Clinical trial NCT06188702: S095035 as a Single Agent and in Combination in Adult Participants With Advanced or Metastatic Solid Tumors With Deletion of MTAP
Official title: A Phase 1/2, Open-label, Multicenter Clinical Trial Investigating the Safety, Tolerability, Pharmacokinetics, and Antineoplastic Activity of S095035 (MAT2A Inhibitor) as a Single Agent and in Combination in Adult Participants With Advanced or Metastatic Solid Tumors With Homozygous Deletion of MTAP
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: MTAP-deleted Solid Tumors
Keywords: MAT2A
MTAP
Solid Tumors
PRMT5
SAM
Synthetic Lethality
MTAP deletion
MAT2A Inhibitor
Advanced Solid Tumors
Biliary Tract Cancer
Non-small Cell Lung Cancer
Pancreatic Adenocarcinoma
Gastroesophageal Cancer
Lead sponsor: Servier
Sponsor class: INDUSTRY
Collaborators: name: Institut de Recherches Internationales Servier
name: Tango Therapeutics, Inc.
First posted: 2024-01-03
Enrollment: 308
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.).

Primary outcomes:
measure: Dose limiting toxicities (DLTs)
timeFrame: Through cycle 1 (each cycle is 28 days)
measure: Total number of adverse events (AEs)
timeFrame: Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years
measure: Total number of serious adverse events (SAEs)
timeFrame: Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years
measure: Objective response rate (ORR)
timeFrame: Through the end of the study (approximately 5 years)
Secondary outcomes:
measure: Area under the concentration-vs-time curve (AUC) from 0 to time of last measurable concentration (AUC0-t)
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: AUC from 0 to infinity (AUC0-∞)
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: AUC over 1 dosing interval at steady state (AUCtau,ss)
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: Time to maximum concentration (Tmax)
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: Maximum concentration (Cmax)
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: Trough concentration (Ctrough)
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: Half-life (t½)
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: Apparent volume of distribution (Vd/F)
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: Apparent clearance (CL/F)
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: Change from baseline in plasma concentrations of S-adenosylmethionine (SAM) and/or tumor symmetric dimethylarginine (SDMA) residues during treatment
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: Objective response rate (ORR)
timeFrame: Through the end of the study (approximately 5 years)
measure: Best overall response (BOR)
timeFrame: Through the end of the study (approximately 5 years)
measure: Clinical benefit rate (CBR)
timeFrame: Through the end of the study (approximately 5 years)
measure: Duration of response (DOR)
timeFrame: Through the end of the study (approximately 5 years)
measure: Time to response (TTR)
timeFrame: Through the end of the study (approximately 5 years)
measure: Progression-free Survival (PFS)
timeFrame: Through the end of the study (approximately 5 years)
measure: Overall Survival (OS)
timeFrame: Through the end of the study (approximately 5 years)
measure: Total number of adverse events (AEs)
timeFrame: Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years
measure: Total number of serious adverse events (SAEs)
timeFrame: Through the Safety Follow-up Visit (until 30 days after the last dose of study treatment) approximately 5 years
measure: Number of dose interruptions
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: Number of dose reductions
timeFrame: Through the last dose of study treatment (approximately 5 years)
measure: Dose intensity
timeFrame: Through the last dose of study treatment (approximately 5 years)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco (Ucsf) School of Medicine
state: California
city: Lake Mary
country: United States
facility: Lake Mary Cancer Center - Florida Cancer Specialists & Research Institute
state: Florida
city: Indianapolis
country: United States
facility: Community Health Network
state: Indiana
city: Durham
country: United States
facility: Duke University School of Medicine
state: North Carolina
city: Maumee
country: United States
facility: Taylor Cancer Research Center
state: Ohio
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Austin
country: United States
facility: NEXT Oncology
state: Texas
city: Randwick
country: Australia
facility: Scientia Clinical Research
state: New South Wales
city: Prahran
country: Australia
facility: The Alfred
state: Victoria
city: Douglas
country: Australia
facility: Townsville University Hospital
city: Hobart
country: Australia
facility: Royal Hobart Hospital
city: Copenhagen
country: Denmark
facility: University Hospital Rigshospitalet
city: Odense
country: Denmark
facility: Odense Universitets Hospital
city: Bordeaux
country: France
facility: Institut Bergonié
city: Dijon
country: France
facility: Centre Georges-François Leclerc
city: Toulouse
country: France
facility: Institut Oncopole Claudius Regaud
city: Berlin
country: Germany
facility: Charite Universitatsmedizin
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Heidelberg
country: Germany
facility: Med Fakultaet Heidelberg
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Milano
country: Italy
facility: Istituto Europeo Di Oncologia
city: Napoli
country: Italy
facility: A.O.U. Seconda Università Degli Studi Di Napoli
city: Napoli
country: Italy
facility: Ist. Nazionale Tumori Irccs Fondazione G Pascale
city: Rozzano
country: Italy
facility: Instituto Clinico Humanitas Irccs
city: Verona
country: Italy
facility: Policlinico G.B. Rossi A.O.U.I. Di Verona
city: Aichi
country: Japan
facility: Aichi Cancer Center
city: Ehime
country: Japan
facility: National Hospital Organization Shikoku Cancer Center
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital of JFCR
city: Barcelona
country: Spain
facility: Next Oncology-Hospital Quironsalud Barcelona
city: Barcelona
country: Spain
facility: Hospital Vall D'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Start Madrid Group - Hm Ciocc
Study officials:
References: