A Phase Ib/II, Open-Label, Multicentre Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9150 Plus Durvalumab Alone or in Combination With Chemotherapy in Patients With Advanced, Solid Tumours and Subsequently in Patients With Non-Small-Cell Lung Cancer

Brief Summary

Detailed Description

This international, multicenter study was originally intended to be conducted in four parts, designated as Parts A, B, C, and D. The protocol was amended in December 2018 to remove Parts B and C. Parts B and C were intended to evaluate patients with locally advanced or metastatic Stage IV NSCLC; however, these parts of the study will not be conducted. Part A of this study will evaluate the safety and tolerability of durvalumab and AZD9150 with and without selected chemotherapy regimens, and will include patients with advanced solid malignancies that are refractory to standard therapy or for whom no standard of care (SOC) regimen currently exists. Part D will compare the relative bioavailability of the AZD9150 subcutaneous (SC) versus intravenous (IV) formulations in patients with confirmed solid malignancies that are refractory to standard therapy or for whom no SOC regimen currently exists. Approximately 50 to 62 PK-evaluable patients will be enrolled in Part D. Patients will be randomly assigned to either SC or IV AZD9150. For Part D, the PK Analysis set will include all patients who receive both study drugs (both AZD9150 and durvalumab) and have at least one PK sample collection. A complementary anti-tumour strategy will be used in this study with 2 immuno-therapeutics applied to restore effective anti-tumour immunity at 2 distinct stages: promoting the effector function of T-cell responses with an anti-PD-L1 mAb, durvalumab, while hindering immune escape in the tumour bed with AZD9150. In addition, chemotherapy will be added to this combination to investigate possible future enhancement of response. In preclinical models, conventional platinum-based chemotherapy has been shown to induce T-cell activation through the release of tumour-specific antigens during cancer cell death. The elimination of persistent tolerogenic tumour antigen environment via chemotherapy-induced debulking may also play a role in generating an effective immune response. In this setting, immunotherapy has the potential to mount an ongoing and dynamic immune response that can kill tumour cells for an extended time. Part A of the study will be conducted in five arms, designated Arms A1, A2, A3, A4, and A5. The primary objective of Part A is to assess the safety and tolerability, and determining the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of AZD9150 plus durvalumab in patients with advanced solid malignancies. In addition, another primary objective is to assess the safety and tolerability, and determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of AZD9150 plus durvalumab in combination with standard chemotherapy regimens in patients with advanced solid malignancies. Approximately 30 to 78 DLT-evaluable patients will be enrolled in Part A. In Arm A1, patients will receive AZD9150 by (IV) infusion Q2W + durvalumab by IV infusion Q4W. Chemotherapy will not be given in Arm A1. Arm A2 patients will receive AZD9150 IV QW + durvalumab IV Q3W, cisplatin by slow IV infusion over 1-4 hours on Day 1 + 5-fluorouracil (5FU) by continuous IV infusion over 96 hours (Days 1 through 4, repeated every 3 weeks for up to 18 weeks). In Arm A2 there will be a AZD9150 + chemotherapy lead-in period prior to durvalumab dosing. The last chemotherapy dose will be given in Week 15. After discontinuation of chemotherapy the regimen will include AZD9150 IV QW + durvalumab IV Q4W. Administration of durvalumab will continue Q3W through Week 19, at which time the schedule will switch to Q4W (e.g., Week 23, 27, 31, etc.). Depending on the results from Arm A2, Arm A3 may not be conducted. If the Safety Review Committee (SRC) decides to open Arm A3, the SRC will determine the starting dose. Patients will be administered one of the following 4 chemotherapy regimens in combination with AZD9150 and durvalumab appropriate for their tumour type: * In Arm A3, patients will receive cisplatin by slow IV infusion over 1-4 hours on Day 1 + 5FU by continuous IV infusion over 96 hours (Days 1 through 4, repeated every 3 weeks for up to 18 weeks). * In Arm A4, patients will receive gemcitabine by IV infusion over 30 minutes on Days 1 and 8 every 3 weeks for 12 to 18 weeks, plus either: * for cisplatin-eligible patients: cisplatin IV over 30 minutes on Day 1 (every 3 weeks for up to 12 to 18 weeks); or * for cisplatin-ineligible patients: carboplatin IV over 30 to 60 minutes on Day 1 (every 3 weeks for up to 12 to 18 weeks). * In Arm A5, patients will receive carboplatin at AUC 5 IV over 30 to 60 minutes on Day 1 + nab-paclitaxel IV over 30 to 40 minutes on Days 1, 8, and 15 (every 3 weeks for up to 12 to 18 weeks) There will be an AZD9150 7-day lead-in period (termed Week 0) in all arms in all parts of the study. AZD9150 will be given IV on Days 1,3, and 5 of the lead-in week. When chemotherapy is administered, the dosing of chemotherapy will also commence during the lead-in period with AZD9150. In Arm A2 of Part A, dosing with AZD9150 IV, durvalumab, and chemotherapy will commence on Day 1 of Week 0. In Part D, dosing with AZD9150 IV or SC will commence on Day 1 of Week 0

