This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical
activity of AG-636, an oral Dihydroorotate Dehydrogenase (DHODH) inhibitor, in subjects with
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
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
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
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
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.
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
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
8. Have an active infection (bacterial, viral, or fungal) that cannot be controlled with
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.
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.