S095035 as a Single Agent and in Combination in Adult Participants With Advanced or Metastatic Solid Tumors With Deletion of MTAP
- Registration Number
- NCT06188702
- Lead Sponsor
- Servier Bio-Innovation LLC
- Brief Summary
This is a first-in-human Phase 1/2, multicenter, open-label study of S095035 as single-agent, or in combination with TNG462 in adult participants with advanced or metastatic solid tumors with homozygous deletion of MTAP who have failed to respond to or have progressed after at least 1 prior treatment regimen, and for whom additional effective standard treatment is not available. S095035 is an oral methionine adenosyltransferase 2A \[MAT2A\] inhibitor. TNG462 is a protein arginine N-methyltransferase 5 \[PRMT5\] inhibitor.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 308
- Estimated life expectancy ≥3 months.
- ECOG PS 0-1
- Participants able to comply with highly effective method of birth control requirements.
- Participants with histologically confirmed advanced or metastatic solid tumor's (excluding central nervous system tumors other than IDHwt glioblastoma), with measurable disease as per RECIST 1.1 or RANO 2.0 criteria for participants with IDHwt glioblastoma, that have progressed after at least one prior treatment regimen given for advanced/metastatic disease, and for whom additional effective standard therapy is not available.
- Participants with pre-existing documented MTAP homozygous gene deletion in their tumor tissue, determined using a next generation sequencing in vitro diagnostic test prior to screening.
- Phase 1 only - Participants (except IDHwt glioblastoma) willing to undergo paired fresh biopsy (pre-treatment and on-treatment) procedure. Exceptions may be made for feasibility and safety concerns. IDHwt glioblastoma must provide archival tissue from most recent surgery or biopsy.
- Adequate organ functions.
- Phase 2 only - Participants in dose expansion, except those with IDHwt glioblastoma, must provide newly collected tumor biopsies at screening. If it is not medically feasible, then archival tissue is acceptable if it was collected within 3 months before study entry and no treatment has been received since the most recent biopsy.
- Phase 2 only - Participants with IDHwt glioblastoma must provide archival tissue from their most recent surgery or biopsy, collected before screening, even if that occurred >3 months before study entry.
- Phase 2 Arm 1a only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with homozygous deletion of MTAP, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy.
- Phase 2 Arm 1b only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced BTC with homozygous deletion of MTAP, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy.
- Phase 2 Arm 1c only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced PDAC with homozygous deletion of MTAP, who have progressed or experienced disease recurrence during or after at least 1 prior line of standard-of-care systemic therapy.
- Phase 2 Arm 1d only - Participants with any other locally advanced or metastatic malignancies with homozygous deletion of MTAP, who have received and progressed of experienced recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy.
- Phase 2 Arm 2a only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced BTC with homozygous deletion of MTAP, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of care systemic therapy.
- Phase 2 Arm 2b only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced gastroesophageal cancer with homozygous deletion of MTAP, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy.
- Phase 2 Arm 2c only - Participants with histologically or cytologically confirmed metastatic or unresectable locally advanced PDAC with homozygous deletion of MTAP, who have progressed or experienced disease recurrence during or after receiving at least 1 prior line of standard-of-care systemic therapy.
- Inability to take an orally administered drug, or medical disorder or prior surgical resection that may affect the absorption of the study drug.
- Active second primary malignancy other than non-melanoma skin cancers, nonmetastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor's Medical monitor and investigator agree and document that it should not be exclusionary.
- Known prior severe hypersensitivity to any component of the study drug formulation.
- Major surgery within 4 weeks prior to the first study drug administration or participants who have not recovered from side effects of the surgery.
- Have a known history of Gilbert's syndrome.
- Participants with a known clinically significant cardiovascular disease or condition.
- Participants with thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to first IMP administration.
- Active brain metastases.
- Participants who have received systemic anticancer treatment or radiotherapy less than 2 weeks before the first dose of study drug
- Pregnant or lactating women.
- Women of childbearing potential who have a positive pregnancy test within 7 days prior to the first day of study drug administration.
- History of gastrointestinal perforation and /or fistula or aorto-esophageal fistula within 6 months prior to first study drug intake.
- Severe or uncontrolled active acute or chronic infection.
- Participants who have already received a MAT2A or PRMT5 inhibitor.
