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Fludarabine phosphate

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Enzyme Inhibitors

Patients receive filgrastim IV or SC daily, fludarabine intravenously IV over 30 minutes, cytarabine IV over 1-3 hours and wee1 kinase inhibitor AZD1775 PO on days 1-5. Patients who meet criteria for CR, CRp or PR may receive a second course of therapy. Courses repeat every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Filgrastim

Fludarabine Phosphate

Laboratory Biomarker Analysis

Pharmacological Study

WEE1 Inhibitor AZD1775

Maureen O'Brien

This phase I trial studies the side effects and best dose of wee1 kinase inhibitor AZD1775 when given together with fludarabine, cytarabine, and filgrastim (FLAG) combination chemotherapy in treating children, adolescents and young adults with relapsed or refractory acute myeloid leukemia. Wee1 kinase inhibitor AZD1775 may help combination chemotherapy work better by making tumor cells more sensitive to the drugs. Drugs used in chemotherapy, such as fludarabine and cytarabine, may prevent tumor cells from multiplying by damaging their deoxyribonucleic acid (DNA), which in turn stops the tumor from growing. Giving wee1 kinase inhibitor AZD1775 and FLAG chemotherapy may work better in treating patients with acute myeloid leukemia.

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of wee1 kinase inhibitor AZD1775 (AZD1775) administered orally daily for 5 days in combination with FLAG (fludarabine, cytarabine, filgrastim) chemotherapy in children and adolescents with recurrent or refractory acute myeloid leukemia (AML).

II. To define and describe the toxicities of AZD1775 in combination with FLAG chemotherapy administered on this schedule.

III. To characterize the pharmacokinetics AZD1775 in combination with FLAG chemotherapy in pediatric patients with relapsed or refractory AML.

SECONDARY OBJECTIVES:

I. To preliminarily define the antitumor activity of AZD1775 plus FLAG within the confines of a phase 1 study.

II. To evaluate pharmacodynamic biomarkers of wee1 inhibition with administration of AZD1775 including cyclin-dependent kinase 1 (CDC2) phosphorylation at tyrosine 15 (Tyr15) and induction of gamma H2AX in pre- and post-treatment leukemic blasts.

III. To explore mechanisms of apoptosis induction and cell death in leukemic blasts treated with AZD1775 plus chemotherapy.

IV. To identify genomic alterations in leukemic blasts that may correlate with response to therapy with AZD1775 plus FLAG chemotherapy.

OULTINE: This is a phase I dose escalation study of wee1 kinase inhibitor AZD1775.

Patients receive filgrastim intravenously (IV) or subcutaneously (SC) daily, fludarabine intravenously IV over 30 minutes, cytarabine IV over 1-3 hours and wee1 kinase inhibitor AZD1775 orally (PO) on days 1-5. Patients who meet criteria for complete remission (CR), complete remission with partial recovery of platelet count (CRp) or partial response (PR) may receive a second course of therapy. Courses repeat every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Wee1 Kinase Inhibitor AZD1775 and Combination Chemotherapy in Treating Children, Adolescents and Young Adults With Relapsed or Refractory Acute Myeloid Leukemia

A Phase 1 Trial of the Wee1 Kinase Inhibitor AZD1775 in Combination With Flag Chemotherapy in Children, Adolescents, and Young Adults With Relapsed or Refractory Acute Myeloid Leukemia

Plasma will be collected and wee1 kinase inhibitor AZD1775 concentrations will be analyzed.

Attainment of an M1 bone marrow (\< 5% blasts) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral blood counts (ANC \>= 1000/µL and platelet count \>= 100,000/µL). Flow cytometry may also be useful to distinguish between leukemia and a regenerating bone marrow.

Attainment of an M1 bone marrow (\< 5% blasts) and no evidence of circulating blasts or extramedullary disease and with ANC \< 1000/µL or platelet count \< 100,000/µL without platelet transfusion independence (defined as: no platelet transfusions x 1 week).

Attainment of an M1 bone marrow (\< 5% blasts) and no evidence of circulating blasts or extramedullary disease and with recovery of ANC \>= 1000/µL and platelet transfusion independence (defined as: no platelet transfusions x 1 week)

Defined as the sum of the number of patients with complete remission (CR) plus those with complete remission in the absence of total platelet recovery (CRp) divided by the total number of evaluable enrolled patients.

M2 bone marrow (5% to 25% blasts) and at least a 50% decrease in bone marrow blast percent from baseline, or for patients with known chloroma, at least a 50% decrease of extramedullary disease (EMD) with no new lesions. Bone marrow must have adequate cellularity (e.g., \>= 10%, if a biopsy is performed) to determine response.

National Cancer Institute (NCI)

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Every month we try and update this database with for cns1 cancer trials from around the world to help patients and their families find trials that might be right for them.
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Spots Global Cancer Trial Database for cns1

Every month we try and update this database with for cns1 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for cns1 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.