AZD1775 Combined With Olaparib in Patients With Refractory Solid Tumors
- Conditions
- Refractory Solid TumoursRelapsed Small Cell Lung Cancer (SCLC)
- Interventions
- Registration Number
- NCT02511795
- Lead Sponsor
- AstraZeneca
- Brief Summary
The purpose of this Phase 1b, multi-centre, dose escalation study is to find the maximum tolerated dose (MTD) of AZD1775 combined with olaparib in patients with refractory solid tumours
- Detailed Description
This is a Phase Ib, multi-centre study of AZD1775 combined with olaparib administered orally in patients with refractory solid tumours, or as combination therapy for relapsed small-cell lung cancer (SCLC). There are 2 parts to the study:
Part A: Dose Escalation Part B: Dose Expansion
In Part A, patients with refractory solid tumours will be assessed for safety, tolerability, and pharmacokinetics (PK) of AZD 1775 when combined with olaparib. Different dose levels will be administered to identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D).
The dose expansion part (Part B) will further explore the safety, PK, and preliminary efficacy of the AZD1775 RP2D and dosing schedule for the treatment of patients with SCLC who previously had a confirmed response (either a Complete Response or Partial Response) to first-line platinum therapy and then relapsed. Patients who progressed whilst on platinum-containing therapy (platinum refractory) are not permitted to enter the study..
An olaparib pharmacokinetic (PK) sub-study will precede the combined treatment with AZD1775 and olaparib for all patients in Part A. In the sub-study single agent olaparib will be given orally BID for 3 or 5 consecutive days and venous blood samples will be collected on Day 3 or Day 5 as appropriate for assessment of the multiple dose pharmacokinetics of single agent olaparib. Patients will experience a short gap in treatment (approximately 4-5 days) between Day 3 or Day 5 of the olaparib PK sub-study and Cycle 1 Day 1 of the combination treatment.
Patients will continue to receive treatment with AZD1775 and Olaparib until disease progression, intolerable toxicity, or discontinuation criteria have been met.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 128
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description AZD1775 (10 doses/week) + Olaparib AZD1775 In this Arm, AZD1775 will be given twice daily over 5 days (10 doses) on Days 1-5 of Week 1 and Days 8-12 of Week 2. Olaparib will be given orally BID on Days 1-14. All patients will enter an olaparib sub-study in order to assess multiple dose pharmacokinetics of olaparib prior to entering the main study. In the olaparib PK sub-study patients will take olaparib for 3 consecutive days and venous blood samples will be collected on Day 3. The PK sub-study must be initiated 10 days prior to the Cycle 1 Day 1 administration of the AZD1775 and olaparib combination. The patient will experience a short gap in treatment (approximately 4-5 days) between Day 3 of the olaparib PK sub-study and Cycle 1 Day 1 AZD1775 and olaparib combined dosing. AZD1775 (6 doses/week) + Olaparib AZD1775 In this Arm, AZD1775 will be given twice daily over 3 days (6 doses) on Days 1-3 of Week 1 and Days 8-10 of Week 2. Olaparib will be given orally BID on Days 1-14. All patients will enter an olaparib sub-study in order to assess multiple dose pharmacokinetics of olaparib prior to entering the main study. In the olaparib PK sub-study patients will take olaparib for 3 consecutive days and venous blood samples will be collected on Day 3. The PK sub-study must be initiated 10 days prior to the Cycle 1 Day 1 administration of the AZD1775 and olaparib combination. The patient will experience a short gap in treatment (approximately 4-5 days) between Day 3 of the olaparib PK sub-study and Cycle 1 Day 1 AZD1775 and olaparib combined dosing. AZD1775 (6 doses/week) + Olaparib Olaparib In this Arm, AZD1775 will be given twice daily over 3 days (6 doses) on Days 1-3 of Week 1 and Days 8-10 of Week 2. Olaparib will be given orally BID on Days 1-14. All patients will enter an olaparib sub-study in order to assess multiple dose pharmacokinetics of olaparib prior to entering the main study. In the olaparib PK sub-study patients will take olaparib for 3 consecutive days and venous blood samples will be collected on Day 3. The PK sub-study must be initiated 10 days prior to the Cycle 1 Day 1 administration of the AZD1775 and olaparib combination. The patient will experience a short gap in treatment (approximately 4-5 days) between Day 3 of the olaparib PK sub-study and Cycle 1 Day 1 AZD1775 and olaparib combined dosing. AZD1775 (10 doses/week) + Olaparib Olaparib In this Arm, AZD1775 will be given twice daily over 5 days (10 doses) on Days 1-5 of Week 1 and Days 8-12 of Week 2. Olaparib will be given orally BID on Days 1-14. All patients will enter an olaparib sub-study in order to assess multiple dose pharmacokinetics of olaparib prior to entering the main study. In the olaparib PK sub-study patients will take olaparib for 3 consecutive days and venous blood samples will be collected on Day 3. The PK sub-study must be initiated 10 days prior to the Cycle 1 Day 1 administration of the AZD1775 and olaparib combination. The patient will experience a short gap in treatment (approximately 4-5 days) between Day 3 of the olaparib PK sub-study and Cycle 1 Day 1 AZD1775 and olaparib combined dosing.
