Phase Ib Study AZD1775 in Combination With Carboplatin and Paclitaxel in Adult Asian Patients With Solid Tumours

Phase 1

Completed

Conditions: Advanced Solid Tumours

Interventions: Drug: Paclitaxel
Drug: AZD1775
Drug: carboplatin

Registration Number: NCT02341456

Lead Sponsor: AstraZeneca

Brief Summary: This is a phase Ib, open-label, multicentre study of AZD1775 administered orally in monotherapy and in combination with carboplatin and paclitaxel to Asian patients with advanced solid tumours.

Detailed Description: This is a phase Ib, open label, multicentre study of AZD1775 administered orally in monotherapy and in combination with carboplatin and paclitaxel in Asian patients with advanced solid tumours. The study design allows escalation or de-escalation of AZD1775 in combination with carboplatin and paclitaxel with intensive safety monitoring to ensure the safety of the patients. Approximately 12 evaluable patients will be enrolled in the dose-finding portion of this study. The total number of patients will depend upon the number of combination dose level evaluations necessary to define the recommended dose for further clinical evaluation. The proposed combination doses are : Dose level-1; Dose level 1; Dose level 2 (if Dose Level 1 tolerated). All combination doses other than Combination Dose level 1 may be subject to change by the SRC in light of emerging data. At least 3 and up to 6 evaluable patients will be required for each dose finding cohort. Once the recommended dose for further clinical evaluation is established, additional 3 to 6 patients may be enrolled to the cohort where the recommended dose has been defined to further characterise the safety, tolerability, pharmacokinetics, and efficacy profiles of AZD1775 in combination with paclitaxel and carboplatin. If this dose is subsequently found to be non-tolerated, alternative doses and/or schedules may be explored. This will be determined by the SRC.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 19

Inclusion Criteria

Histological or cytological confirmation of a locally advanced or metastatic solid tumour, excluding lymphoma, that failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist.
At least 1 measureable lesion that can be accurately assessed at baseline by computerised tomography (CT) or magnetic resonance imaging (MRI) for solid tumours assessed using RECIST v1.1.
World Health Organisation performance status 0 to 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of ≥12 weeks.

Exclusion Criteria

Any cytotoxic chemotherapy, investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days (if investigational agent does not have well characterised PK profile) or 5 × half-lives of the first dose of study treatment
Patient has had prescription or non-prescription drugs or other products (ie, grapefruit juice) known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors or inducers of CYP3A4, which cannot be discontinued 2 weeks before Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug. Co-administration of aprepitant during this study is prohibited.
AZD1775 is an inhibitor of breast cancer resistance protein (BCRP). The use of statins including Atorvastatin which are substrates for BCRP are therefore prohibited and patients should be moved on to non-BCRP alternatives.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Paclitaxel	Paclitaxel	Commercially available paclitaxel will be administered at a dosage of 175 mg/m2 as a 3-hour IV infusion on Cycle Day 1 of a 21-day cycle for 6 cycles.
AZD1775	AZD1775	AZD1775 will be administered orally as a single dose on Day 1 Cycle 0. Following a 5±2 days washout period, AZD1775 (5 doses BID over 2.5 days) will be taken in combination with paclitaxel and carboplatin in each 21-day cycle for 6 cycles. Following 6 cycles of combination treatment, patients may continue on AZD1775 monotherapy (5 doses BID Day 1 to Day 2.5 in each 21-day cycle) at the investigator's discretion.
Carboplatin	carboplatin	Following the paclitaxel infusion, carboplatin will be administered at a dose of AUC 5 as an IV infusion on Cycle Day 1 of a 21-day cycle for 6 cycles. According to the Cancer Therapy Evaluation Program Information Letter Regarding the AUC Based Dosing of Carboplatin, the maximum carboplatin dose should not exceed the target AUC (mg\min/mL)\150 mL/min, but it may be less (Ivy et al 2010). For this study, the maximum dose of carboplatin cannot exceed a total dose of 750 mg.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Treatment-Emergent Adverse Events	Up to 21 days (1 Cycle)	The number of patients with treatment-emergent adverse events was analyzed on the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.
Number of Treatment-Emergent Adverse Events (TEAE)	Up to 21 days (1 Cycle)	The number of treatment-emergent adverse events was counted in the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.
Number of Patients With Treatment-Emergent Adverse Events During AZD1775 Monotherapy Cycle by System Organ Class and Preferred Term	Up to 1 week	The number of patients with TEAEs during AZD1775 Monotherapy Cycle was analyzed in the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.
Number of Patients With Clinically Important Changes in Haematology and Coagulation TEAEs by System Organ Class and Preferred Term	Up to 21 days (1 Cycle)	The number of patients with clinically important changes in haematology and coagulation TEAEs was analyzed in the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.
Number of Patients With Clinically Important Abnormalities in Clinical Chemistry by Preferred Term	Up to 21 days (1 Cycle)	The number of patients with clinically important changes in clinical chemistry TEAEs was analyzed in the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.
Number of Patients With Clinically Important Abnormalities in Vital Signs by Preferred Term	Up to 21 days (1 Cycle)	The number of patients with clinically important changes in vital sign TEAEs was analyzed in the safety analysis set which was comprised of all patients who received at least one dose of the investigational drug.

