Study of AG-270 in Participants With Advanced Solid Tumors or Lymphoma With MTAP Loss

NCT03435250 | Terminated Phase 1 FDA Drug

• 1 other identifier: AG270-C-001
• Study Type: interventional
• Target: 123
• Locations: 3 countries
• Sites: 8

Brief Summary

This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of AG-270 in participants with advanced solid tumors or lymphoma with homozygous MTAP deletion.

Conditions

Advanced Solid Tumors; Lymphoma

Keywords

MTAP; MTAP deletion; CDKN2A deletion; MAT2A inhibitor; Advanced solid tumors; Lymphoma

Outcome Measures

Primary Outcomes (3)

• Percentage of Participants with DLTs Associated with AG-270 Administration During the First Cycle (First 28 Days) of Treatment

  Up to 28 days, on average

• Percentage of Participants with DLTs Associated with the Combination of AG-270 and Docetaxel Administration During the First Cycle (First 28 Days) of Treatment

  Up to 28 days, on average

• Percentage of Participants with DLTs Associated with the Combination of AG-270, nab-paclitaxel, and Gemcitabine Administration During the First Cycle (First 28 Days) of Treatment

  Up to 28 days, on average

Secondary Outcomes (17)

• Percentage of Participants with Treatment-related Adverse Events and Serious Adverse Events

  Up to 30 weeks, on average

• Changes in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score

  Up to 30 weeks, on average

• Area under the Concentration-versus-time Curve (AUC) from 0 to Time of Last Measurable Concentration (AUC0-t) of AG-270

  At multiple time points up to 30 weeks, on average

• AUC from 0 to Infinity (AUC0-∞) of AG-270

  At multiple time points up to 30 weeks, on average

• AUC over One Dosing Interval at Steady State (AUCtau,ss) of AG-270

  At multiple time points up to 30 weeks, on average

Study Arms (3)

AG-270

EXPERIMENTAL

AG-270 will be administered on Days 1 to 28 of each 28-day cycle. Treatment will continue until disease progression or unacceptable toxicity.

Drug: AG-270

AG-270/docetaxel

EXPERIMENTAL

AG-270 will be administered daily, starting 1 week prior to docetaxel infusion. Starting on Cycle 1 Day 1, docetaxel (by intravenous infusion \[IV\]) will be administered once during each 21-day cycle. Treatment with AG-270 and docetaxel will continue until disease progression or unacceptable toxicity.

Drug: AG-270; Drug: docetaxel

AG-270/nab-paclitaxel/gemcitabine

EXPERIMENTAL

AG-270 will be administered daily, starting 1 week prior to nab-paclitaxel and gemcitabine infusion. Starting on Cycle 1 Day 1, nab-paclitaxel and gemcitabine IV will be administered on Days 1,8, and 15 during each 28-day cycle. Treatment with AG-270, nab-paclitaxel, and gemcitabine will continue until disease progression or unacceptable toxicity.

Drug: AG-270; Drug: nab-paclitaxel; Drug: gemcitabine

Interventions

AG-270 DRUG

AG-270, orally, once or twice daily, on Days 1 through 28 of each 28-day cycle, until disease progression or unacceptable toxicity.

Also known as: MAT2A inhibitor

AG-270

docetaxel DRUG

Docetaxel, IV, once during each 21-day cycle, until disease progression or unacceptable toxicity.

Also known as: Taxotere®

AG-270/docetaxel

nab-paclitaxel DRUG

Nab-paclitaxel, IV, on Days 1, 8, and 15 of each 28-day cycle, until disease progression or unacceptable toxicity.

Also known as: Abraxane®

AG-270/nab-paclitaxel/gemcitabine

gemcitabine DRUG

Gemcitabine, IV, on Days 1, 8, and 15 of each 28-day cycle, until disease progression or unacceptable toxicity.

Also known as: Gemzar®

AG-270/nab-paclitaxel/gemcitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• AG-270 Monotherapy
• Be ≥18 years of age;
• Have a histologically confirmed diagnosis of an advanced solid tumor or lymphoma that has progressed in spite of at least one prior line of treatment, and for which additional effective standard therapy is not available. For this study, effective standard therapy is defined as treatment that has been shown to be curative and/or to prolong survival. In addition, participants who are considered to not be candidates for standard therapy or who decline standard therapy are eligible for this study; in such cases, documentation of the reason for omitting or declining a standard therapy is required;
• Have evidence of homozygous loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) and/or MTAP in the participant's tumor tissue;
• Have disease that can be clinically evaluated for improvement or progression. In the dose-expansion phase of the study arm, participants must have disease that is measurable, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria for solid tumors (Eisenhauer et al, 2009) or the Lugano criteria for lymphoma (Cheson et al, 2014);
• Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2;
• Have a hemoglobin ≥9.0 grams per deciliter (g/dL) without red blood cell transfusion for ≥1 month;
• Have an absolute neutrophil count (ANC) ≥1.0 × 10\^9/liter (L);
• Have a platelet count ≥75 × 10\^9/L;
• Have a serum total bilirubin ≤1.5 × upper limit of normal (ULN);
• Have an alanine aminotransferase (ALT) ≤3.0 × ULN. (Note: There are no specific requirements for aspartate aminotransferase (AST) or Alkaline phosphatase \[ALP\]);
• Have a serum creatinine ≤1.5 × ULN;
• Be fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy. Residual chronic toxicities of prior therapy ≤Grade 2 (eg, peripheral neuropathy, residual alopecia) are allowed;
• Female participants who are pre-menopausal or have experienced menopause for less than 2 years and who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion must have a negative serum pregnancy test during screening and a serum or urine pregnancy test must be re-confirmed as negative no more than 72 hours before starting AG-270. Females of reproductive potential as well as fertile men with partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use 2 effective forms of contraception (including at least 1 barrier form) from the time of giving informed consent, during the study, and for 6 months (for females) and for 3 months (for males) following the last dose of AG-270. Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier methods (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization;
• Able to understand and has provided written informed consent. A legally authorized representative may consent on behalf of a participant who is otherwise unable to provide informed consent, if acceptable to and approved by the site and/or site's Institutional Review Board (IRB)/Independent Ethics Committee (IEC).

