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Phase I

A Phase 1 Study of AG-270 in the Treatment of Subjects With Advanced Solid Tumors or Lymphoma With Homozygous Deletion of MTAP

  • Study HIC#:2000022322
  • Last Updated:07/15/2021

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

  • Start Date06/20/2018
  • End Date11/30/2021

Trial Purpose and Description

The purpose of this Phase 1, multicenter, open label study is to determine the maximum tolerated dose (MTD) of AG-270 and characterize its dose-limiting toxicities (DLTs) when given daily by mouth to subjects with advanced solid tumors or lymphoma with homozygous deletion of methylthioadenosine phosphorylase (MTAP). The first portion of this study is dose escalation, where cohorts of subjects will receive ascending oral doses of AG-270 to determine the MTD, the dose with maximum pharmacologic activity or a maximum feasible dose. In the dose expansion portion of the study, additional subjects will be treated at the MTD (or one of the described alternative doses) to further characterize that dose's safety, tolerability, PK and PD, and to detect preliminary evidence of anti-tumor activity. The dose-expansion phase of the study will support the selection of a dose for future clinical studies (recommended Phase 2 dose [RP2D]).

Eligibility Criteria

Inclusion Criteria:

  1. Be ≥18 years of age.
  2. 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, subjects 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.
  3. Have evidence of homozygous loss of CDKN2A or MTAP in the subject's tumor tissue.
  4. Have disease that can be clinically evaluated for improvement or progression. In the dose-expansion phase of the study, subjects must have disease that is measurable, as defined by the RECIST Version 1.1 criteria for solid tumors (Eisenhauer et al, 2009) or the Lugano criteria for lymphoma (Cheson et al, 2014).
  5. Have an ECOG performance status (PS) of ≤2.
  6. Have a hemoglobin ≥9.0 g/dL without red blood cell transfusion for ≥1 month.
  7. Have an absolute neutrophil count (ANC) ≥1.0 × 109/L.
  8. Have a platelet count ≥75 × 109/L.
  9. Have a serum total bilirubin ≤1.5 × ULN (upper limit of normal).
  10. Have an alanine aminotransferase (ALT) ≤3.0 × ULN. (Note: There are no specific requirements for AST or alkaline phosphatase.)
  11. Have a serum creatinine ≤1.5 × ULN.
  12. 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.
  13. Female subjects 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 and their partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use 2 effective forms of contraception from the time of giving informed consent, during the study, and for 3 months (females and 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.
  14. Able to understand and has provided written informed consent. A legally authorized representative may consent on behalf of a subject 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).

Exclusion Criteria:

  1. Have a primary CNS malignancy (eg, GBM).
  2. Have metastasis to the CNS that is symptomatic and/or requires therapy with corticosteroids or anti-convulsant medication. However, subjects 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.
  3. Have a history of Gilbert's syndrome.
  4. Have a degenerative retinal disease. Retinal diseases that require a subject's exclusion include: glaucoma, hereditary retinal diseases such as retinitis pigmentosa; retinal arterial occlusive disease; and retinal disease with advanced scarring, to include age-related macular degeneration and myopic degeneration with geographic atrophy.
  5. 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.
  6. Have had significant active cardiac disease within 6 months prior to the start of study treatment, including any of the following:
    1. New York Heart Association (NYHA) class III or IV congestive heart failure.
    2. Acute myocardial infarction or angina pectoris.
    3. Stroke.
    4. Uncontrolled cardiac arrhythmia (subjects with rate-controlled atrial fibrillation are not excluded).
    5. A past medical history of other clinically significant cardiovascular disease (eg, uncontrolled hypertension, history of labile hypertension, history of poor compliance with an antihypertensive regimen).
  7. Have a heart-rate corrected QT interval using Fridericia's method (QTcF) >470 msec.
  8. 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).
  9. Have received systemic anti-cancer treatment or radiotherapy less than 2 weeks before the first dose of AG-270. Subjects 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.
  10. Have received radioimmunotherapy (eg, 131I-tositumomab, 90Y-ibritumomab tiuxetan) less than 6 weeks before the first dose of AG-270.
  11. 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 subjects with rapidly progressive or aggressive subtypes of lymphoma following discussion with the medical monitor.
  12. 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.
  13. Require continued treatment with a medication that is known to be a strong inhibitor of CYP3A enzymes. (Treatment with moderate or weak CYP enzyme inhibitors is allowed.)
  14. Require continued treatment with a medication that is known to be a strong inducer of CYP3A.
  15. Require continued treatment with a medication that is known to be a strong inhibitor of CYP2C8.
  16. Require continued treatment with a medication that is a sensitive CYP2C9 substrate with a narrow therapeutic index.
  17. Require continued treatment with medications that are known to carry a risk of torsades de pointes.
  18. Are pregnant or breastfeeding.
  19. Have any other medical or psychological condition deemed by the Investigator to likely interfere with the subject's ability to give informed consent or participate in the study.
  20. Are unable to take no food or liquids other than water for 2 hours before and 2 hours after each dose of AG-270.