Secondary Outcome Measures

Name	Time	Method
Best Overall Response	Up to 18 months	The number of subjects with best overall response in CR, PR, NE, SD, PD subcategory. Best overall response is calculated based on the overall visit responses from each RECIST assessment.
Number of Patients With an Objective Response	Up to 18 months	Objective response is defined as either a complete response or a partial response.
Percentage of Patients With an Objective Response	Up to 18 months	Objective response is defined as either a complete response or a partial response.
Number of Patients With Clinical Benefit	Up to 18 months	Clinical benefit is defined as achieving complete response, partial response, or stable disease.
Percentage of Patients With Clinical Benefit	Up to 18 months	Clinical benefit is defined as achieving complete response, partial response, or stable disease.
Duration of Response	Up to 18 months	The duration of response is defined as the time in weeks from the date of first documented overall response occurrence of CR or PR, (whichever was recorded first) to the earliest date that progressive disease/death was documented. If progression or death has not been documented, a patient's DoR was censored at the date of last tumour assessment.
Peak Plasma Concentration (Cmax) of AZD1775 Following Single Dose Administration of AZD1775 Monotherapy	PK Samples collected in all treatment groups on Cycle 0 Day 1, Cycle 1 Day 1, and Cycle 1 Day 3 before the first (morning) dose of AZD1775 (predose) and at 1, 2, 4, 6, and 8 hours postdose
Time to Maximum Plasma Concentration (Tmax) of AZD1775 Following Single Dose Administration of AZD1775 Monotherapy	PK Samples will be collected in all treatment groups on Cycle 0 Day 1, Cycle 1 Day 1, and Cycle 1 Day 3 before the first (morning) dose of AZD1775 (predose) and at 1, 2, 4, 6, and 8 hours postdose
Area Under the Plasma Concentration-time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) Following Single Dose Administration of AZD1775 Monotherapy	PK Samples will be collected in all treatment groups on Cycle 0 Day 1, Cycle 1 Day 1, and Cycle 1 Day 3 before the first (morning) dose of AZD1775 (predose) and at 1, 2, 4, 6, and 8 hours postdose
Plasma Concentration of AZD1775 8 Hours After Single Dose Administration (C8h) of AZD1775 Monotherapy	PK Samples will be collected in all treatment groups on Cycle 0 Day 1, Cycle 1 Day 1, and Cycle 1 Day 3 before the first (morning) dose of AZD1775 (predose) and at 1, 2, 4, 6, and 8 hours postdose
Peak Plasma Concentration (Cmax) of AZD1775 Following Oral Dose of AZD1775 in Combination With IV Infusion of Paclitaxel and Carboplatin (Cohorts 1 and 2) or Carboplatin Alone (Cohort 1a)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Time to Maximum Plasma Concentration (Tmax) of AZD1775 Following Single Dose of AZD1775 in Combination With IV Paclitaxel and Carboplatin (Cohorts 1 and 2) or Carboplatin Alone (Cohort 1a)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Area Under the Plasma Concentration-time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) Following Single Dose of AZD1775 in Combination With IV Paclitaxel and Carboplatin (Cohorts 1 and 2) or Carboplatin Alone (Cohort 1a)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Plasma Concentration of AZD1775 8 Hours After Single Dose Administration (C8h) of AZD1775 in Combination With IV Paclitaxel and Carboplatin (Cohorts 1 and 2) or Carboplatin Alone (Cohort 1a)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Peak Plasma Concentration (Cmax) of AZD1775 at Steady State When Given in Combination With IV Infusion of Paclitaxel and Carboplatin (Cohorts 1 and 2) or Carboplatin Alone (Cohort 1a)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Time to Maximum Plasma Concentration (Tmax) of AZD1775 at Steady State When Given in Combination With IV Paclitaxel and Carboplatin (Cohorts 1 and 2) or Carboplatin Alone (Cohort 1a)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Area