Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Recurrence

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Disease Attributes

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Cytarabine

Fludarabine

Fludarabine phosphate

Lenograstim

Adavosertib

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antiviral Agents

Adjuvants, Immunologic

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)

Carcinoma

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms, Squamous Cell

Head and Neck Neoplasms

Docetaxel

Cisplatin

Tubulin Modulators

Antimitotic Agents

Patients receive WEE1 inhibitor MK-1775 PO BID on days 2-4, 9-11, and 16-18, and day -7 prior to course 1, day 1 for PD assessment. Patients also receive cisplatin IV on days 1 (or up to two days after last dose of WEE1 inhibitor MK-1775 lead-in is completed), 8 (or 7 days after first chemotherapy dose), and 15, and docetaxel IV on days 1, 8, and 15. Patients experiencing progressive disease undergo surgical resection. Patients not deemed surgically resectable proceed to chemoradiation as clinically indicated. Patients experiencing stable disease or partial response may receive 2 additional courses of treatment every 28 days in the absence of disease progression or unacceptable toxicity.

Therapeutic Conventional Surgery

Eduardo Mendez

This phase I trial studies the side effects and the best dose of WEE1 inhibitor MK-1775 when given together with docetaxel and cisplatin in treating patients with stage III-IVB squamous cell carcinoma of the head and neck that may or may not be able to be removed by surgery (borderline resectable). WEE1 inhibitor MK-1775 may block the growth of tumor cells by blocking some of enzymes that are needed for tumor growth and may also help docetaxel and cisplatin work better by making tumor cells more sensitive to the drug. Drugs used in chemotherapy, such as docetaxel and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving WEE1 inhibitor MK-1775 with docetaxel and cisplatin before surgery may kill more tumor cells and shrink the tumor, allowing patients to undergo surgery to remove it.

PRIMARY OBJECTIVES:

I. To evaluate the safety profile and determine a maximum tolerated dose (MTD) dose of AZD1775 (WEE1 inhibitor MK-1775) in combination with weekly cisplatin and docetaxel as a neoadjuvant approach in locally advanced borderline resectable and/or surgically unresectable with high nodal burden (e.g., \>= N2b disease) and judged appropriate for non-surgical definitive therapy.

II. To determine the pharmacokinetics (PK) of the combination of single doses of AZD1775 with fixed weekly dosing of docetaxel and cisplatin given on a three out of four week cycle.

III. To evaluate pharmacodynamic (PD) biomarkers of AZD1775 drug effect in head and neck squamous cell carcinoma (HNSCC) cancers, and in particular p53 mutated HNSCC patients.

SECONDARY OBJECTIVES;

I. To evaluate the preliminary activity and efficacy of the combination in terms of objective response rate in patients with borderline resectable and unresectable HNSCC and in particular, in p53 mutated HNSCC patients.

II. The rate of resectability for borderline unresectable patients will be noted post neoadjuvant therapy.

III. The rate of unresectable patients who underwent definitive therapy via chemoradiation.

IV. Progression-free survival will be noted as part of the preliminary efficacy determination of this study.

VI. During all parts of the study, patients will be monitored carefully for the development of adverse experiences and will be monitored for clinical and/or radiographic evidence of disease progression according to usual standards of clinical practice.

TERTIARY OBJECTIVES:

I. To gain mechanistic understanding of the link between p53 mutation status and disruption of immunoglobulin heavy constant gamma 2 (G2M) regulation deregulation.

II. To confirm kinase inhibition in tumor primary cultures as well as in patient tumor-derived xenografted (PDX) mice extracts, downstream signaling consequences (WEE1 G2 checkpoint kinase \[WEE1\]; WEE1's target, cyclin-dependent kinase 1 \[CDC2\]), and mechanisms of p53 synthetic lethality which sensitize cancer cells to genotoxic therapy.

OUTLINE: This is a dose-escalation study of WEE1 inhibitor MK-1775.

Patients receive WEE1 inhibitor MK-1775 orally (PO) twice daily (BID) on days 2-4, 9-11, and 16-18, and day -7 prior to course 1, day 1 for PD assessment. Patients also receive cisplatin intravenously (IV) on days 1 (or up to two days after last dose of WEE1 inhibitor MK-1775 lead-in is completed), 8 (or 7 days after first chemotherapy dose), and 15, and docetaxel IV on days 1, 8, and 15. Patients experiencing progressive disease undergo surgical resection. Patients not deemed surgically resectable proceed to chemoradiation as clinically indicated. Patients experiencing stable disease or partial response may receive 2 additional courses of treatment every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 4 years.

WEE1 Inhibitor MK-1775, Docetaxel, and Cisplatin Before Surgery in Treating Patients With Borderline Resectable Stage III-IVB Squamous Cell Carcinoma of the Head and Neck

A Phase I Clinical Trial of AZD1775 in Combination With Neoadjuvant Weekly Docetaxel and Cisplatin Prior to Surgery in Squamous Cell Carcinoma of the Head and Neck (HNSCC)

Summary tables and graphic displays, as appropriate, will be prepared to examine the distribution of these toxicities per cycle.

DLT is defined as any adverse event judged by the investigator to be drug-related (i.e., causality rated as possible or greater) that is assessed as grade 3 or worse. Summary tables and graphic displays, as appropriate, will be prepared to examine the distribution of these toxicities per cycle.

Pharmacodynamic parameters will be studied during lead-in monotherapy to determine target engagement, mainly phosphorylated WEE1 and CDC2. Prior to treatment normal tissue in the opposite side of the tumor in the oral mucosa will be used for controls. Biological specificity will be verified by assessing the phosphorylated state of WEE1 and downstream effector molecules: total CDC2, ptyr15 CDC2, for G2/M. Other relevant biomarkers and molecular or genetic analyses may be performed.

Maximum concentration and mean terminal half-life will be focused on during PK analysis.

PFS will be determined in days or weeks and waterfall plots and graphical data will be provided where suitable.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Wee1 Kinase Inhibitor AZD1775 and Combination Chemotherapy in Treating Children, Adolescents and Young Adults With Relapsed or Refractory Acute Myeloid Leukemia	NCT02791919	CNS 2a CNS 2b CNS 2c CNS1 Recurrent Adult... Recurrent Child...	Cytarabine Filgrastim Fludarabine Pho... Laboratory Biom... Pharmacological... WEE1 Inhibitor ...	1 Year - 21 Years	National Cancer Institute (NCI)
WEE1 Inhibitor MK-1775, Docetaxel, and Cisplatin Before Surgery in Treating Patients With Borderline Resectable Stage III-IVB Squamous Cell Carcinoma of the Head and Neck	NCT02508246	Head and Neck S...	Cisplatin Docetaxel Laboratory Biom... Pharmacological... Therapeutic Con... WEE1 Inhibitor ...	18 Years -	University of Washington
WEE1 Inhibitor MK-1775, Docetaxel, and Cisplatin Before Surgery in Treating Patients With Borderline Resectable Stage III-IVB Squamous Cell Carcinoma of the Head and Neck	NCT02508246	Head and Neck S...	Cisplatin Docetaxel Laboratory Biom... Pharmacological... Therapeutic Con... WEE1 Inhibitor ...	18 Years -	University of Washington

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