AZD4573 in Novel Combinations With Anti-cancer Agents in Patients With Advanced Blood Cancer

Phase 1

Completed

Conditions: Advanced Haematological Malignancies

Interventions: Drug: AZD4573
Drug: Acalabrutinib

Registration Number: NCT04630756

Lead Sponsor: AstraZeneca

Brief Summary: This is a modular, multicentre, open-label, non-randomised, Phase I/II, dose-setting and expansion study including an intra-participants dose ramp up. AZD4573 will be administered intravenously, in novel combinations with anti-cancer agents, to participants with relapsed/refractory (r/r) haematological malignancies.

Detailed Description: In Module 1 Part A (dose-setting), this study module will enrol participants with r/r Diffuse large B-cell lymphoma (DLBCL) or r/r Marginal zone lymphoma (MZL) who have failed prior therapy(ies), are not eligible for curative treatment options, for whom there is no standard therapy available, and will initially explore once weekly administration of AZD4573 at up to three target dose levels in combination with oral acalabrutinib 100 mg twice daily. The primary objective of Part A will be to identify the maximum tolerated dose and/or Recommended Phase II dose (RP2D) for further evaluation in Part B. A 5-week DLT-assessment period will incorporate the whole of Cycle 1 in Part A, including the dose ramp up and the first 3 weeks at the target dose. In Module 1 Part B (expansion), separate expansion cohorts for participants with Germinal Centre B-cell (GCB) and non-GCB DLBCL subtypes will be opened at the RP2D.

In Module 2, this study module will enroll participants with r/r Mantle Cell Lymphoma (MCL) who have failed at least one line of prior therapy, are not eligible for curative treatment options. Module 2, Part A consist of AZD4573 monotherapy (Period 1) followed by AZD4573 + acalabrutinib combination treatment (Period 2). Period 1: AZD4573 will be administered weekly (12 mg, infusion). Period 2: AZD4573 (RP2D from Module 1) will be administered (weekly) in combination with oral acalabrutinib 100 mg twice daily. Cycle 1 of each dosing period has a duration of 5 weeks; subsequent cycles have a duration of 3 weeks. The AZD4573 monotherapy (Period 1) includes an intra-patient ramp up; participants will receive AZD4573 at Cycle 1 Week 1, Cycle 1 Week 2, and Cycle 1 Week 3 in 3 dose escalation manner (6, 9 and 12 mg respectively). Part A, Period 1 of Module 2 aims to confirm the AZD4573 monotherapy RP2D in MCL participants. In Period 2, the safety and tolerability of the RP2D of AZD4573 + acalabrutinib established in Module 1 will be assessed in participants with MCL. The study design of Part B of Module 2 will be determined from the data emerging from Part A.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

Inclusion Criteria

Not provided

Exclusion Criteria

Module 1

Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, stomach resection, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, bowel obstruction, or gastric restrictions and bariatric surgery.
Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of receiving the first dose of study treatment.
Requires treatment with strong CYP3A inhibitors or inducers.
Requires treatment with proton-pump inhibitors. Participants receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study.
Serologic status reflecting active hepatitis B or C infection.
Active Cytomegalovirus (CMV) infection.
Requires or receiving therapeutic anticoagulants, with the exception of short-acting heparins, within 7 days of first dose of study treatment. Novel oral anticoagulants are allowed except for the initial high dose treatment period.
Participants on dual antiplatelet and therapeutic anticoagulant therapy.
Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
History of or ongoing confirmed progressive multifocal leukoencephalopathy

Exclusion Criteria: Module 2

Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, stomach resection, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery.
Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of receiving the first dose of study treatment.
Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
Requires treatment with strong CYP3A inhibitors or inducers.
Requires treatment with proton-pump inhibitors. Participants receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study.
Serologic status reflecting active hepatitis B or C infection.
Active CMV infection.
Requires or receiving therapeutic anticoagulants, with the exception of short-acting heparins, within 7 days of first dose of study treatment. Novel oral anticoagulants are allowed except for the initial high dose treatment period.
Participants on dual antiplatelet and therapeutic anticoagulant therapy.
History of or ongoing confirmed progressive multifocal leukoencephalopathy