Primary Outcomes

Secondary Outcomes

• Part A: Duration of Overall Response (DoR)(Throughout the study (approximately 6 months).)
• Part A: Trough plasma concentration (Ctrough) of AZD9150 after single-dose.(Blood samples for the PK analysis of AZD9150 will be collected at prespecified intervals during Weeks 0, 1, 5, 6, and 9.)
• Part A: Durvalumab anti-drug antibody titres(Blood samples for durvalumab anti-drug antibodies (ADAs) will be collected predose on prespecified dosing days up to 13 weeks.)
• Part A: Disease Control Rate (DCR)(12 weeks)
• Part A: Baseline tumour PD-L1 expression(Pre-dose)
• Part A: Peak plasma concentration (Cmax) of AZD9150 after single-dose.(Blood samples for the PK analysis of AZD9150 will be collected at prespecified intervals during Weeks 0, 1, 5, 6, and 9.)
• Part D: Peak plasma concentration (Cmax,ss) of AZD9150 at steady state after multiple doses.(Through study completion (an average of 6 months))
• Part A: Peak plasma concentration (Cmax,ss) of AZD9150 after multiple doses.(Blood samples for the PK analysis of AZD9150 will be collected at prespecified intervals during Weeks 0, 1, 5, 6, and 9.)
• Part D: Area under the plasma concentration versus time curve [AUC(0-inf)] after single-dose.(Through study completion (an average of 6 months))
• Part D: The elimination half-life (t1/2) of AZD9150 after single-dose(Through study completion (an average of 6 months))
• Part A: Progression-Free Survival (PFS)(From the date of documented complete response or partial response, whichever comes first, until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months)
• Part A: AZD9150 anti-drug antibody titres(Blood samples for AZD9150 anti-drug antibodies (ADAs) will be collected predose on prespecified dosing days up to 9 weeks.)
• Part A: STAT3 protein in tumour biopsies(Predose and 3 weeks after start of treatment)
• Part A: Area under the plasma concentration versus time curve [AUC(ss)] at steady state after multiple doses.(Through study completion (an average of 6 months))
• Part D: Peak plasma concentration (Cmax) of AZD9150 after single-dose.(Through study completion (an average of 6 months))
• Part A: Trough plasma concentration (Ctrough,ss) of AZD9150 after multiple doses.(Blood samples for the PK analysis of AZD9150 will be collected at prespecified intervals during Weeks 0, 1, 5, 6, and 9.)
• Part D: Injection site tolerability for patients receiving subcutaneous injections.(Through study completion (an average of 6 months))
• Part D: The systemic clearance (CL) of AZD9150 after single-dose.(Through study completion (an average of 6 months))
• Part D: The systemic clearance [CL(ss)] of AZD9150 after multiple doses.(Through study completion (an average of 6 months))
• Part A: Area under the plasma concentration versus time curve (AUC) of AZD9150 after single-dose.(Through study completion (an average of 6 months))
• Part D: The incidence of adverse events (AEs) in subjects receiving AZD9150.(Through study completion (an average of 6 months))
• Part D: Area under the plasma concentration versus time curve from time zero to 48 hours [AUC(0-48] after single-dose.(Through study completion (an average of 6 months))
• Part D: The apparent systemic clearance (CL/F) of AZD9150 after single-dose.(Through study completion (an average of 6 months))
• Part D: The mean residence time (MRT) of AZD9150 after single-dose.(Through study completion (an average of 6 months))
• Part D: Injection site tolerability of AZD9150 given by subcutaneous injection every 4 weeks relative to AZD9150 200 mg IV QW in(Through study completion (an average of 6 months))
• Part D: The incidence of serious adverse events (SAEs) in subjects receiving AZD9150.(Through study completion (an average of 6 months))
• Part D: Time to peak plasma concentration (tmax) of AZD9150 after single-dose.(Through study completion (an average of 6 months))
• Part D: Area under the plasma concentration versus time curve [AUC(ss)] at steady state after multiple doses.(Through study completion (an average of 6 months))
• Part D: Area under the plasma concentration versus time curve [AUC(0-t)] after single-dose.(Through study completion (an average of 6 months))
• Part D: The volume of distribution (Vz/F) of AZD9150 after single-dose.(Through study completion (an average of 6 months))