A Multi-phase Study of ASTX030 (Azacitidine and Cedazuridine) in Myeloid Neoplasm Alone or in Combination With Venetoclax in AML (AZTOUND Study)

Taiho Pharma

Status and phase: Enrolling; Phase 3; Phase 2

Conditions: Myelodysplastic Syndrome/Neoplasm; Myelodysplastic Syndromes; Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia

Treatments: Drug: Venetoclax; Drug: ASTX030 (cedazuridine + azacitidine); Drug: Cedazuridine; Drug: Azacitidine

Study type: Interventional

Funder types: Industry

Identifiers

NCT04256317

2024-515098-93 (Other Identifier)

ASTX030-01

Details and patient eligibility

About

Study ASTX030-01 is a multi-phase study comprising of Phases 1-3 Monotherapy arms and a Phase 1 Combination Therapy arm Phase 1 Monotherapy consists of an open-label Dose Escalation Stage (Stage A) using multiple cohorts at escalating dose levels of oral cedazuridine and azacitidine (only one study drug will be escalated at a time) followed by a Dose Expansion Stage (Stage B). Phase 2 Monotherapy is a randomized, open-label, crossover study to compare oral ASTX030 to subcutaneous (SC) azacitidine. Phase 3 Monotherapy is a randomized open-label crossover study comparing the final fixed dose of oral ASTX030 to SC azacitidine. Phase 1 Combination Therapy is an open-label, multicenter, randomized, exploratory study comparing ASTX030 and SC azacitidine in combination with venetoclax in participants with AML.

The duration of this multi-phase study is approximately 7 years.

Full description

The Phase 1 and Phase 2 Monotherapy arms have completed enrolment. The Phase 3 Monotherapy and Phase 1 Combination Therapy arms are open for enrolment.

Enrollment: 236 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Phase 2 Monotherapy:

  1. Has Confirmed MDS, CMML, or other MDS/MPN diagnosis who are candidates to receive and benefit from single agent azacitidine and as applicable according to local country approvals and/or local institution standard practice.

• Phase 3 Monotherapy:

  1. Has confirmed MDS or CMML and is a candidate to receive and benefit from single agent azacitidine as applicable according to local country approvals and/or local institution standard practice:

     a) French-American-British myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and CMML or MDS with intermediate-2 or high risk MDS according to the International Prognostic Scoring System (IPSS).

  2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

  3. Participants with adequate organ function.

  4. For participants with prior allogeneic stem cell transplant, no evidence of graft-versus-host disease (GVHD).

  5. Participants with no major surgery within 3 weeks before first study treatment.

  6. Participants with no cytotoxic chemotherapy (excluding hydroxyurea) within 4 weeks before first study treatment.

  7. Is able to swallow the number of tablets/capsules required for the treatment assignment within a 10-minute period and tolerate 4 hours of fasting.

  8. Participants with projected life expectancy of at least 12 weeks.

• Phase 1 Combination Therapy:

  1. Has histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2022 criteria.

  2. Participants with projected life expectancy of at least 12 weeks.

  3. Must be considered ineligible for intensive induction chemotherapy defined by the following:

     a. Aged 75 years or older, or b. Aged 18 to 74 years with at least one of the following comorbidities: i. Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina).

     ii. Severe pulmonary disorder (e.g., diffusing capacity of the lung for carbon monoxide (DLCO) ≤65% or forced expiratory volume in 1 second [FEV1] ≤65%). iii. Creatinine clearance ≥30 mL/min to <45 mL/min. iv. Moderate hepatic impairment with total bilirubin >1.5 to ≤3.0 × upper limit of normal (ULN).

     v. ECOG Performance Status of 2 or 3.

  4. Has an ECOG Performance Status of 0-2 for participants ≥75 years of age or 0-3 for participants 18 to 74 years of age.

Exclusion criteria

• All Monotherapy Phases:

  1. Has an active uncontrolled gastric or duodenal ulcer.
  2. Has poor medical risk because of other conditions.
  3. Has known human immunodeficiency virus (HIV) infection.
  4. Is known to be positive for Hepatitis B or C infection.
  5. Has a life-threatening illness.
  6. Has a history of other malignancies prior to study entry, with the exception of adequately treated in situ carcinoma of the breast or cervix uteri; localized basal cell carcinoma or squamous cell carcinoma of the skin; previous malignancy confined and surgically resected or adequately treated and controlled with other modalities; and any early stage malignancy for which no definitive therapy is required.
  7. Participants with MDS/MPN including CMML who have clinical extramedullary disease including clinically palpable hepatomegaly or splenomegaly.
  8. Has previous treatment with more than 1 cycle of decitabine, azacitidine, or guadecitabine (Phases 2 and 3 only).
  9. Has been treated with any investigational drug or therapy within 2 weeks, or 5 half-lives, whichever is longer, before the protocol-defined first dose of study treatment, or ongoing clinically significant adverse events from previous treatment with investigational drug or therapy.
  10. Has a known or suspected hypersensitivity to cedazuridine or azacitidine or any of their excipients.
  11. Cannot discontinue treatment with any drugs that delay gastric emptying such as glucagon-like peptide-1 (GLP-1) and/or gastric inhibitory polypeptide (GIP) agonists in Cycles 1 and 2 of the study.
  12. Has a known or suspected hypersensitivity to cedazuridine or azacitidine or any of their excipients.

• Phase 1 Combination Therapy:

  1. Has a history of MPN including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation, or AML with BCR-ABL1 translocation.

  2. Has the following karyotype abnormalities: t(15;17) or other acute promyelocytic leukemia variants that remain sensitive to all-trans retinoic acid (ATRA) therapy.

