Clinical Trials /

A Study of AG-636 in the Treatment of Subjects With Advanced Lymphoma

NCT03834584

Description:

This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of AG-636, an oral Dihydroorotate Dehydrogenase (DHODH) inhibitor, in subjects with advanced lymphoma.

Related Conditions:
  • Hodgkin Lymphoma
  • Immunodeficiency-Associated Lymphoproliferative Disorder
  • Mature B-Cell Neoplasm
  • Mature T-Cell and NK-Cell Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of AG-636 in the Treatment of Subjects With Advanced Lymphoma
  • Official Title: A Phase 1 Study of AG-636 in the Treatment of Subjects With Advanced Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: AG636-C-001
  • NCT ID: NCT03834584

Conditions

  • Lymphoma

Interventions

DrugSynonymsArms
AG-636AG-636

Purpose

This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of AG-636, an oral Dihydroorotate Dehydrogenase (DHODH) inhibitor, in subjects with advanced lymphoma.

Detailed Description

      The purpose of this Phase 1, multicenter, open-label study is to determine the maximum
      tolerated dose (MTD) of AG-636 and characterize its dose-limiting toxicities (DLTs) when
      given by mouth to subjects with advanced lymphoma that is refractory to standard treatment.
      During the dose escalation part of the study successive cohorts of subjects will be treated
      with increasing doses of AG-636 in order to determine its maximum tolerated dose (MTD).
      Subsequently, in the dose expansion part of the study, additional subjects will be treated at
      the MTD in order to confirm that dose's safety, tolerability, PK and PD, and to provide an
      opportunity to detect anti-lymphoma activity. The dose expansion part of the study will
      support the selection of a dose for future clinical studies (a recommended Phase 2 dose
      [RP2D]).
    

Trial Arms

NameTypeDescriptionInterventions
AG-636ExperimentalAG-636 dosed orally.
  • AG-636

Eligibility Criteria

        Inclusion Criteria:

          1. Be ≥18 years of age.

          2. Have a pathologically confirmed diagnosis of a non-Hodgkin or Hodgkin lymphoma that
             has progressed in spite of prior treatment, and for whom additional effective
             (curative or life-prolonging) standard therapy is not available. The lymphomas
             included in this study must fall within one of the following 2017 World Health
             Organization categories:

               1. Mature B-cell neoplasms (excluding plasma cell neoplasms, heavy chain disease,
                  and primary central nervous system [CNS] lymphoma)

               2. Mature T- and NK-cell neoplasms

               3. Hodgkin lymphomas

               4. Immunodeficiency-associated lymphoproliferative disorders

          3. In the case of subjects who have lymphoma for which high-dose chemotherapy and
             autologous stem cell transplantation (HD-ASCT) is considered a standard curative
             therapy, eligibility for this study requires that the subject's disease has relapsed
             after HD-ASCT, that the subject is not eligible for HD-ASCT, or that the subject has
             refused HD-ASCT.

          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 either the Lugano criteria for lymphoma or the 2011 ISCL/USCLC/EORTC
             criteria for MF/SS).

          5. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

          6. Have an absolute neutrophil count (ANC) ≥1,000/uL.

          7. Have a platelet count ≥75,000/uL.

          8. Have a serum total bilirubin level ≤1.5×ULN (upper limit of normal) in the absence of
             Gilbert syndrome. Subjects with Gilbert syndrome must have a serum total bilirubin
             level ≤1.5× their baseline value.

          9. Have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels
             ≤3.0×ULN, unless due to underlying hematologic malignancy. If ALT/AST elevations are
             determined to be due to involvement by the underlying hematologic malignancy, subjects
             must have ALT/AST levels <5.0× the ULN.(Note: There are no specific requirements for
             alkaline phosphatase [ALP].)

         10. Have a creatinine clearance (CrCl) ≥ 30 mL/min (either measured or estimated by the
             Cockcroft-Gault formula). (Cockcroft-Gault formula for estimated creatinine clearance
             [eCrCl]: eCrCl = [140 - Age] × Weight [kg] × [0.85 if Female] / [72 × serum creatinine
             (mg/dL)]).

