Phase I Trial of AZD1775 and Belinostat in Treating Patients With Relapsed or Refractory Myeloid Malignancies or Untreated Acute Myeloid Leukemia

NCT02381548 | Terminated Phase 1

• 7 other identifiers: NCI-2015-00257MCC-12-07328NCI-98539853N01CM00100UM1CA186644UM1CA186716
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

This phase I trial studies the side effects and best dose of WEE1 inhibitor AZD1775 and belinostat when given together in treating patients with myeloid malignancies that have returned after a period of improvement or have not responded to previous treatment or patients with untreated acute myeloid leukemia. WEE1 inhibitor AZD1775 and belinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Conditions

Acute Myeloid Leukemia; Acute Myeloid Leukemia Post Cytotoxic Therapy; Blast Phase Chronic Myeloid Leukemia, BCR-ABL1 Positive; Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Recurrent Chronic Myeloid Leukemia, BCR-ABL1 Positive; Refractory Acute Myeloid Leukemia; Refractory Chronic Myeloid Leukemia, BCR-ABL1 Positive; Secondary Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• Recommended phase 2 dose (RP2D) for the combination of WEE1 inhibitor AZD1775 and belinostat, defined as the dose in which =< 1 out of 6 patients at highest dose level below the maximally administered dose experience dose-limiting toxicities (DLTs)

  Patients' treatment dosing level, dose modification, DLTs, and evaluability for DLTs will be listed and summarized by basic descriptive statistics (such as frequency and proportion). DLTs will be assessed according to the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

  21 days

Secondary Outcomes (8)

• Incidence of toxicity graded according to the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

  Up to 30 days after completion of study treatment

• Response rate (complete remission [CR] + CR with incomplete blood count recovery [CRi] + cytogenetic CR [CRc] + molecular CR [CRm]) according to International Working Group and European Leukemia Net criteria

  Up to 2 years

• Duration of response (in patients with (complete remission [CR] + CR with incomplete blood count recovery [CRi] + cytogenetic CR [CRc] + molecular CR [CRm])

  From documentation of tumor response to disease progression or death, whichever occurs first, assessed up to 2 years

• Time to response

  From registration to the time of documentation of tumor response, assessed up to 2 years

• p53 and FLT3 mutation status

  Up to 24 hours after first dose of study treatment

Study Arms (1)

Treatment (belinostat, WEE1 inhibitor AZD1775)

EXPERIMENTAL

Patients receive belinostat IV over 30-90 minutes QD on days 1-5 and 8-12 and WEE1 inhibitor AZD1775 PO QD on days 1-5 and 8-12. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Responding patients with CR, CRi, CRc, or CRm and do not go on to have stem cell transplant may only continue treatment for 3-4 additional courses after response.

Drug: Adavosertib; Drug: Belinostat; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study

Interventions

Adavosertib DRUG

Given PO

Also known as: AZD 1775, AZD-1775, AZD1775, MK 1775, MK-1775, MK1775

Treatment (belinostat, WEE1 inhibitor AZD1775)

Belinostat DRUG

Given IV

Also known as: Beleodaq, PXD 101, PXD-101, PXD101

Treatment (belinostat, WEE1 inhibitor AZD1775)

Pharmacological Study OTHER

Correlative studies

Treatment (belinostat, WEE1 inhibitor AZD1775)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (belinostat, WEE1 inhibitor AZD1775)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have one of the following, histologically or cytologically confirmed:
• Acute myeloid leukemia (AML) \[non- acute promyelocytic leukemia (APL) AML\]
• If previously treated:
• AML that is relapsed or refractory to at least one prior line of therapy
• If previously untreated, must meet all of the following:
• \>= 60 years of age
• Secondary or therapy-related AML
• Does NOT bear favorable cytogenetic and/or molecular features, eg, core-binding factor abnormalities, FLT3 Internal Tandem Duplication (FLT3-ITD) negative/NPM1 mutated, biallelic CCAAT/enhancer binding protein alpha (CEBPA) mutation without FLT3-ITD
• Chronic myeloid leukemia blast crisis (CML-BC)
• Relapsed or refractory to at least one Bcr-Abl-TKI-containing regimen
• Myelodysplastic syndrome (MDS), must meet all of the following:
• Higher risk MDS \[intermediate-2 or high risk by the original International Prognostic Scoring System (IPSS)\]
• Relapsed, refractory, or intolerant to at least one prior line of therapy containing hypomethylating agents (deoxyribonucleic acid \[DNA\] methyltransferase inhibitors)
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 50%)
• Total bilirubin =\< 1.5 × upper limit of normal (ULN) for the laboratory unless resulting from hemolysis

You may not qualify if:

• Clinical picture indicative of leukostasis or evidence of disseminated intravascular coagulopathy
• Other investigational agent within 3 weeks prior to initiation of study therapy
• Ongoing toxicities \>= grade 2 from prior therapy
• Acute promyelocytic leukemia (APL, M3)
• Active central nervous system (CNS) leukemia
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775 or belinostat
• Stem cell transplant within previous 3 months prior to initiation of study therapy
• Major surgical procedures =\< 28 days before beginning study treatment or minor surgical procedures =\< 7 day before beginning study treatment; no waiting required after placement of a vascular access device
• Uncontrolled infection
• Pregnant or nursing; women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study therapy
• Note: Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with AZD1775/belinostat
• Circulating blast count \>= 50,000/uL within the week preceding enrollment
• Current candidacy for a potentially curative allogeneic stem cell transplant, unless declined
• Corrected QT (QTc) interval \>= 450 ms (ie, grade 1 or higher) on electrocardiogram (ECG) prior to initiation of study treatment
• If baseline QTc on screening ECG is \>= 450 ms (ie, grade 1 or higher):

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

VCU Massey Comprehensive Cancer Center

Richmond, Virginia, 23298, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Blast Crisis; Myelodysplastic Syndromes; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Interventions

adavosertib; belinostat

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Cell Transformation, Neoplastic; Carcinogenesis; Neoplastic Processes; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Danielle A Shafer

  University Health Network Princess Margaret Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 5, 2015
• First Posted: March 6, 2015
• Study Start: August 18, 2015
• Primary Completion: May 23, 2018
• Study Completion: May 23, 2018
• Last Updated: January 30, 2026

Record last verified: 2026-01

Locations

US (2)