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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Modular Phase I/II, Open-label, Multicentre Study to Assess AZD4573 in Novel Combinations With Anti-cancer Agents in Patients With Advanced Haematological Malignancies

Conditions
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Advanced Haematological Malignancies

Intervention / Treatment
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* Drug: AZD4573
* Drug: Acalabrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - Core Participant must be ≥ 18 years of age at the time of signing the informed consent. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Must have received at least one prior line of therapy for the treatment of current disease and a clinical study is the best option for next treatment based on prior response and/or tolerability. Documented active disease requiring treatment that is r/r defined as: Recurrence of disease after response to at least one prior line(s) of therapy or Progressive disease after completion of or on the treatment regimen preceding entry into the study or Disease that did not achieve an objective response (overall response of CR or PR). Adequate haematological function. Adequate organ function at Screening. Uric acid level < upper limit of normal (ULN). Inclusion Criteria - Module 1 - Participants with histologically confirmed, r/r DLBCL, or r/r MZL, for whom a clinical study is the best option for next treatment based on response and/or tolerability to prior lines of therapy. PART A • Participants with r/r DLBCL, including subtypes such as DLBCL not otherwise specified [NOS], high-grade B cell lymphoma [HGBCL], primary mediastinal large B-cell lymphoma [PMBCL], or large B cell lymphoma transformed from indolent B-cell lymphomas (including but not limited to Richter Syndrome, transformed Follicular Lymphoma, transformed MZL), or r/r MZL: participants with r/r MZL are eligible as well. In case fresh tumor biopsy is not available, archival tumor samples are acceptable, if done with 24 months PART B • Participants with r/r de novo r/r DLBCL only, fresh tumor biopsy, done at screening or within 60 days before planned 1st dosing, unless there was any anticancer treatment given after tumor biopsy, but prior initiated study treatment. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy. Participants must have failed at least two prior therapies for the treatment of current disease. Participants shall not be eligible for curative treatment options, and have no standard therapy available (including CAR-T cell therapy). Adequate haematologic function at screening: No growth factor support within 14 days prior to the date of the screening laboratory assessment; No transfusions within 7 days prior to the date of the screening laboratory assessment. Optional tumour biopsy on study: Participants are also encouraged to consent to and undergo an optional tumour biopsy at disease progression to support correlative biomarker studies. All participants must be willing and able to provide mandatory baseline bone marrow biopsy/aspirate. Inclusion Criteria - Module 2 - Participants with histologically confirmed r/r MCL for whom a clinical study is the best option (in the opinion of the investigator) for next treatment based on response and/or tolerability to prior lines of therapy. PART A Participants with r/r MCL: Diagnosis must be confirmed by biopsy and be immunohistologically characterised. Tumour tissue must also be available for sending to AstraZeneca for pathology testing. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy Participants must have failed at least one prior therapy for the treatment of current disease and not be eligible for treatment with curative intent (e.g. allogenichaematopoietic cell transplantation [HCT]). Eligible participants include both BTKi-naïve and BTKi-exposed. Adequate haematologic function at screening: No growth factor support within 14 days prior to the date of the screening laboratory assessment; No transfusions within 7 days prior to the date of the screening laboratory assessment. Optional tumour biopsy on study: Participants are also encouraged to consent to and undergo an optional tumour biopsy at disease progression to support correlative biomarker studies. All participants must be willing and able to provide mandatory baseline bone marrow biopsy/aspirate. Exclusion Criteria - Core Participants with non-secretory myeloma. With the exception of alopecia, any unresolved non-haematological toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment. Presence of, or history of, central nervous system (CNS) lymphoma, leptomeningeal disease, or spinal cord compression. History of prior non-haematological malignancy except for the following: Malignancy treated with curative intent and with no evidence of active disease for >1 year before Screening and felt to be at low risk for recurrence by treating physician; Adequately treated lentigo maligna melanoma without evidence of disease or adequately controlled non-melanomatous skin cancer; Adequately treated carcinoma in situ without current evidence of disease. Any evidence of severe or uncontrolled systemic disease (eg, severe hepatic impairment, interstitial lung disease), or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, history of, or active, bleeding diatheses or uncontrolled active systemic fungal, bacterial, viral, or other infection, or IV anti infective treatment within two weeks before first dose of study drug. Known history of infection with human immunodeficiency virus (HIV). Serologic status reflecting active hepatitis B or C infection. Any of the following cardiac criteria: Resting QT interval corrected using Fridericia's formula (QTcF) ≥ 470 msec obtained from a single electrocardiogram (ECG); any clinically important abnormalities in rhythm (except for participants with a pacemaker in place), conduction or morphology of resting ECG); any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age. Concomitant medications known to prolong QTc should be used with caution and cannot be used starting with the first dose of study drug and through the DLT-assessment period (Part A) or during the scheduled ECG assessments. History of severe allergic or anaphylactic reactions to BH3 mimetics or history of hypersensitivity to active or inactive excipients of study treatment. Documented confirmation and ongoing treatment of adrenal gland insufficiency or pancreatitis. History, within the previous 6 months prior to first dose, of: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; congestive heart failure (New York Heart Association Class ≥ 2); ventricular arrhythmias requiring continuous therapy; atrial fibrillation, which is judged as uncontrolled by the treating physician; haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other CNS bleeding. 