S095035 as a Single Agent and in Combination in Adult Participants With Advanced or Metastatic Solid Tumors With Deletion of MTAP

Servier

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: MTAP-deleted Solid Tumors

Treatments: Drug: S095035; Drug: TNG462

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT06188702

2025-521249-25-00 (EU Trial (CTIS) Number)

CL1-95035-001

Details and patient eligibility

About

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.

Enrollment: 308 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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.

Exclusion criteria

• 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.).

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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308 participants in 9 patient groups

Phase 1 Arm 1 - S095035 single-agent dose escalation

Experimental group

Treatment:

Drug: S095035

Phase 1 Arm 2 - S095035-TNG462 combination dose escalation

Experimental group

Treatment:

Drug: TNG462

Drug: S095035

Phase 2 Arm 1a NSCLC - S095035 single-agent dose expansion

Experimental group

Description:

Non-Small Cell Lung Cancer

Treatment:

Drug: S095035

Phase 2 Arm 1b BTC - S095035 single-agent dose expansion

Experimental group

Description:

Biliary Tract Cancer

Treatment:

Drug: S095035

Phase 2 Arm 1c PDAC - S095035 single-agent dose expansion

Experimental group

Description:

Pancreatic Ductal Adenocarcinoma

Treatment:

Drug: S095035

Phase 2 Arm 1d Basket arm - S095035 single-agent dose expansion

Experimental group

Treatment:

Drug: S095035

Phase 2 Arm 2a BTC - S095035-TNG462 combination dose expansion

Experimental group

Description:

Biliary Tract Cancer

Treatment:

Drug: TNG462

Drug: S095035

Phase 2 Arm 2b Gastroesophageal - S095035-TNG462 combination dose expansion

Experimental group

Treatment:

Drug: TNG462

Drug: S095035

Phase 2 Arm 2c PDAC - S095035-TNG462 combination dose expansion

Experimental group

Description:

Pancreatic Ductal Adenocarcinoma

Treatment:

Drug: TNG462

Drug: S095035