  3. Has known active central nervous system involvement from AML.

  4. Has known human immunodeficiency virus (HIV) infection.

  5. Is known to be positive for Hepatitis B or C infection.

  6. Has severe hepatic impairment

  7. Has severe renal impairment

  8. Has a malabsorption syndrome or other condition that precludes enteral route of administration.

  9. Has a cardiovascular disability status of New York Heart Association Class >2.

  10. Has significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular, or pulmonary disease; or any other medical condition that in the opinion of the investigator would adversely affect his/her participation in this study.

  11. Has clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).

  12. Has a history of other malignancies prior to study entry with the exception of adequately treated in situ carcinoma of the breast or cervix uteri; localized basal cell carcinoma or squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or adequately treated and controlled with other modalities); and any early stage malignancy for which no definitive therapy is required.

  13. Has a WBC count >25,000/ microliters (μL) (hydroxyurea treatment is permitted to meet this criterion).

  14. Has received treatment with any of the following:

      1. A hypomethylating agent (azacitidine or decitabine) or venetoclax, including prior treatment for MDS.
      2. Chimeric Antigen Receptor (CAR)-T cell therapy.
      3. Investigational therapies for MDS or AML.

  15. Cannot discontinue treatment with any of the following:

      1. Prophylactic antifungal therapy with CYP3A inhibitor activity or other concomitant medications with moderate or strong CYP3A inhibitor activity ≥7 days or 5 halflives, whichever is greater, prior to Cycle 1 Day 1 (C1D1).
      2. Drugs that are strong CYP3A or P-gp inhibitors ≥7 days or 5 half-lives, whichever is greater, prior to C1D1.

  16. Cannot avoid concomitant drugs known as moderate or strong CYP3A inducers.

  17. Cannot discontinue treatment with any drugs that delay gastric emptying such as GLP-1 and/or GIP agonists in Cycles 1 and 2 of the study.

  18. Is participating in another research study requiring interventions such as drug therapy or study procedures.

  19. Has a known or suspected hypersensitivity to cedazuridine, azacitidine, venetoclax, or any of their excipients.

  20. Has known significant mental illness or other conditions such as alcohol or other substance abuse or addictions

  21. Consumes grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit ≤7 days prior to C1D1.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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236 participants in 5 patient groups

Phase 1 Monotherapy , Stage A (Dose Escalation)

Experimental group

Description:

In Cycle 1 (28 days per cycle), single dose oral azacitidine will be administered, followed by SC azacitidine, ASTX030 and oral cedazuridine on a specific dosing schedule; in Cycle 2, oral ASTX030 (cedazuridine + azacitidine) will be administered.

Treatment:

Drug: Azacitidine

Drug: Azacitidine

Drug: Cedazuridine

Drug: ASTX030 (cedazuridine + azacitidine)

Drug: ASTX030 (cedazuridine + azacitidine)

Phase 1 Monotherapy, Stage B (Dose Expansion)

Experimental group

Description:

In Cycle 1 (28 days per cycle), single dose oral azacitidine will be administered, followed by SC azacitidine, ASTX030 and oral cedazuridine on a specific dosing schedule; in Cycle 2, oral ASTX030 (cedazuridine + azacitidine) will be administered. On Day 7 of Cycle 2 drug products will administered in a fed state and all other doses will be administered in fasted state.

Treatment:

Drug: Azacitidine

Drug: Azacitidine

Drug: Cedazuridine

Drug: ASTX030 (cedazuridine + azacitidine)

Drug: ASTX030 (cedazuridine + azacitidine)

Phase 2 Monotherapy, Part B, Sequence A & B

Experimental group

Description:

In Sequence A: Oral ASTX030 (cedazuridine + azacitidine) will be administered in Cycle 1, followed by SC azacitidine in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3). In Sequence B: SC azacitidine will be administered in Cycle 1, followed by oral cedazuridine + azacitidine tablets/capsules in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3).

Treatment:

Drug: Azacitidine

Drug: Azacitidine

Drug: ASTX030 (cedazuridine + azacitidine)

Drug: ASTX030 (cedazuridine + azacitidine)

Phase 3 Monotherapy, Sequence A & B

Experimental group

Description:

In Sequence A: Participants will receive ASTX030 in Cycle 1, followed by SC azacitidine in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3). In Sequence B: Participants will receive SC azacitidine in Cycle 1 followed by ASTX030 in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3).

Treatment:

Drug: Azacitidine

Drug: Azacitidine

Drug: ASTX030 (cedazuridine + azacitidine)

Drug: ASTX030 (cedazuridine + azacitidine)

Phase 1 Combination Therapy

Experimental group

Description:

Treatment Arm 1: Participants will receive oral dose of ASTX030 along with ramp-up oral dosing of venetoclax in Cycle 1 (cycle length = 28 days); participants will receive ASTX030 along with venetoclax on a specific dosing schedule in subsequent cycles (Cycles ≥2). Treatment Arm 2: Participants will receive SC azacitidine along with ramp-up oral dosing of venetoclax in Cycle 1 (cycle length = 28 days); participants will receive SC azacitidine along with oral dose of venetoclax on a specific dosing schedule in subsequent cycles (Cycles ≥2). At the beginning of Cycle 5, Arm 2 patients may be permitted to cross over to Arm 1.

Treatment:

Drug: Azacitidine

Drug: Azacitidine

Drug: ASTX030 (cedazuridine + azacitidine)

Drug: ASTX030 (cedazuridine + azacitidine)

Drug: Venetoclax