- Primary Outcome Measures
Name Time Method Part A: The incidence of dose-limiting toxicities (DLTs) 21 days (Cycle 1 duration) The maximum tolerated dose (MTD) of the AZD1775/olaparib combination will be the highest dose level at which less than one-third of patients experience a DLT during Cycle 1. Toxicity will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.
Part B: The incidence of treatment-emergent adverse events (TEAEs) Up to 12 months Treatment-emergent adverse events will be assessed through reports of clinical events and changes from baseline in vital signs and laboratory parameters.
- Secondary Outcome Measures
Name Time Method Part A: QTc Interval Pre-dose and at pre-specified times on Day 1 and 3 (or 5) of the olaparib PK sub-study, prespecified times on Days 1, 3, and 10 (or 1, 5, and 12) of Cycle 1, and pre-specified times on Days 1 and 3 (or 1 and 5) of Cycle 2, up to 9 weeks. Triplicate 12-lead ECGs will be performed approximately 2-5 minutes apart. The QTc interval will be calculated using Friderica's formula.
Objective Response Rate (ORR) Through study completion (an average of 6 months) The objective response rate (ORR) is the number of patients with a confirmed best objective response of Complete Response (CR) or Partial Response (PR) divided by the number of patients in the full analysis set with measurable disease at baseline. ORR is determined by the Investigator in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Disease Control Rate (DCR) Through study completion (an average of 6 months) Disease Control Rate (DCR) is defined (RECIST v1.1) as the percentage of patients in the full analysis set with a confirmed best objective response of complete response (CR), partial response (PR), or a best objective response of stable disease (SD).
Part A: Peak plasma concentration (Cmax) of olaparib when given as monotherapy in the olaparib PK sub-study. Olaparib plasma concentration will be measured on Day 3 or Day 5 of the olaparib PK sub-study pre-dose and 1, 2, 4, 6, 8, and 10 hours post-dose. Pharmacokinetic parameters will be derived from the plasma concentration data for olaparib. The date and actual time of the PK sample is to be recorded in the medical records and eCRF.
Part A: Peak plasma concentration (Cmax) of olaparib when given in combination with AZD 1775. Olaparib plasma conc. will be measured pre-dose & 1, 2, 4, 6, 8, & 10 hours post-dose on Days 3, 8, 10, & 15 (or Days 5, 8, 12, & 15) of Cycle 1; & Days 1, 3, & 8 (or Days 1, 5, & 8) of Cycle 2; & Days 3 or 10 (or Days 5 or 12) of Cycle 3. Pharmacokinetic parameters will be derived from the plasma concentration data for olaparib when given in combination with AZD1775. The date and actual time of the PK sample is to be recorded in the medical records and eCRF.
Part B: Peak plasma concentration (Cmax) of olaparib when given in combination with AZD1775. Olaparib plasma concentration will be measured pre-dose and 1, 2, 4, 6, 8, and 10 hours post-dose on Days 3 and 10 of Cycle 1. Pharmacokinetic parameters will be derived from the plasma concentration data for olaparib given in combination with AZD1775. The date and actual time of the PK sample is to be recorded in the medical records and eCRF.
Part B: Area under the plasma concentration versus time curve (AUC) of olaparib when given in combination with AZD1775. AUC for olaparib will be measured pre-dose and 1, 2, 4, 6, 8, and 10 hours post-dose on Days 3 and 10 of Cycle 1. Pharmacokinetic parameters will be derived from the plasma concentration data for olaparib when given in combination with AZD1775. The date and actual time of the PK sample is to be recorded in the medical records and eCRF.