         11. Be fully recovered from major surgery and from the acute toxic effects of prior
             chemotherapy and radiotherapy. Residual chronic toxicities of prior therapy, eg,
             alopecia, Grade ≤2 peripheral neuropathy, are allowed.

         12. If female with reproductive potential, must have a negative serum pregnancy test prior
             to the start of study therapy. Females of reproductive potential, as well as fertile
             men and their female partners of reproductive potential, must agree to use 2 effective
             forms of contraception.

         13. Able to understand and have provided written informed consent.

        Exclusion Criteria:

          1. Have a primary central nervous system (CNS) lymphoma.

          2. Have lymphomatous involvement of the CNS that is symptomatic or requires therapy.
             However, subjects who have completed treatment for lymphoma involving the CNS and have
             no further evidence of disease in the CNS may be enrolled in this study.

          3. Have lymphoma that requires immediate cytoreductive therapy.

          4. Have low-grade lymphoma that does not meet conventional criteria for requiring
             treatment.

          5. Have impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of AG-636, including any unresolved nausea, vomiting, or diarrhea
             that is National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
             (CTCAE) Grade >1.

          6. Are unable to abstain from food or liquids other than water for 2 hours before and 2
             hours after each dose of AG-636.

          7. Have an active infection with human immunodeficiency virus (HIV), hepatitis B, or
             hepatitis C.

          8. Have an active infection (bacterial, viral, or fungal) that cannot be controlled with
             treatment.

          9. 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).

         10. Have a heart rate-corrected QT interval using Fridericia's method (QTcF) >470 msec.
             Patients with bundle branch block and a QTcF >470 msec should be discussed with the
             Medical Monitor for potential inclusion.

         11. 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 neurologic disorder).

         12. Have received any systemic anticancer treatment or radiotherapy less than 2 weeks
             before the first dose of AG-636.

         13. Have received radioimmunotherapy less than 6 weeks before the first dose of AG-636.

         14. Have received treatment with an investigational small molecule <2 weeks before the
             first dose of AG-636.

         15. Are taking medications that are sensitive substrates of CYP2C8, and that cannot be
             discontinued prior to starting treatment with AG-636.

         16. Are taking medications that are sensitive substrates of either P-glycoprotein (P-gp)
             or breast cancer resistance protein (BCRP), and that cannot be discontinued prior to
             starting treatment with AG-636.

         17. Are pregnant or breastfeeding.

         18. Have any other medical or psychological condition deemed by the Investigator to be
             likely to interfere with the subject's ability to give informed consent or participate
             in the study.

         19. Have concurrent malignancy other than lymphoma; subjects must have been free of other
             malignancies for ≥1 year before the start of study treatment. However, subjects with
             the following history/concurrent conditions are allowed:

               1. Basal or squamous cell carcinoma of the skin

               2. Carcinoma in situ of the cervix

               3. Carcinoma in situ of the breast

               4. Incidental histologic finding of prostate cancer.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The frequency of dose limiting toxicities (DLTs) associated with AG-636 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-636 (number of treatment-related Adverse Events and Serious Adverse Events)
Time Frame:Up to 24 weeks, on average
Safety Issue:
Description:As determined by the number of treatment-related Adverse Events and Serious Adverse Events
Measure:Characterize the Pharmacodynamics of AG-636
Time Frame:Up to 24 weeks, on average
Safety Issue:
Description:Measured by changes from baseline in circulating upstream metabolites
Measure:Pharmacokinetics of AG-636 in plasma
Time Frame:Up to 24 weeks, on average
Safety Issue:
Description:Determined by the plasma concentration versus time profile of AG-636
Measure:Clinical activity of AG-636 in Lymphoma
Time Frame:Up to 24 weeks, on average
Safety Issue:
Description:Assessed by either the Lugano criteria for lymphoma or the 2011 International Society for Cutaneous Lymphomas (ISCL)/United States Cutaneous Lymphoma Consortium (USCLC)/ European Organization for Research and Treatment of Cancer (EORTC) criteria for mycosis fungoides (MF)/Sézary syndrome (SS)

Details

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

Trial Keywords

  • Lymphoma
  • DHODH
  • Hodgkins Lymphoma
  • Non-Hodgkins Lymphoma
  • T-Cell Lymphoma

Last Updated

February 25, 2020