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Module 1: Part A and Part B	Acalabrutinib	Participants will receive intravenous ascending doses of AZD4573 once weekly with oral acalabrutinib twice daily continuously in Part A. For Part A, cohorts 1, 2, and 3 have different target dose levels respectively. In Part B, participants will receive the RP2D of AZD4573 from Part A.
Module 2: Part A and Part B	Acalabrutinib	Participants will receive AZD4573 as monotherapy for Period 1 and AZD4573 + acalabrutinib as combination therapy for Period 2. Part B of Module 2 will be determined from the data emerging from Part A.
Module 1: Part A and Part B	AZD4573	Participants will receive intravenous ascending doses of AZD4573 once weekly with oral acalabrutinib twice daily continuously in Part A. For Part A, cohorts 1, 2, and 3 have different target dose levels respectively. In Part B, participants will receive the RP2D of AZD4573 from Part A.
Module 2: Part A and Part B	AZD4573	Participants will receive AZD4573 as monotherapy for Period 1 and AZD4573 + acalabrutinib as combination therapy for Period 2. Part B of Module 2 will be determined from the data emerging from Part A.

Primary Outcome Measures

Name	Time	Method
Module 1: Number of Participants With Adverse Events	From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)	Safety and tolerability of AZD4573 in combination with acalabrutinib was assessed.
Module 2: Number of Participants With Adverse Events	From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)	Assessed safety and confirmed the RP2D of AZD4573 monotherapy in MCL participants and assessed the safety and tolerability of AZD4573 in combination with acalabrutinib in participants administered AZD4573 monotherapy.
Module 1: Overall Response Rate (ORR) of AZD4573 in Combination With Acalabrutinib	From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)	Overall response rate (ORR), defined as the proportion of participants who have a tumour response (complete response \[CR\] and partial response \[PR\]).

Secondary Outcome Measures

Name	Time	Method
Module 1: Complete Response (CR) Rate	From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)	CR is defined as no detectable evidence of tumor, according to the revised response criteria for malignant lymphoma.
Module 1: Duration of Response (DoR)	From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)	DoR, defined as the time from the first objective response of CR or PR to the time of documented disease progression or death due to any cause, whichever occurs first.
Module 1: Progression Free Survival (PFS)	From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)	PFS, defined as the time from first dose date to documented disease progression, or death from any cause, whichever occurs first
Module 1: Overall Survival (OS)	From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 2.5 years)	OS, defined as the time from first dose until the date of death from any cause.
Module 1: Cmax of AZD4573	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Maximum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered (Cmax).
Module 1: Cmax of Acalabrutinib	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Maximum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered (Cmax).
Module 1: Cmax of ACP-5862	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Maximum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered (Cmax).
Module 1: AUClast of AZD4573	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Area under the plasma concentration time curve from zero to the time of the last measurable concentration (AUClast).
Module 1: AUClast of Acalabrutinib	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Area under the plasma concentration time curve from zero to the time of the last measurable concentration (AUClast).
Module 1: AUClast of ACP-5862	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Area under the plasma concentration time curve from zero to the time of the last measurable concentration (AUClast).
Module 1: AUCinf of AZD4573	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Area under the plasma concentration time curve from zero extrapolated to infinity (AUCinf).
Module 1: AUCinf of Acalabrutinib	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Area under the plasma concentration time curve from zero extrapolated to infinity (AUCinf).
Module 1: AUCinf of ACP-5862	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Area under the plasma concentration time curve from zero extrapolated to infinity (AUCinf).
Module 1: Tmax of AZD4573	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Time to reach peak or maximum observed concentration following drug administration (tmax).
Module 1: Tmax of Acalabrutinib	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Time to reach peak or maximum observed concentration following drug administration (tmax).
Module 1: Tmax of ACP-5862	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Time to reach peak or maximum observed concentration following drug administration (tmax).
Module 1: t1/2 of AZD4573	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Time taken for half the initial dose of drug administered to be eliminated from the body (t1/2).
Module 1: t1/2 of Acalabrutinib	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Time taken for half the initial dose of drug administered to be eliminated from the body (t1/2).
Module 1: t1/2 of ACP-5862	Cycle 1 (5 weeks in total) on Day 1 of Week 1, 2 and 3, and Cycle 2 (3 weeks in total) on Day 1 of Week 1	Time taken for half the initial dose of drug administered to be eliminated from the body (t1/2).