You may not qualify if:

• Have a primary central nervous system (CNS) malignancy (eg, glioblastoma multiforme \[GBM\]);
• Have metastasis to the CNS that is symptomatic and/or requires therapy with corticosteroids or anti-convulsant medication. However, participants who have completed treatment (radiation therapy) for CNS metastases and do not require continued treatment with corticosteroids or anti-convulsants may be enrolled in this study;
• Have a history of Gilbert's syndrome;
• Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of AG-270, including any unresolved nausea, vomiting, or diarrhea that is National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade \>1;
• Have had significant active cardiac disease within 6 months prior to the start of study treatment, including any of the following:
• New York Heart Association (NYHA) class III or IV congestive heart failure;
• Acute myocardial infarction or angina pectoris;
• Stroke;
• Uncontrolled cardiac arrhythmia (participants with rate-controlled atrial fibrillation are not excluded).
• Have a heart-rate corrected QT interval using Fridericia's method (QTcF) \>470 milliseconds (msec);
• Have any other concurrent severe and/or uncontrolled concomitant medical condition that could compromise participation in the study (eg, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection);
• Have received systemic anti-cancer treatment or radiotherapy less than 2 weeks before the first dose of AG-270. Participants with castration-resistant prostate cancer may continue therapy with a luteinizing hormone releasing hormone (LHRH) agonist while participating in this study. Continuation of supportive therapy with bisphosphonates or denosumab is also allowed, regardless of the underlying malignancy;
• Have received radioimmunotherapy (eg, 131I-tositumomab, 90Y-ibritumomab tiuxetan) less than 6 weeks before the first dose of AG-270;
• Have received treatment with a therapeutic antibody less than 4 weeks before the first dose of AG-270. A minimum 2-week period between the last treatment with a therapeutic antibody and the first dose of AG-270 may be permitted in participants with rapidly progressive or aggressive subtypes of lymphoma following discussion with the medical monitor;
• Have received treatment with an investigational small molecule less than 2 weeks before the first dose of AG-270. In addition, the first dose of AG-270 should not occur before a period greater than or equal to 5 half-lives of the investigational small molecule has elapsed;

Sponsors & Collaborators

• Institut de Recherches Internationales Servier: lead

Study Sites (8)

Yale University

New Haven, Connecticut, 06519, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Beth Israel

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering Cance Center

New York, New York, 10065, United States

Location

Sarah Cannon Cancer Center

Nashville, Tennessee, 37203, United States

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

Related Publications (3)

• Heist RS, Gounder MM, Postel-Vinay S, Wilson F, Garralda E, Do K, Shapiro GI, Martin-Romano P, Wulf G, Cooper M, Almon C, Nabhan S, Iyer V, Zhang Y, Marks K, Aguado-Fraile E, Basile F, Flaherty K, Burris HA. A phase 1 trial of AG-270 in patients with advanced solid tumors or lymphoma with homozygous MTAP deletion [abstract]. Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR03. doi:10.1158/1535-7163.TARG-19-PR03

  BACKGROUND

• Gounder M, Johnson M, Heist RS, Shapiro GI, Postel-Vinay S, Wilson FH, Garralda E, Wulf G, Almon C, Nabhan S, Aguado-Fraile E, He P, Romagnoli M, Hossain M, Narayanaswamy R, Sadou-Dubourgnoux A, Cooper M, Askoxylakis V, Burris HA, Tabernero J. MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial. Nat Commun. 2025 Jan 6;16(1):423. doi: 10.1038/s41467-024-55316-5.

  PMID: 39762248 DERIVED

• Konteatis Z, Travins J, Gross S, Marjon K, Barnett A, Mandley E, Nicolay B, Nagaraja R, Chen Y, Sun Y, Liu Z, Yu J, Ye Z, Jiang F, Wei W, Fang C, Gao Y, Kalev P, Hyer ML, DeLaBarre B, Jin L, Padyana AK, Dang L, Murtie J, Biller SA, Sui Z, Marks KM. Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion. J Med Chem. 2021 Apr 22;64(8):4430-4449. doi: 10.1021/acs.jmedchem.0c01895. Epub 2021 Apr 8.

  PMID: 33829783 DERIVED

MeSH Terms

Conditions

Lymphoma

Interventions

Docetaxel; 130-nm albumin-bound paclitaxel; Albumin-Bound Paclitaxel; Gemcitabine

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Paclitaxel; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 1, 2018
• First Posted: February 19, 2018
• Study Start: March 4, 2018
• Primary Completion: April 20, 2023
• Study Completion: April 20, 2023
• Last Updated: July 25, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.

Locations

ES (1); US (6); FR (1)