Clinical Trials /

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

NCT04630756

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

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

DrugSynonymsArms
AZD4573AZ13810325AZD4573: Cohorts 1, 2, and 3
AcalabrutinibACP-196 /CalquenceAZD4573: 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

NameTypeDescriptionInterventions
AZD4573: Cohorts 1, 2, and 3ExperimentalEach 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.
  • AZD4573
  • Acalabrutinib

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

November 16, 2020