Part B: Peak plasma concentration (Cmax) of AZD1775 when given in combination with olaparib. AZD1775 plasma concentration will be measured pre-dose and 1, 2, 4, 6, 8, and 10 hours post-dose on Days 3 and 10 of Cycle 1. Pharmacokinetic parameters will be derived from the plasma concentration data for AZD1775 given in combination with olaparib. The date and actual time of the PK sample is to be recorded in the medical records and eCRF.
Part B: Area under the plasma concentration versus time curve (AUC) of AZD1775 when given in combination with olaparib. AUC for AZD1775 will be measured pre-dose and 1, 2, 4, 6, 8, and 10 hours post-dose on Days 3 and 10 of Cycle 1. Pharmacokinetic parameters will be derived from the plasma concentration data for AZD1775 when given in combination with olaparib. The date and actual time of the PK sample is to be recorded in the medical records and eCRF.
Part B: Presence of genetic alterations Screening (prior to any study treatment), or at any visit throughout the life of the study (up to approximately 12 months). If the patient has given informed consent for genetic sampling and analysis a 10 mL sample of whole blood will be collected and tested for the presence of genetic alterations.
Part A: Area under the plasma concentration versus time curve (AUC) of olaparib when given in combination with AZD 1775. AUC for olaparib will be measured pre-dose and 1, 2, 4, 6, 8, and 10 hours post-dose on Days 3, 8, 10, and 15 (or Days 5, 8, 12, and 15) of Cycle 1; and Days 1, 3, and 8 (or Days 1, 5, and 8) of Cycle 2; and Days 3 or 10 (or Days 5 or 12) of Cycle 3. Pharmacokinetic parameters will be derived from the plasma concentration data for olaparib when given in combination with AZD1775. The date and actual time of the PK sample is to be recorded in the medical records and eCRF.
Part A: Peak plasma concentration (Cmax) of AZD1775 when given in combination with olaparib. AZD1775 plasma conc. will be measured pre-dose & 1, 2, 4, 6, 8, & 10 hours post-dose on Days 3, 8, 10, & 15 (or Days 5, 8, 12, & 15) of Cycle 1; & Days 1, 3, & 8 (or Days 1, 5, & 8) of Cycle 2; & Days 3 or 10 (or Days 5 or 12) of Cycle 3. Pharmacokinetic parameters will be derived from the plasma concentration data for AZD1775 given in combination with olaparib. The date and actual time of the PK sample is to be recorded in the medical records and eCRF.
Part A: Area under the plasma concentration versus time curve (AUC) of AZD1775 when given in combination with olaparib. AUC for AZD1775 be measured pre-dose and 1, 2, 4, 6, 8, and 10 hours post-dose on Days 3, 8, 10, and 15 (or Days 5, 8, 12, and 15) of Cycle 1; and Days 1, 3, and 8 (or Days 1, 5, and 8) of Cycle 2; and Days 3 or 10 (or Days 5 or 12) of Cycle 3. Pharmacokinetic parameters will be derived from the plasma concentration data for AZD1775 when given in combination with olaparib. The date and actual time of the PK sample is to be recorded in the medical records and eCRF.
Part A: The incidence of treatment-emergent adverse events (TEAEs). Up to 12 months Treatment-emergent adverse events will be assessed through reports of clinical events and changes from baseline in vital signs and laboratory parameters.
Part A: Area under the plasma concentration versus time curve (AUC) of olaparib when given as monotherapy in the olaparib PK sub-study. Olaparib plasma concentration will be measured on Day 3 or Day 5 of the olaparib PK sub-study: pre-dose and 1, 2, 4, 6, 8, and 10 hours post-dose. Pharmacokinetic parameters will be derived from the plasma concentration data for olaparib. The date and actual time of the PK sample is to be recorded in the medical records and eCRF.
Progression-Free Survival (PFS) From the beginning of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months Progression-free survival (PFS) is defined as the time from the beginning of treatment to disease progression or death from any cause.
Overall Survival (OS) From the beginning of treatment until the date of death from any cause, assessed up to 12 months. Overall survival (OS) is defined as the time from the beginning of treatment to death from any cause.
Trial Locations
- Locations (1)
Research Site
🇨🇦Toronto, Ontario, Canada