Title
Phase Ib Study AZD1775 in Combination With Carboplatin and Paclitaxel in Adult Asian Patients With Solid Tumours
A Phase Ib, Dose Finding Study Evaluating AZD1775 in Monotherapy, in Combination With Carboplatin and Paclitaxel, and in Combination With Only Carboplatin in Adult Asian Patients With Advanced Solid Tumours
Phase
Phase 1Lead Sponsor
AstraZenecaStudy Type
InterventionalStatus
Completed Results PostedIndication/Condition
Advanced Solid TumoursIntervention/Treatment
mk-1775 paclitaxel carboplatin ...Study Participants
19This 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.
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.
AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small-molecule inhibitor of the WEE1 kinase that sensitizes tumour cells to cytotoxic agents and is being developed for the treatment of advanced solid tumours and p53 pathway deficient malignancies. Gemcitabine is a nucleoside analog used as chemotherapy.
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy ; it and docetaxel represent the taxane family of drugs.
Carboplatin is a chemotherapy drug used against some forms of cancer (mainly ovarian carcinoma, lung, head and neck cancers as well as endometrial, esophageal, bladder, breast and cervical; central nervous system or germ cell tumors; osteogenic sarcoma, and as preparation for a stem cell or bone marrow transplant.).
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.
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.
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.
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.
| Event Type | Organ System | Event Term | Cohort 1 | Cohort 1a | Cohort 2 |
|---|
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.
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.
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.
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.
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.
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.
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.
Objective response is defined as either a complete response or a partial response.
Objective response is defined as either a complete response or a partial response.
Clinical benefit is defined as achieving complete response, partial response, or stable disease.
Clinical benefit is defined as achieving complete response, partial response, or stable disease.
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.
