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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
3
Given IV
Given IV
M D Anderson Cancer Center
Houston, Texas, United States
Clinical benefit rate (CBR)
Defined as complete response (CR) + partial response (PR) + stable disease (SD) \> 12 weeks \> 12 weeks assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Will estimate CBR with 95% confidence intervals (CI). Will assess associations between marker levels and outcome using receiver operator characteristics curve analysis, graphical analysis and logistic regression analysis as appropriate.
Time frame: 12 weeks
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
AEs will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. AEs will be summarized by patient incidence rates, therefore, in any tabulation, a patient contributes only once to the count for a given AE preferred term. The number and percentage of patients with any treatment-emergent by NCI CTCAE v5.0 will be summarized for all study patients combined. The number and percentage of patients with treatment-emergent AEs assessed by the Investigator as at least possibly related to treatment will also be tabulated. The number and percentage of patients with any grade \>= 3 treatment-emergent AE per NCI CTCAE v5.0 will be tabulated in the same manner. Serious AEs will also be tabulated.
Time frame: Up to 1 year after completion of study treatment
Clinical benefit rate
Defined as CR+PR+SD \> 12 weeks assessed by immune-related (ir)RECIST. A 95% CI of response rate will be estimated based on the binomial distribution.
Time frame: Up to 1 year after completion of study treatment
Overall response rate
A 95% CI of response rate will be estimated based on the binomial distribution.
Time frame: Up to 1 year after completion of study treatment
Progression free survival
Will be summarized using Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles with associated 2-sided 95% confidence intervals, as well as percentage of censored observations.
Time frame: Up to 1 year after completion of study treatment
Duration of response
Assessed by RECIST v1.1 and irRECIST.
Time frame: Up to 1 year after completion of study treatment
Overall survival
Will be summarized using Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles with associated 2-sided 95% confidence intervals, as well as percentage of censored observations.
Time frame: Up to 1 year after completion of study treatment
Correlation of somatic mutations
Will be evaluated using whole-exome sequencing of pre-, on-treatment, and disease progression tumor biopsies. Will assess changes in frequency and type of mutations using paired t-tests for interval-scaled, normal data or Wilcoxon signed rank test for other numeric data, and exact version of McNemar's chi-squared test for binary data.
Time frame: Up to 1 year after completion of study treatment
Correlation of change in protein expression
Will be evaluated by reverse phase protein array (PPPA) analysis on pre-, on-treatment, and disease progression tumor biopsies. Will assess changes in normalized protein expression levels using paired t-tests for interval-scaled, normal data or Wilcoxon signed rank test for other numeric data, and exact version of McNemar's chi-squared test for binary data.
Time frame: Up to 1 year after completion of study
Correlation of change in ribonucleic acid expression
Will be evaluated by ribonucleic acid (RNA) sequencing on pre-, on-treatment, and disease progression tumor biopsies. Will assess changes in normalized RNA expression levels using paired t-tests for interval-scaled, normal data or Wilcoxon signed rank test for other numeric data, and exact version of McNemar's chi-squared test for binary data.
Time frame: Up to 1 year after completion of study
Circulating-free deoxynucleic acid as a biomarker of response and resistance
Plasma for circulating-free deoxyribonucleic acid will be collected pre-, on-treatment, and at time of disease progression. Will assess changes in DN concentration levels using paired t-tests for interval-scaled, normal data or Wilcoxon signed rank test for other numeric data, and exact version of McNemar's chi-squared test for binary data.
Time frame: Up to 1 year after completion of study treatment
Peripheral mononuclear blood cells as a biomarker of response and resistance
Peripheral mononuclear blood cells (PMBCs) from whole blood specimens will be collected pre-, on-treatment, and at time of disease progression. Will assess for changes in proportion of PMBC cell phenotypes using paired t-tests for interval-scaled, normal data or Wilcoxon signed rank test for other numeric data, and exact version of McNemar's chi-squared test for binary data.
Time frame: Up to 1 year after completion of study treatment
Cytokine levels as a biomarker of response and resistance
Plasma for cytokine analysis will be collected pre-, on-treatment, and at time of disease progression. Will assess for changes in normalized cytokine levels using paired t-tests for interval-scaled, normal data or Wilcoxon signed rank test for other numeric data, and exact version of McNemar's chi-squared test for binary data.
Time frame: Up to 1 year after completion of study treatment
TGF-beta as a biomarker or response and resistance
Plasma for TGF-beta analysis will be collected pre-, on-treatment, and at the time of disease progression. Will assess changes in normalized TGF-beta levels using paired t-tests for interval-scaled, normal data or Wilcoxon signed rank test for other numeric data, and exact version of McNemar's chi-squared test for binary data. Platelet factor 4 will be collected from plasma simultaneously as a marker of platelet contamination to monitor the quality of TGF-beta measurement.
Time frame: Up to 1 year after completion of study treatment
Microbiome analysis
Fecal sample and buccal swab sample collected for 16S ribosomal RNA microbiome profiling analysis.
Time frame: Baseline
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