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This is a single-arm study in which all patients will receive AZD1775 orally. Patients will continue to receive treatment with AZD1775 until disease progression, intolerable toxicity, or discontinuation criteria are met.

All patients will receive intervention with AZD1775 orally. Patients will continue to receive treatment with AZD1775 until disease progression, intolerable toxicity, or discontinuation criteria are met.

AZD1775

Gerald Falchook, MD

This Phase Ib study will identify the Maximum Tolerated Dose (MTD) of AZD1775 monotherapy when administered orally once daily (QD) or two times per day (BID) on Days 1 to 5 followed by 9 days of rest in 14-day cycles, or QD on a 5/2 dosing schedule (5 days on, followed by 2 days rest) in 21-day cycles in patients with locally advanced or metastatic solid tumours. Alternative treatment schedules may be explored if preliminary data suggest these would be more appropriate.

The effect of food on single dose PK of AZD1775 will be assessed in 12 patients. In this sub-study, patients will receive a single oral dose of AZD1775 with 240 mL of water, once in the fasted state and once following a high-fat meal.

This study will attempt to determine the Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of AZD1775 monotherapy when administered orally once daily (QD) or two times per day (BID) on Days 1 to 5 followed by 9 days of rest in 14-day cycles, or QD on a 5/2 dosing schedule (5 days on, followed by 2 days rest) in 21-day cycles in patients with locally advanced or metastatic solid tumours. Both the QD 5/9 and 5/2 dosing schedules will run in parallel. An evaluation will be made after the second QD cohort has been completed to determine whether to proceed with one or both dosing schedules.

The AZD1775 MTD will be determined through dose-escalation using a 3+3 cohort design. If less than one-third of evaluable patients in a given cohort (0 of 3 patients or 1 of 6 patients) experiences a Dose-Limiting Toxicity (DLT); escalation may proceed to the next higher dose level. If one of the first 3 patients enrolled in a given cohort experiences a DLT, 3 additional patents will be enrolled in that cohort. If a DLT is observed in one-third or more of patients, the dose at which this occurs will be considered not tolerated and the MTD will have been exceeded. The highest dose level(s) at which less than one-third of patients (0 of 3 patients or 1 of 6 patients) experiences a DLT will be declared the MTD. Up to 6 patients will be enrolled in each cohort. Dose escalation will continue until identification of the MTD or Sponsor termination of the study.

A maximum of 10 dose escalations are anticipated in the determination of MTD. Approximately 6 subjects may be added to replace non-evaluable patients. Therefore, a total of 66 patients are expected to be treated.

Dose-limiting toxicities will be evaluated during Cycles 1 and 2 of treatment. If appropriate the DLT observation period can be expanded by up to 2 weeks in case of treatment delay due to study drug-related adverse events. Toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Patients must complete Cycle 1 and Cycle 2 safety evaluations which will conclude on Cycle 3 Day 1, and must receive at least 80% of the planned dose to be considered evaluable. Patients receiving less than 80% of Cycle 1 and Cycle 2 dose (28 days) will be replaced unless they experienced a confirmed DLT.

The patient population used to determine the MTD will consist of patients who have met the minimum safety evaluation requirements of the study, and/or who have experienced a DLT in Cycle 1 or Cycle 2. Minimum safety requirements will be met if during Cycle 1 and Cycle 2 of treatment the patient receives a minimum of 80% of treatment doses of AZD1775, completes the safety evaluations, and is observed for at least 28 days. Patients who do not meet these minimum safety evaluation and treatment requirements and whom do not experience a DLT will be replaced.

Patients will be allowed to continue treatment with AZD1775 until evidence of disease progression, unacceptable toxicity, or other discontinuation criterion has occurred.

Phase Ib Study to Determine MTD of AZD1775 Monotherapy in Patients With Locally Advanced or Metastatic Solid Tumours.

A Phase Ib Study to Determine the Maximum Tolerated Dose (MTD) of AZD1775 Monotherapy in Patients With Locally Advanced or Metastatic Solid Tumours.

The MTD will be determined through dose-escalation using a 3+3 cohort design. If less than one-third of evaluable patients in a given cohort (0 of 3 patients or 1 of 6 patients) experiences a DLT; escalation may proceed to the next higher dose level. If one of the first 3 patients enrolled in a given cohort experiences a dose-limiting toxicity (DLT), at least 3 additional patents will be enrolled in that cohort. If a DLT is observed in one-third or more of patients, the dose at which this occurs will be considered not tolerated and the MTD will have been exceeded. The highest dose level(s) at which less than one-third of patients (0 of 3 patients or 1 of 6 patients) experiences a DLT will be declared the MTD.

Blood samples for determination of AZD1775 concentration will be collected during dose escalation and dose expansion.

Treatment-emergent adverse events will be assessed by physical examinations, ECOG performance status, complete blood count (CBC) with differential and platelets, clinical chemistry and haematology, triplicate 12-lead ECG, changes in vital signs, and patient reported symptoms.

RECIST v1.1 criteria will be used to assess response to treatment. Tumour imaging studies will be repeated every 4 cycles (8 weeks) to assess response until objective disease progression as defined by RECIST v1.1 or withdrawal from study.

Categorisation of objective tumour response assessment will be based on the RECIST v1.1 criteria of response: Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD). Target lesion progression will be calculated in comparison to when the tumour burden was at a minimum. In the absence of progression, tumour response will be calculated in comparison to the baseline tumour measurements obtained before starting treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase Ib Study to Determine MTD of AZD1775 Monotherapy in Patients With Locally Advanced or Metastatic Solid Tumours.	NCT02610075	Locally Advance... Metastatic Soli... Ovarian Cancer	AZD1775	18 Years - 130 Years	AstraZeneca
Phase Ib Study to Determine MTD of AZD1775 Monotherapy in Patients With Locally Advanced or Metastatic Solid Tumours.	NCT02610075	Locally Advance... Metastatic Soli... Ovarian Cancer	AZD1775	18 Years - 130 Years	AstraZeneca
Phase Ib Study to Determine MTD of AZD1775 Monotherapy in Patients With Locally Advanced or Metastatic Solid Tumours.	NCT02610075	Locally Advance... Metastatic Soli... Ovarian Cancer	AZD1775	18 Years - 130 Years	AstraZeneca

Spots Global Cancer Trial Database for locally advanced solid tumours