A Study of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)

Acute Myeloid Leukemia Clinical Trial

Official title:

A Phase 1, Parallel, Open-Label Study of the Safety and Tolerability, Pharmacokinetics, and Antileukemic Activity of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04155580
• Other study ID #: ASTX660-02
• Status: Terminated
• Phase: Phase 1
• Start date: June 12, 2020
• Est. completion date: January 14, 2022

Study information

• Verified date: February 2023
• Source: Astex Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To evaluate the safety, pharmacokinetics (PK), and efficacy of ASTX660 when given alone and in combination with ASTX727 in participants with relapsed/refractory (R/R) acute myeloid leukemia (AML). The duration of the study is expected to be approximately 30 months.

Description:

This is a three-part dose escalation and dose expansion Phase 1 study of ASTX660 alone and in combination with ASTX727 in adults with R/R AML.

Part 1 is an open-label, single arm, dose escalation with ASTX660 in combination with ASTX727 at the standard fixed dose combination (FDC).

Part 2 is an open-label, randomized, dose escalation intended to evaluate ASTX660 as a monotherapy and ASTX660 in combination with ASTX727 FDC.

Part 3 is an exploratory single arm dose expansion to further expand the number of participants treated with ASTX660 in combination with ASTX727 FDC.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 68
• Est. completion date: January 14, 2022
• Est. primary completion date: January 14, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Have a projected life expectancy of at least 12 weeks, as assessed by the Investigator.

2. Have histological confirmation of AML by World Health Organization (WHO) 2016 criteria and are either:

1. refractory to intensive induction chemotherapy OR

2. relapsed after intensive induction chemotherapy or stem cell transplant OR

3. relapsed after or refractory to treatment with molecularly targeted and/or low-intensity chemotherapeutic regimens.

3. Have an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2.

4. Have adequate renal function as demonstrated by measured or calculated creatinine clearance =60 mL/min.

5. Have adequate liver function as demonstrated by:

1. Aspartate aminotransferase (AST) =2.5 × upper limit of normal (ULN)

2. Alanine aminotransferase (ALT) =2.5 × ULN

3. Bilirubin =1.5 × ULN - unless considered due to leukemic organ involvement.

6. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening.

Exclusion Criteria:

1. Poor medical risk in the investigator's opinion because of systemic diseases in addition to the cancer under study, for example, uncontrolled infections.

2. Known clinically active central nervous system (CNS) leukemia.

3. BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).

4. Diagnosis of acute promyelocytic leukemia (M3 AML or APML).

5. Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.

6. Graft Versus Host Disease (GVHD), or any GVHD requiring treatment with immunosuppression. Any GVHD treatment (including calcineurin inhibitors) must be discontinued at least 28 days prior to Day 1 of study treatment.

7. Presence of persistent toxicities of Grade >1 from prior treatment including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, and surgery (except for alopecia).

8. Hypersensitivity to decitabine, ASTX727, ASTX660, or any of their excipients.

9. Liver cirrhosis, or chronic liver disease Child-Pugh Class B or C.

10. Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator's opinion, could compromise participant safety, or the integrity of study outcomes, or interfere with the absorption or metabolism of ASTX660 or ASTX727.

11. History of, or at risk for, cardiac disease.

12. Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV), or active hepatitis C virus (HCV) infection (participants with laboratory evidence of no active replication will be permitted).

13. Known significant mental illness or other conditions, such as active alcohol or other substance abuse that, in the opinion of the investigator, predispose the participant to high risk of noncompliance with the protocol treatment or assessments.

14. Treated with any investigational therapy within 2 weeks of the first dose of study treatment or treatment with a myelosuppressive therapy within 4 weeks of the first dose of study treatment.

15. In Parts 1 and 2, prior treatment with decitabine for more than 2 cycles. In Part 3, any treatment with an HMA (azacitidine or decitabine, for more than one cycle).

16. Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to ASTX660-02 (Note: G-tube administration is not allowed).

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• ASTX660
Capsule for oral administration
• ASTX727
Tablet for oral administration

Locations

Country	Name	City	State
United States	Northside Hospital - The Blood and Marrow Transplant Group of Georgia	Atlanta	Georgia
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	The University of Kansas Clinical Research Center	Fairway	Kansas
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Franciscan Health Indianapolis (Blood and Marrow Transplantation)	Indianapolis	Indiana
United States	Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Vanderbilt - Ingram Cancer Center	Nashville	Tennessee
United States	Smilow Cancer Hospital	New Haven	Connecticut
United States	Mount Sinai Medical Center	New York	New York
United States	New York University Langone Health	New York	New York
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Astex Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety Assessment: Number of participants with treatment-emergent adverse events (TEAEs)		Up to 30 months
Secondary	Response rate: Number of participants achieving complete response (CR), complete response with incomplete hematological recovery (CRi), and partial response (PR) as determined by the European LeukemiaNet (ELN) 2017 response criteria for AML		Up to 30 months
Secondary	Time to response: Time from first dose to the first documented evidence of response		Up to 30 months
Secondary	Duration of response: Time from the start of response until disease progression or relapse		Up to 30 months
Secondary	Overall survival: Time since first dose until death due to any cause		Up to 30 months
Secondary	Composite complete response: Number of participants (sum of CR+CRi)		Up to 30 months
Secondary	Complete response with partial hematological recovery (CRh): Number of participants		Up to Month 30
Secondary	Pharmacokinetic parameter: Area under the curve (AUC)		On Days 1, 5 and 6 of Cycle 1 and Day 1 of Cycle 2 (28 days per cycle)
Secondary	Pharmacokinetic parameter: Maximum plasma concentration (Cmax)		On Days 1, 5 and 6 of Cycle 1 and Day 1 of Cycle 2 (28 days per cycle)
Secondary	Pharmacokinetic parameter: Minimum plasma concentration (Cmin)		On Days 1, 5 and 6 of Cycle 1 and Day 1 of Cycle 2 (28 days per cycle)
Secondary	Pharmacokinetic parameter: Time to reach maximum plasma concentration (Tmax)		On Days 1, 5 and 6 of Cycle 1 and Day 1 of Cycle 2 (28 days per cycle)
Secondary	Pharmacokinetic parameter: Half-life (t½)		On Days 1, 5 and 6 of Cycle 1 and Day 1 of Cycle 2 (28 days per cycle)