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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04630756
Recruitment Status : Recruiting
First Posted : November 16, 2020
Last Update Posted : September 10, 2021
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Advanced Haematological Malignancies Drug: AZD4573 Drug: Acalabrutinib Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This is a single group assignment study. The goal of the study is to establish the recommended dose via three target dose levels in combination with oral acalabrutinib which is designed as dose escalation cohorts.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 17, 2021
Estimated Primary Completion Date : July 24, 2023
Estimated Study Completion Date : July 24, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: AZD4573: Cohorts 1, 2, and 3

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.

Drug: AZD4573
AZD4573 will be administered as an absolute (flat) dose, 2-hour (± 15 minutes) IV infusion once weekly 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.
Other Name: AZ13810325

Drug: Acalabrutinib
Oral Acalabrutinib capsule will be administered twice daily continuously from Day 1 of Cycle 1 Week 1 in combination with AZD4573.
Other Name: ACP-196 /Calquence




Primary Outcome Measures :
  1. 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 and tolerability, describe the dose limiting toxicity (DLTs), and identify the maximum tolerated dose (MTD) and/or RP2D of AZD4573 in combination with acalabrutinib.

  2. Module 1 Part B: Overall response rate (ORR) of AZD4573 in combination with acalabrutinib [ Time Frame: From Screening (Day -30 to Day -1) until disease progression or survival until death (approximately 6 months) ]
    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 :
  1. 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) ]
    CR is defined as no detectable evidence of tumor, according to the revised response criteria for malignant lymphoma.

  2. 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) ]
    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.

  3. 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) ]
    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.

  4. 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) ]
    PFS, defined as the time from first dose date to documented disease progression, or death from any cause, whichever occurs first

  5. 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) ]
    OS, defined as the time from first dose until the date of death from any cause.

  6. 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 and tolerability of the RP2D of AZD4573 in combination with acalabrutinib.

  7. 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 ]
    Maximum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered (Cmax).

  8. 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 ]
    Area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUC0-t)

  9. 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 ]
    Area under the plasma concentration time curve from zero to the time of the last measurable concentration (AUClast).

  10. 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 ]
    Area under the plasma concentration time curve from zero extrapolated to infinity (AUCinf).

  11. 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 ]
    Time to reach peak or maximum observed concentration following drug administration (tmax).

  12. 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 ]
    Time taken for half the initial dose of drug administered to be eliminated from the body (t1/2).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04630756


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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United States, California
Research Site Recruiting
Duarte, California, United States, 91010
Research Site Recruiting
La Jolla, California, United States, 92093-0052
United States, Florida
Research Site Withdrawn
Tampa, Florida, United States, 33612
United States, Texas
Research Site Recruiting
Houston, Texas, United States, 77030
United States, Utah
Research Site Not yet recruiting
Salt Lake City, Utah, United States, 84112
Australia
Research Site Recruiting
Clayton, Australia, 3168
Research Site Recruiting
Nedlands, Australia, 6009
Canada, Ontario
Research Site Not yet recruiting
Toronto, Ontario, Canada, M5G 2M9
Canada
Research Site Not yet recruiting
Quebec, Canada, G1R 2J6
France
Research Site Not yet recruiting
Lille Cedex, France, 59037
Research Site Not yet recruiting
Rouen, France, 76038
Germany
Research Site Withdrawn
Essen, Germany, 45147
Research Site Withdrawn
Homburg, Germany, 66421
Research Site Withdrawn
Muenster, Germany, 48149
Research Site Withdrawn
Munchen, Germany, 81377
Ireland
Research Site Not yet recruiting
Dublin, Ireland, D08 NHY1
Research Site Not yet recruiting
Galway, Ireland, H91 YR71
Italy
Research Site Not yet recruiting
Brescia, Italy, 25123
Research Site Not yet recruiting
Modena, Italy, 41124
Research Site Not yet recruiting
Monza, Italy, 20900
Research Site Not yet recruiting
Rozzano, Italy, 20089
Korea, Republic of
Research Site Recruiting
Seoul, Korea, Republic of, 03080
Research Site Recruiting
Seoul, Korea, Republic of, 05505
Research Site Recruiting
Seoul, Korea, Republic of, 06351
Poland
Research Site Not yet recruiting
Katowice, Poland, 40-519
Research Site Not yet recruiting
Kraków, Poland, 30-510
Research Site Not yet recruiting
Lublin, Poland, 20-059
Research Site Not yet recruiting
Warszawa, Poland, 02-781
Research Site Not yet recruiting
Wroclaw, Poland, 50-367
Spain
Research Site Not yet recruiting
Barcelona, Spain, 08035
Research Site Not yet recruiting
Madrid, Spain, 28040
Research Site Not yet recruiting
Palma de mallorca, Spain, 07120
United Kingdom
Research Site Not yet recruiting
Glasgow, United Kingdom, G12 0YN
Research Site Recruiting
Plymouth, United Kingdom, PL6 8DH
Research Site Not yet recruiting
Sutton, United Kingdom, SM2 5PT
Sponsors and Collaborators
AstraZeneca
Parexel
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04630756    
Other Study ID Numbers: D8230C00002
First Posted: November 16, 2020    Key Record Dates
Last Update Posted: September 10, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame:

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Access Criteria:

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
AZD4573
Anti-cancer Agents
Sequential dose-setting and expansion treatment
Additional relevant MeSH terms:
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Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Hematologic Diseases
Acalabrutinib
Antineoplastic Agents