Status and phase
Conditions
Treatments
Study type
Funder types
Identifiers
About
This randomized phase II trial studies how well WEE1 inhibitor AZD1775 with or without cytarabine works in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has spread to other places in the body and usually cannot be cured or controlled with treatment. WEE1 inhibitor AZD1775 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving WEE1 inhibitor AZD1775 works better with or without cytarabine in treating patients with advanced acute myeloid leukemia or myelodysplastic syndrome.
Full description
PRIMARY OBJECTIVES:
I. To estimate the clinical efficacy of AZD1775 (WEE1 inhibitor AZD1775) in combination with AraC (cytarabine) in patients with newly diagnosed acute myeloid leukemia (AML) by assessing complete response (complete remission [CR] plus CR with incomplete blood count recovery [CRi]) rates.
II. To estimate the clinical efficacy of AZD1775 alone or in combination with AraC in patients with relapsed/refractory AML and hypomethylating agent failure myelodysplastic syndrome (MDS) by assessing complete response (CR plus CRi) rates.
SECONDARY OBJECTIVES:
I. To determine the safety and tolerability of AZD1775 alone or combined with AraC in the study population.
II. To estimate additional measures of clinical benefit (i.e. hematological improvements, transfusion requirements).
III. To measure the duration of response of AZD1775 alone or combined with AraC.
IV. To measure time to response of AZD1775 alone or combined with AraC. V. To measure time to progression of AZD1775 alone or combined with AraC. VI. To measure overall survival of AZD1775 alone or combined with AraC. VII. To measure time to AML (for MDS subjects) of AZD1775 alone or combined with AraC.
TERTIARY OBJECTIVES:
I. To determine the pharmacokinetics (PK) of AZD1775 alone or combined with AraC in the study population.
II. To conduct correlative research studies characterizing underlying molecular events and solidifying putative mechanism of action in vivo and to identify potential pharmacodynamic/biomarkers of response to AZD1775 alone or combined with AraC.
III. To evaluate quality of life (QOL) and patient-reported symptoms in subjects treated with AZD1775 alone or combined with AraC.
OUTLINE: Elderly newly diagnosed patients are assigned to arm A.
ARM A (ELDERLY NEWLY DIAGNOSED PATIENTS): Patients receive cytarabine subcutaneously (SC) twice daily (BID) on days 1-5 and 8-12 and WEE inhibitor AZD1775 orally (PO) daily on days 1-5 and 8-12.
Patients are randomized to 1 of 2 treatment arms.
ARM B: Patients receive cytarabine and WEE1 inhibitor AZD1775 as in Arm A.
ARM C: Patients receive WEE inhibitor AZD1775 PO daily on days 1-5, 8-12, 15-19, and 22-26.
In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3-6 months for 2 years.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Patient population (histological or cytologically confirmed diagnosis):
Untreated elderly (> 60 years) AML if in the intermediate and poor-risk cytogenetic group and not candidates (as judged by treating doctor of medicine [MD]) for or willing to undergo standard induction therapy (i.e. elderly unfavorable cytogenetic AML) or any untreated AML age > 65 years
Relapsed or refractory AML (>= 18 years)
Any MDS (>= 18 years) having failed or been intolerant to prior hypomethylating agent (HMA) treatment
Failure is defined as any disease progression while on HMA, relapse after HMA treatment or no response after 4 cycles of 5-Azacitidine or decitabine
Patients with isolated 5q-/5q- syndrome must have failed, not tolerated, or lenalidomide in addition to having failed or been intolerant to HMA treatment
Total bilirubin =< 1.5 mg/dL (except Gilbert's syndrome or known hemolysis or leukemic infiltration)
Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x upper limit normal (ULN) or < 5 x ULN if organ involvement
Alkaline phosphatase < 5 x ULN
Serum creatinine =< 2 x ULN or 24 hour creatinine (Cr) clearance > 30 ml/min
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
Ability to provide informed written consent and be able to adhere to the study visit schedule and other protocol requirements
Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
Willing to provide blood and bone marrow aspirate samples for correlative research purposes
Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
Men and women must be willing to use appropriate contraception throughout study and for 6 months after
Male patients who are sexually active with a female partner of childbearing potential must be either surgically sterilized or agree to use barrier contraception (ie, condoms) for the duration of study participation, and for 90 days after the final dose of study drug; cessation of birth control after this point should be discussed with a responsible physician
Patients who have undergone stem cell transplantation (SCT), autologous or allogeneic, are eligible provided that they are > 60 days from stem cell infusion, have graft-versus-host disease (GVHD) =< grade 1 and are off immunosuppressive agents for > 28 days at time of registration
Exclusion criteria
Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, known positive for active infectious hepatitis, type A, B or C (past infection allowed), or psychiatric illness/social situations that would limit compliance with study requirements; Note: ongoing infection controlled on antibiotics/antifungal/antiviral medications are allowed
Any of the following prior therapies:
Cytotoxic chemotherapy =<14 days prior to registration
Immunotherapy =< 14 days prior to registration
Biologic therapy (i.e. antibody therapies) =< 14 days prior to registration
Radiation therapy =<14 days prior to registration
Targeted therapies (i.e. kinase inhibitors, =< 7 days or 5 half-life's whichever is shorter)
• For steroids or other non-cytotoxics given for blast count control, patient must be off for > 24 hours (hrs) before starting therapy; NOTE: hydroxyurea (HU) is allowed for blast count control throughout study
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm =< 14 days prior to registration
Active uncontrolled central nervous system (CNS) leukemia; NOTE: positive (cyto)pathology is allowed and patient can receive intrathecal chemotherapy
Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; NOTE: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
Any previous treatment with AZD1775 or allergic reactions to excipients of AZD1775
Acute promyelocytic leukemia (APL, M3) unless failed regimens that included tretinoin, arsenic trioxide, anthracyclines and cytarabine and currently NOT candidates for stem cell transplantation
Major surgery =< 28 days prior to registration
Clinically significant heart disease, including the following:
Active severe angina pectoris within 3 months prior to registration
Acute myocardial infarction within 3 months prior to registration
New York Heart Association classification IV cardiovascular disease or symptomatic class III disease
Any of the following:
Subject has had prescription or non-prescription drugs or other products known to be sensitive cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued two weeks prior (alternatively 5 half lives if T1/2 is known) prior to day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug
Patients may not be on an inhibitor of breast cancer resistance protein (BCRP)
Not willing to avoid grapefruit, grapefruit juices, grapefruit hybrids, Seville oranges, pummelos, and exotic citrus fruits from 7 days prior to the dose of study medication and during the entire study; NOTE: orange juice is allowed
Corrected QT interval (QTc) > 470 msec (as calculated per institutional standards) at study entry or congenital long QT syndrome
Primary purpose
Allocation
Interventional model
Masking
3 participants in 2 patient groups
Loading...
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal