NCT02381548

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

A Phase 1 Study of AZD1775 in Combination With Belinostat in Relapsed and Refractory Myeloid Malignancies and Selected Untreated Patients With Acute Myeloid Leukemia

• Status: Terminated
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 20 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Detailed description

PRIMARY OBJECTIVES: I. To identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for a regimen combining WEE1 inhibitor AZD1775 (AZD1775) with belinostat in patients with refractory/relapsed acute myeloid leukemia (AML), chronic myeloid leukemia in blast crisis (CML-BC), or intermediate-2 or high-risk myelodysplastic syndrome (MDS), and selected previously untreated poor-prognosis patients with AML. SECONDARY OBJECTIVES: I. To describe the toxicities of this regimen. II. To observe and record anti-tumor activity. III. If responses are observed, to determine what relationship, if any, exists between such responses and tumor protein 53 (p53)/fms-related tyrosine kinase 3 (FLT3) mutational status. IV. To describe pharmacokinetic (PK) interactions, if any, between AZD1775 and belinostat. V. To test the feasibility of performing correlative studies involving leukemic blasts obtained pre-treatment and 24-hours post-treatment to determine if events associated with in vitro synergism (eg, down-regulation of phosphorylated \[p\]-Wee1 and p-checkpoint kinase 1 \[Chk1\]; dephosphorylation of cyclin-dependent kinase-like 1 \[cdc2\] at both tyrosine \[Tyr\]15 and threonine \[Thr\]14; increased expression of gamma H2A histone family, member X \[H2A.X\] and of p-histone H3 \[HH3\]) can be recapitulated following exposure to AZD1775 and belinostat in patients. OUTLINE: This is a dose-escalation study. Patients receive belinostat intravenously (IV) over 30-90 minutes once daily (QD) on days 1-5 and 8-12 and WEE1 inhibitor AZD1775 orally (PO) QD on days 1-5 and 8-12. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients achieving complete remission (CR), complete remission with incomplete blood count recovery (CRi), cytogenetic complete remission (CRc), or molecular complete remission (CRm) who do not go on to have stem cell transplant may only continue treatment for 3-4 additional courses after response. After completion of study treatment, all patients are followed up for 30 days and responding patients are followed up every 2 months for 1 year.

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

Interventions

Type	Name	Description
DRUG	Adavosertib	Given PO
DRUG	Belinostat	Given IV
OTHER	Laboratory Biomarker Analysis	Correlative studies
OTHER	Pharmacological Study	Correlative studies

Timeline

• Start date: 2015-08-18
• Primary completion: 2018-05-23
• Completion: 2018-05-23
• First posted: 2015-03-06
• Last updated: 2026-01-30

Locations

2 sites across 1 country: United States