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module 1: Part A and Part B<br>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. | Drug: AZD4573<br>* AZD4573 will be administered as an absolute (flat) dose, 2-hour (± 15 minutes) IV infusion once weekly (as monotherapy for Module 2 only) and in combination with orally administered acalabrutinib twice daily continuously. For both Part A and Part B of this study, Cycle 1 consists of 5 weeks, with a dose ramp-up. Subsequent cycles are 21 days (3 weeks) with once weekly dosing of AZD4573 in combination with acalabrutinib twice daily continuously (in Module 1 and Module 2, period 2).<br>* Other names: AZ13810325;Drug: Acalabrutinib<br>* Oral Acalabrutinib capsule will be administered twice daily continuously from Day 1 of Cycle 1 Week 1 in combination with AZD4573.<br>* Other names: ACP-196 /Calquence;|
| Experimental: Module 2: Part A and Part B<br>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. | Drug: AZD4573<br>* AZD4573 will be administered as an absolute (flat) dose, 2-hour (± 15 minutes) IV infusion once weekly (as monotherapy for Module 2 only) and in combination with orally administered acalabrutinib twice daily continuously. For both Part A and Part B of this study, Cycle 1 consists of 5 weeks, with a dose ramp-up. Subsequent cycles are 21 days (3 weeks) with once weekly dosing of AZD4573 in combination with acalabrutinib twice daily continuously (in Module 1 and Module 2, period 2).<br>* Other names: AZ13810325;Drug: Acalabrutinib<br>* Oral Acalabrutinib capsule will be administered twice daily continuously from Day 1 of Cycle 1 Week 1 in combination with AZD4573.<br>* Other names: ACP-196 /Calquence;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Module 1 Part A : Number of participants with serious and non-serious adverse events | Safety and tolerability, describe the dose limiting toxicity (DLTs), and identify the maximum tolerated dose (MTD) and/or RP2D of AZD4573 in combination with acalabrutinib. | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) | 
| Module 2 Part A : Number of participants with serious and non-serious adverse events | Assess safety and confirm the RP2D of AZD4573 monotherapy in MCL participants and assess the safety and tolerability of AZD4573 in combination with acalabrutinib in participants administered AZD4573 monotherapy. | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) | 
| Module 1 Part B: Overall response rate (ORR) of AZD4573 in combination with acalabrutinib | Overall response rate (ORR), defined as the proportion of participants who have a tumour response (complete response [CR] and partial response [PR]). | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via CR rate | CR is defined as no detectable evidence of tumor, according to the revised response criteria for malignant lymphoma. | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) | 
| Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via duration of response (DoR) | 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. | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) | 
| Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via Time to Response (TTR) | TTR, defined as the time from the first dose of study treatment to the first objective response observed for participants who achieved a CR or PR. | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) | 
| Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via Progression free survival (PFS) | PFS, defined as the time from first dose date to documented disease progression, or death from any cause, whichever occurs first | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) | 
| Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via Overall survival (OS) | OS, defined as the time from first dose until the date of death from any cause. | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) | 
| Module 1 Part B: Number of participants with serious and non-serious adverse events | Safety and tolerability of the RP2D of AZD4573 in combination with acalabrutinib. | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) | 
| Module 1 Part A and Part B; Module 2 Part A: Plasma pharmacokinetics (PK) (Cmax) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination | Maximum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered (Cmax). | 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 | 
| Module 1 Part A and Part B; Module 2 Part A: Plasma PK (AUC0-t) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination | Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUC0-t) | 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 | 
| Module 1 Part A and Part B; Module 2 Part A: Plasma PK (AUClast) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination | Area under the plasma concentration time curve from zero to the time of the last measurable concentration (AUClast). | 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 | 
| Module 1 Part A and Part B; Module 2 Part A: Plasma PK (AUCinf) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination | Area under the plasma concentration time curve from zero extrapolated to infinity (AUCinf). | 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 | 
| Module 1 Part A and Part B; Module 2 Part A: Plasma PK (tmax) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination | Time to reach peak or maximum observed concentration following drug administration (tmax). | 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 | 
| Module 1 Part A and Part B; Module 2 Part A: Plasma PK (t1/2) of AZD4573 (given as monotherapy for Module 2 only) and acalabrutinib (plus its active metabolite ACP-5862), when given in combination | Time taken for half the initial dose of drug administered to be eliminated from the body (t1/2). | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD4573, Anti-cancer Agents, Sequential dose-setting and expansion treatment