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ASTX727 for the Treatment of Advanced, Unresectable, or Metastatic Solid Tumors

Trial Status: Active

This phase I trial studies the side effects and best dose of ASTX727 for the treatment of solid tumors that have spread to nearby tissue, lymph nodes, or distant parts of the body (advanced), cannot be removed by surgery (unresectable), or have spread to other places in the body (metastatic). ASTX727 is made up of two investigational drugs. One study drug is oral decitabine, which blocks abnormal cells or tumor cells from growing. The other study drug is called cedazuridine (E7727), which is a cytidine deaminase inhibitor, or CDAi. CDAi slows down how fast the oral decitabine disappears in the body.

Inclusion Criteria

  • Participants must have advanced, unresectable, and/or metastatic solid tumor malignancy that is histologically or cytologically confirmed
  • Patients must have received at least 2 lines of therapy in the advanced/metastatic setting (if 2 lines exist) and have no other possible therapies or refuse therapies that have shown clinical benefit for their condition
  • Patients must have measurable disease per RECIST 1.1 * Patients with biopsiable disease must be amenable to mandatory research biopsies
  • Archival tissue must be procured if available
  • Life expectancy of greater than 12 weeks
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin < 3 X institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5.0 X institutional upper limit of normal with liver metastases or AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal without liver metastases
  • Creatinine < 1.5X institutional upper limit of normal or creatinine clearance >= 50 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal
  • The effects of ASTX727 on the developing human fetus are unknown. For this reason and because oncological agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Men should be advised not to father a child while receiving treatment with cedazuridine, decitabine, the combination product ASTX727, and for 60 days after completion of treatment
  • Ability to understand and the willingness to sign a written informed consent document
  • Ability to swallow oral medications
  • Human immunodeficiency virus (HIV)-Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive patients must have: * A stable regimen of highly active anti-retroviral therapy (HAART) not including drugs known to be metabolized by CDA * No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections * A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based test

Exclusion Criteria

  • Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events =< grade 1 (=< grade 2 for sensory neuropathy) due to agents administered more than 3 weeks earlier
  • Participants may not be receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical to decitabine or ASTX727
  • Subjects who have received prior therapy with any hypomethylating agents
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because ASTX727 is a hypomethylating agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with ASTX727, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study
  • Drugs known to be metabolized by CDA (e.g., cytarabine, gemcitabine, azacytidine, vidarabine, zalcitabine, zidovudine, telbivudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, entecavir, apricitabine, idoxuridine, trifluridine, tenofovir and adefovir) should not be administered with ASTX727
  • Active hepatitis B or hepatitis C infection
  • Active or untreated gastric or duodenal ulcer
  • Hospitalization for an acute medical issue within 4 weeks prior to screening visit that would otherwise not be managed in an infusion center or outpatient clinic setting (e.g., a patient admitted to complete a transfusion would not be ineligible)
  • Symptomatic bowel obstruction within 3 months prior to screening visit
  • Symptomatic ascites in the last 4 weeks (requiring a paracentesis or causing discomfort)

California

Los Angeles
USC / Norris Comprehensive Cancer Center
Status: ACTIVE
Contact: Anthony El-Khoueiry

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Nilofer Saba Azad
Phone: 410-614-9169

PRIMARY OBJECTIVES:

I. To assess safety and tolerability of combination cedazuridine with decitabine in patients with solid tumor.

II. To determine the phase II dose of the combination of cedazuridine and decitabine.

SECONDARY OBJECTIVES:

I. To assess changes in global methylation and expression at the tumor level with CDA inhibitor E7727/decitabine combination agent ASTX727 (ASTX727) treatment.

II. To assess the pharmacokinetics of components of ASTX727 in solid tumor patients and correlate with changes in global methylation.

III. To estimate the objective response rate (ORR) in solid tumor patients who are treated with ASTX727 using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

EXPLORATORY OBJECTIVE:

I. To determine range of decitabine incorporation into deoxyribonucleic acid (DNA) and correlate the incorporation with global methylation.

OUTLINE: This is a dose-escalation study of decitabine.

Patients receive CDA inhibitor E7727/decitabine combination agent ASTX727 orally (PO) on days 1-10 or 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Nilofer Saba Azad

  • Primary ID J18115
  • Secondary IDs NCI-2019-06310, CRMS-69828
  • Clinicaltrials.gov ID NCT03875287