- A medical condition that results in increased clinically significant photosensitivity (e.g., solar urticaria, lupus erythematosus, etc.).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase 1 Arm 1 - S095035 single-agent dose escalation S095035 - Phase 1 Arm 2 - S095035-TNG462 combination dose escalation S095035 - Phase 1 Arm 2 - S095035-TNG462 combination dose escalation TNG462 - Phase 2 Arm 1a NSCLC - S095035 single-agent dose expansion S095035 Non-Small Cell Lung Cancer Phase 2 Arm 1b BTC - S095035 single-agent dose expansion S095035 Biliary Tract Cancer Phase 2 Arm 1c PDAC - S095035 single-agent dose expansion S095035 Pancreatic Ductal Adenocarcinoma Phase 2 Arm 1d Basket arm - S095035 single-agent dose expansion S095035 - Phase 2 Arm 2a BTC - S095035-TNG462 combination dose expansion S095035 Biliary Tract Cancer Phase 2 Arm 2a BTC - S095035-TNG462 combination dose expansion TNG462 Biliary Tract Cancer Phase 2 Arm 2b Gastroesophageal - S095035-TNG462 combination dose expansion S095035 - Phase 2 Arm 2b Gastroesophageal - S095035-TNG462 combination dose expansion TNG462 - Phase 2 Arm 2c PDAC - S095035-TNG462 combination dose expansion S095035 Pancreatic Ductal Adenocarcinoma Phase 2 Arm 2c PDAC - S095035-TNG462 combination dose expansion TNG462 Pancreatic Ductal Adenocarcinoma
- Primary Outcome Measures
Name Time Method Objective response rate (ORR) Through the end of the study (approximately 5 years) Phase 2 only; Per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-oncology (RANO) 2.0 criteria as per the investigator's assessment and by blinded independent central review (BICR)
Dose limiting toxicities (DLTs) Through cycle 1 (each cycle is 28 days) Phase 1 only
Total number of adverse events (AEs) Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years Phase 1 only
Total number of serious adverse events (SAEs) Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years Phase 1 only
- Secondary Outcome Measures
Name Time Method Area under the concentration-vs-time curve (AUC) from 0 to time of last measurable concentration (AUC0-t) Through the last dose of study treatment (approximately 5 years) Phase 1 and 2
AUC over 1 dosing interval at steady state (AUCtau,ss) Through the last dose of study treatment (approximately 5 years) Phase 1 and 2
Time to maximum concentration (Tmax) Through the last dose of study treatment (approximately 5 years) Phase 1 and 2
Maximum concentration (Cmax) Through the last dose of study treatment (approximately 5 years) Phase 1 and 2
Trough concentration (Ctrough) Through the last dose of study treatment (approximately 5 years) Phase 1 and 2
Half-life (t½) Through the last dose of study treatment (approximately 5 years) Phase 1 and 2
Apparent volume of distribution (Vd/F) Through the last dose of study treatment (approximately 5 years) Phase 1 and 2
Apparent clearance (CL/F) Through the last dose of study treatment (approximately 5 years) Phase 1 and 2
Change from baseline in plasma concentrations of S-adenosylmethionine (SAM) and/or tumor symmetric dimethylarginine (SDMA) residues during treatment Through the last dose of study treatment (approximately 5 years) Phase 1 only
Objective response rate (ORR) Through the end of the study (approximately 5 years) Phase 1 only; Per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-oncology (RANO) 2.0 criteria as per the investigator's assessment
Best overall response (BOR) Through the end of the study (approximately 5 years) Phase 1 and 2; Per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-oncology (RANO) 2.0 criteria as per the investigator's assessment for Phase 1 and 2, and by BICR only for Phase 2.
Clinical benefit rate (CBR) Through the end of the study (approximately 5 years) Phase 1 and 2; CBR=complete response \[CR\]+partial response \[PR\]+stable disease \[SD\] ) ≥6 months, Per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-oncology (RANO) 2.0 criteria as per the investigator's assessment for Phase 1 and 2, and by BICR only for Phase 2
Duration of response (DOR) Through the end of the study (approximately 5 years) Phase 1 and 2; Per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-oncology (RANO) 2.0 criteria as per the investigator's assessment for Phase 1 and 2, and by BICR only for Phase 2. The time from date of first documented confirmed CR or confirmed PR to date of first documented disease progression or death due to any cause.
Time to response (TTR) Through the end of the study (approximately 5 years) Phase 1 and 2; Per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-oncology (RANO) 2.0 criteria as per the investigator's assessment for Phase 1 and 2, and by BICR only for Phase 2. The time from the date of randomization to date of first documented confirmed complete response (CR) or confirmed partial response (PR).
Progression-free Survival (PFS) Through the end of the study (approximately 5 years) Phase 2 Only; Per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-oncology (RANO) 2.0 criteria as assessed by investigator and by BICR
Overall Survival (OS) Through the end of the study (approximately 5 years) Phase 2 Only; Per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or Response Assessment in Neuro-oncology (RANO) 2.0 criteria as assessed by investigator and by BICR
Number of dose reductions Through the last dose of study treatment (approximately 5 years) Phase 2 Only
Number of dose interruptions Through the last dose of study treatment (approximately 5 years) Phase 2 Only
Dose intensity Through the last dose of study treatment (approximately 5 years) Phase 2 Only
Total number of adverse events (AEs) Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years Phase 2 Only
Total number of serious adverse events (SAEs) Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years Phase 2 Only
AUC from 0 to infinity (AUC0-∞) Through the last dose of study treatment (approximately 5 years) Phase 1 and 2
Trial Locations
- Locations (33)
University of California Los Angeles
🇺🇸Los Angeles, California, United States
University of California, San Francisco (Ucsf) School of Medicine
🇺🇸San Francisco, California, United States
Lake Mary Cancer Center - Florida Cancer Specialists & Research Institute
🇺🇸Lake Mary, Florida, United States
Community Health Network
🇺🇸Indianapolis, Indiana, United States
Duke University School of Medicine
🇺🇸Durham, North Carolina, United States
Taylor Cancer Research Center
🇺🇸Maumee, Ohio, United States
SCRI Oncology Partners
🇺🇸Nashville, Tennessee, United States
NEXT Oncology
🇺🇸Austin, Texas, United States
Scientia Clinical Research
🇦🇺Randwick, New South Wales, Australia
The Alfred
🇦🇺Prahran, Victoria, Australia
Scroll for more (23 remaining)University of California Los Angeles🇺🇸Los Angeles, California, United States