Description:
This is a modular, multicentre, open-label, non-randomised, Phase I/II, dose-setting and
expansion study including an intra-participant ramp-up.
AZD4573 will be administered intravenously, in novel combinations with anti-cancer agents, to
participants with relapsed/refractory haematological malignancies.
Title
- Brief Title: AZD4573 in Novel Combinations With Anti-cancer Agents in Patients With Advanced Blood Cancer.
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
D8230C00002
- NCT ID:
NCT04630756
Conditions
- Advanced Haematological Malignancies
Interventions
Drug | Synonyms | Arms |
---|
AZD4573 | AZ13810325 | AZD4573: Cohorts 1, 2, and 3 |
Acalabrutinib | ACP-196 /Calquence | AZD4573: Cohorts 1, 2, and 3 |
Purpose
This is a modular, multicentre, open-label, non-randomised, Phase I/II, dose-setting and
expansion study including an intra-participant ramp-up.
AZD4573 will be administered intravenously, in novel combinations with anti-cancer agents, to
participants with relapsed/refractory haematological malignancies.
Detailed Description
In Module 1 Part A (dose-setting), this study module will initially explore once weekly
administration of AZD4573 at up to three target dose levels in combination with oral
acalabrutinib 100 mg twice daily and will enroll participants with Diffuse large B-cell
lymphoma (DLBCL), based on the observation of complete and partial responses amongst DLBCL
patients treated with monotherapy. 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.
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.
Trial Arms
Name | Type | Description | Interventions |
---|
AZD4573: Cohorts 1, 2, and 3 | Experimental | Each cohort (1, 2, and 3) has a different target dose level.
Participants will receive intravenous ascending doses of AZD4573 once weekly with oral acalabrutinib twice daily continuously in Part A. In Part B, participants will receive the RP2D of AZD4573 from Part A. | |
Eligibility Criteria
Inclusion Criteria:
- Participant must be ≥ 18 years of age at the time of signing the informed consent.
- Participants with histologically confirmed, relapsed or refractory DLBCL, and where in
the opinion of the investigator, a clinical trial is the best option for next
treatment based on response and/or tolerability to prior lines of therapy. PART A
- Diagnosis must be confirmed by biopsy and be immunohistologically characterized.
- Tumour tissue must also be available for sending to AstraZeneca for central cell
of origin/pathology testing. PART B
- Must have received standard of care first line therapy.
- Diagnosis must be confirmed by biopsy and be immunohistologically characterised.
- A newly obtained tumour biopsy is mandatory at screening to confirm cell of
origin status and determine DLBCL subtype.
- Presence of radiographically measurable lymphadenopathy or extranodal lymphoid
malignancy.
- Participants must have failed at least 2 prior therapies for the treatment of current
disease, are not eligible for curative treatment options, and have no standard therapy
available.
- Adequate haematologic function, without transfusion and growth factor support for
≥ 14 days before screening.
- 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:
- Treatment with prior Bruton's tyrosine kinase inhibitor.
- Current refractory nausea and vomiting, malabsorption syndrome, disease significantly
affecting gastrointestinal function, resection of the stomach, 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,
such as gastric bypass.
- 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.
- Receipt of live, attenuated vaccine within 28 days before the first dose of study
treatment (s).
- Requires or receiving therapeutic anticoagulants, with the exception of short-acting
heparins, within 7 days of first dose of study treatment.
- Participants on dual antiplatelet and therapeutic anticoagulant therapy.
Maximum Eligible Age: | 130 Years |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Module 1 Part A : Number of participants with serious and non-serious adverse events |
Time Frame: | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) |
Safety Issue: | |
Description: | 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. |
Secondary Outcome Measures
Measure: | Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via CR rate |
Time Frame: | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) |
Safety Issue: | |
Description: | CR is defined as no detectable evidence of tumor, according to the revised response criteria for malignant lymphoma. |
Measure: | Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via duration of response (DoR) |
Time Frame: | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) |
Safety Issue: | |
Description: | 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. |
Measure: | Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via Time to Response (TTR) |
Time Frame: | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) |
Safety Issue: | |
Description: | 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. |
Measure: | Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via Progression free survival (PFS) |
Time Frame: | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) |
Safety Issue: | |
Description: | PFS, defined as the time from first dose date to documented disease progression, or death from any cause, whichever occurs first |
Measure: | Module 1 Part B: Efficacy of AZD4573 in combination with acalabrutinib by evaluation of tumour response and overall survival via Overall survival (OS) |
Time Frame: | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) |
Safety Issue: | |
Description: | OS, defined as the time from first dose until the date of death from any cause. |
Measure: | Module 1 Part B: Number of participants with serious and non-serious adverse events |
Time Frame: | From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) |
Safety Issue: | |
Description: | Safety and tolerability of the RP2D of AZD4573 in combination with acalabrutinib. |
Measure: | Module 1 Part A and Part B: Plasma pharmacokinetics (PK) (Cmax) of AZD4573 and acalabrutinib (plus its active metabolite ACP-5862), when given in combination |
Time Frame: | 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 |
Safety Issue: | |
Description: | Maximum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered (Cmax). |
Measure: | Module 1 Part A and Part B: Plasma PK (AUC0-t) of AZD4573 and acalabrutinib (plus its active metabolite ACP-5862), when given in combination |
Time Frame: | 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 |
Safety Issue: | |
Description: | Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUC0-t) |
Measure: | Module 1 Part A and Part B: Plasma PK (AUClast) of AZD4573 and acalabrutinib (plus its active metabolite ACP-5862), when given in combination |
Time Frame: | 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 |
Safety Issue: | |
Description: | Area under the plasma concentration time curve from zero to the time of the last measurable concentration (AUClast). |
Measure: | Module 1 Part A and Part B: Plasma PK (AUCinf) of AZD4573 and acalabrutinib (plus its active metabolite ACP-5862), when given in combination |
Time Frame: | 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 |
Safety Issue: | |
Description: | Area under the plasma concentration time curve from zero extrapolated to infinity (AUCinf). |
Measure: | Module 1 Part A and Part B: Plasma PK (tmax) of AZD4573 and acalabrutinib (plus its active metabolite ACP-5862), when given in combination |
Time Frame: | 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 |
Safety Issue: | |
Description: | Time to reach peak or maximum observed concentration following drug administration (tmax). |
Measure: | Module 1 Part A and Part B: Plasma PK (t1/2) of AZD4573 and acalabrutinib (plus its active metabolite ACP-5862), when given in combination |
Time Frame: | 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 |
Safety Issue: | |
Description: | Time taken for half the initial dose of drug administered to be eliminated from the body (t1/2). |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | AstraZeneca |
Trial Keywords
- AZD4573
- Anti-cancer Agents
- Sequential dose-setting and expansion treatment
Last Updated
August 6, 2021