A Study Evaluating Anvumetostat in Combination With Other Therapies in Participants With Advanced Gastrointestinal, Biliary Tract, or Pancreatic Cancers With Homozygous Methylthioadenosine Phosphorylase (MTAP)-Deletion (MTAPESTRY 103)

Amgen

Status and phase

Enrolling

Phase 1

Conditions

Advanced Gastrointestinal, Biliary Tract, and Pancreatic Cancers

Treatments

Drug: Gemcitabine

Drug: Nab-paclitaxel

Drug: RMC-6236

Drug: Anvumetostat

Drug: Modified FOLFIRINOX

Study type

Interventional

Funder types

Industry

Identifiers

NCT06360354

20230223

Details and patient eligibility

About

The study aims to determine maximum tolerated dose (MTD) or recommended combination dose of the MTA-cooperative PRMT5 inhibitor Anvumetostat administered in combination with other therapies in adult participants with metastatic or locally advanced methylthioadenosine phosphorylase (MTAP)-deleted gastrointestinal, biliary tract, or pancreatic cancers. The study also aims to determine the safety profile of Anvumetostat administered in combination with other therapies in adult participants with metastatic or locally advanced MTAP-deleted gastrointestinal, biliary tract, or pancreatic cancers.

Enrollment

350 estimated patients

Sex

All

Ages

18 to 100 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Subprotocol B

Inclusion:

Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
Histologically or cytologically confirmed diagnosis of metastatic and/or unresectable (locally advanced) adenocarcinoma of the pancreas.
Tumor tissue (FFPE sample) or an archival block must be available. Participants without archived tumor tissue available may be allowed to enroll by undergoing tumor biopsy before dosing.
Homozygous MTAP-deletion.
Disease measurable as defined by RECIST v1.1.
Adequate organ function as defined in the protocol.

Exclusion:

Prior treatment with a MAT2A inhibitor or a PRMT5 inhibitor.
Radiation therapy within 28 days of first dose.
Major surgery within 28 days of first dose of Anvumetostat.
Cardiovascular and pulmonary exclusion criteria as defined in the protocol.
Gastrointestinal tract disease causing the inability to take PO medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (eg, Crohn's disease, ulcerative colitis).
History of solid organ transplantation.

Subprotocol C

Inclusion:

Age ≥ 18 years (or ≥ legal age within the country if it is older than 18 years).
Histologically or cytologically confirmed diagnosis of metastatic and/or unresectable (locally advanced) adenocarcinoma of the pancreas.
Homozygous MTAP-deletion.
Rat Sarcoma Viral Oncogene Homolog (RAS) mutation
Received at least 1 prior systemic therapy for advanced or metastatic PDAC.
Disease measurable as defined by RECIST v1.1.
Adequate organ function as defined in the protocol.

Exclusion:

Prior treatment with aMAT2A inhibitor, a PRMT5 inhibitor, or a MAPK pathway inhibitor, including KRAS inhibitors.
Cardiovascular and pulmonary exclusion criteria as defined in the protocol.
Gastrointestinal tract disease causing the inability to take PO medication, malabsorption syndrome, requirement for IV alimentation, gastric/jejunal tube feeds, uncontrolled inflammatory gastrointestinal disease (eg, Crohn's disease, ulcerative colitis).
History of solid organ transplantation.

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

350 participants in 4 patient groups

Subprotocol B: Pancreatic Ductal Adenocarcinoma (PDAC) Arm A

Experimental group

Description:

Part 1: Participants with MTAP-deleted PDAC will receive doses of Anvumetostat orally in combination with gemcitabine and nab-paclitaxel IV. Part 2: Participants with MTAP-deleted PDAC will receive the recommended dose of Anvumetostat in combination with gemcitabine and nab-paclitaxel.

Treatment:

Drug: Anvumetostat

Drug: Nab-paclitaxel

Drug: Gemcitabine

Subprotocol B: PDAC Arm B

Experimental group

Description:

Part 1: Participants with MTAP-deleted PDAC will receive doses of Anvumetostat orally in combination with mFOLFIRINOX (irinotecan, fluorouracil, leucovorin calcium, oxaliplatin) IV. Part 2: Participants with MTAP-deleted PDAC will receive the recommended dose of Anvumetostat in combination with mFOLFIRINOX.

Treatment:

Drug: Modified FOLFIRINOX

Drug: Anvumetostat

Subprotocol C: Dose Exploration

Experimental group

Description:

Part 1: Participants with MTAP-deleted PDAC will receive oral doses of Anvumetostat and RMC-6236.

Treatment:

Drug: Anvumetostat

Drug: RMC-6236

Subprotocol C: Dose Expansion

Experimental group