Under the Plasma Concentration-time Curve From Zero to the Time of the Last Measurable Concentration (AUC0-t) at Steady State for AZD1775 in Combination With IV Paclitaxel and Carboplatin (Cohorts 1 and 2) or Carboplatin Alone (Cohort 1a)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Plasma Concentration of AZD1775 8 Hours After Administration (C8h) at Steady State in Combination With IV Paclitaxel and Carboplatin (Cohorts 1 and 2) or Carboplatin Alone (Cohort 1a)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Peak Plasma Concentration (Cmax) of Paclitaxel Following Single IV Infusion in Combination With Single Dose Oral AZD1775 and IV Carboplatin	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Area Under the Plasma Concentration-time Curve (AUC0-t) of Paclitaxel Following Single IV Infusion in Combination With Single Dose Oral AZD1775 and IV Carboplatin	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Plasma Concentration of Paclitaxel at the End of Infusion (Ceoi) When Given Combination With Oral AZD1775 and IV Carboplatin.	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Time to Maximum Plasma Concentration (Tmax) of IV Paclitaxel When Given in Combination With Oral AZD1775 and IV Carboplatin	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Time to Last Detectable Concentration (Tlast) of Paclitaxel When Given in Combination With Oral AZD1775 and IV Carboplatin	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Peak Plasma Concentration (Cmax) of Platinum Following Single IV Infusion of Carboplatin Over 1 Hour in Combination With Single Oral Dose AZD1775 Alone (Cohort 1a) or With IV Paclitaxel (Cohorts 1 and 2)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Area Under Plasma Concentration-time Curve From 0 to Last Measurable Conc. (AUC0-t) of Platinum Following Single IV Infusion of Carboplatin Over 1 Hour in Combination With Single Oral Dose AZD1775 Alone (Cohort 1a) or With IV Paclitaxel (Cohorts 1 & 2)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Plasma Concentration of Platinum at the End of Infusion (Ceoi) When Given as a 1 Hour Infusion in Combination With Oral AZD1775 and IV Paclitaxel.	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Time to Peak Plasma Concentration of Platinum (Tmax) When Given as a 1 Hour Infusion in Combination With Oral AZD1775 and IV Paclitaxel.	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Time to Last Detectable Concentration of Platinum (Tlast) When Given as a 1 Hour Infusion in Combination With Oral AZD1775 and IV Paclitaxel.	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Peak Plasma Concentration (Cmax) of Platinum Following Single IV Infusion of Carboplatin Over 2 Hours in Combination With Single Oral Dose AZD1775 Alone (Cohort 1a) or With IV Paclitaxel (Cohorts 1 and 2)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Area Under Plasma Concentration-time Curve From 0 to Last Measurable Conc. (AUC0-t) of Platinum Following Single IV Infusion of Carboplatin Over 2 Hours in Combination With Single Oral Dose AZD1775 Alone (Cohort 1a) or With IV Paclitaxel (Cohorts 1 & 2)	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Plasma Concentration of Platinum at the End of Infusion (Ceoi) When Given as a 2 Hour Infusion in Combination With Oral AZD1775 and IV Paclitaxel.	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Time to Peak Plasma Concentration of Platinum (Tmax) When Given as a 2 Hour Infusion in Combination With Oral AZD1775 and IV Paclitaxel.	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion
Time to Last Detectable Concentration of Platinum (Tlast) When Given as a 2 Hour Infusion in Combination With Oral AZD1775 and IV Paclitaxel.	AZ1775:C0D1, C1D1, & C1D3 before AZD1775 dose and at 1,2,4,6&8 hrs postdose. Paclitaxel:C1D1 before paclitaxel infusion & at 1.5,3,4,6&8 hrs after start of infusion Carboplatin:C1D1 before carboplatin infusion &at 1,2,4,6&8 hrs after start of infusion