Clinical Trials /

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

NCT03435250

Description:

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.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of AG-270 in Subjects With Advanced Solid Tumors or Lymphoma With MTAP Loss
  • Official Title: A Phase 1 Study of AG-270 in the Treatment of Subjects With Advanced Solid Tumors or Lymphoma With Homozygous Deletion of MTAP

Clinical Trial IDs

  • ORG STUDY ID: AG270-C-001
  • NCT ID: NCT03435250

Conditions

  • Advanced Solid Tumors
  • Lymphoma

Interventions

DrugSynonymsArms
AG-270MAT2A inhibitorAG-270

Purpose

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.

Detailed 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]).
    

Trial Arms

NameTypeDescriptionInterventions
AG-270ExperimentalAG-270 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle.
  • AG-270

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 with
             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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The frequency of DLTs associated with AG-270 administration during the first cycle (first 28 days) of treatment.
Time Frame:Up to 28 days, on average
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Characterize the Safety and Tolerability of AG-270
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:As determined by the number of treatment-related Adverse Events and Serious Adverse Events
Measure:Pharmacokinetics of AG-270 in plasma
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:Determined by the Area Under the Curve (AUC) of AG-270
Measure:Characterize the Pharmacodynamics of AG-270
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:Measured by changes from baseline in circulating concentrations of S-adenosylmethionine (SAM) and methionine.
Measure:Clinical activity of AG-270 in solid tumors
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:Assessed by RECIST V1.1
Measure:Clinical activity of AG-270 in Lymphoma
Time Frame:Up to 30 weeks, on average
Safety Issue:
Description:Assessed by Lugano criteria

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Agios Pharmaceuticals, Inc.

Trial Keywords

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

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