenously every 3 weeks in a 21-day cycle with two
previously determined recommended doses from part 1A
Part 2B:
SAR439459 + cemiplimab combination administered intravenously every 3 weeks in
a 21-day cycle with up to two previously determined SAR439459 doses in
combination with cemiplimab at a standard dose
Study burden and risks
The risks are related to the blood samples and the possible side effects of the
study medication.
The burden on the patient will be the frequency of visits to the research
center.
Paasheuvelweg 25
Amsterdam 1105 BP
NL
Paasheuvelweg 25
Amsterdam 1105 BP
NL
Listed location countries
Age
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 melanoma whom in the opinion of the Investigator does not have a
suitable alternative therapy
-Patients must have failed 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-PDL-1-based therapy 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 and willing to provide mandatory tumor biopsies prior to
and during study treatment.,
Dose expansion (Part 2B):, -Patients with avanced unresectable or metastatic
melanoma who failed after one prior therapy based on anti-PD-1 or anti-PD-L1 or
colorectal adenocarcinoma with mesenchymal molecular subtype or urothelial
cancer and have failed platinum-containing chemotherapy or non-small cell lung
cancer (NSCLC) after failure of anti-PD-1 or anti PD-L1, or hepatocellular
carcinoma (HCC) after failure of anti-PD-1 or anti PD-L1, with or without
bevacizumab.
For all indications patients must not have a suitable alternative approved
standard therapy available in the opinion of the investigator or must be
refused by the patient., Dose expansion parts 2A and 2B:, -At least 1
measurable lesion by RECIST v1.1.
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.
-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.
-History of known 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, acute or chronic heart diseases.
-History of severe, acute or chronic renal diseases or inadequate renal
function.
-History of significant valvular heart disease (including valve replacement),
vascular malformation and anurysm
-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-TGF-β inhibitors.
-Known allergies to any component of SAR439459 and/or REGN2810.
-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 2 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 REGN2810 (occasional
use of inhaled, intraocular, nasal or topical steroids for symptomatic relief
allowed).
-History of pneumonitis or bowel perforation.
-Patients with underlying cancer predisposition syndromes.
-Therapeutic doses of anticoagulants or antiplatelet agents within 7 days prior
the first dose of SAR439459
-Receipt of a live vaccine within 30 days of planned start of study medication.
-Prothrombin time (PT) or international normalized ratio (INR) > 1.5 × ULN
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-001113-32-NL |
| CCMO | NL66868.078.18 |
| Other | U1111-1187-5425 |