Phase III Open-Label, Randomised Study of Consolidation With AZD0120 (Dual-Targeting BCMA/CD19 CAR-T) vs Continuous Standard Therapy in NDMM Patients Ineligible for ASCT as Initial Therapy (DURGA-5)
Trial Snapshot
- Phase
- Phase 3
- Status
- Recruiting
- Sponsor
- AstraZeneca
- Enrollment
- 750
- Locations
- 124
- Primary Endpoint
- PFS in NDMM who are ineligible to receive ASCT is measured to demonstrate the superiority of IsaVRd or DRd induction followed by AZD0120 compared to IsaVRd or DRd induction followed by continuous DRd or IsaRd.
Study Overview
Brief Summary
This is a randomised, multicentre, controlled, open-label, Phase III global study comparing the efficacy and safety of standard induction regimens (IsaVRd and DRd) followed by AZD0120 versus standard induction regimens followed by continuous therapy (IsaRd and DRd) in participants with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT) as initial therapy.
Detailed Description
The primary objective is to demonstrate the superiority of IsaVRd or DRd induction followed by a single administration of AZD0120 compared to IsaVRd or DRd induction followed by continuous IsaRd or DRd in terms of progression-free survival (PFS) according to IMWG 2016 criteria, and as assessed by Blinded Independent Central Review (BICR) and miminal residual disease (MRD) negative complete response (CR) rate at 9 months post-randomisation in participants with NDMM who are ineligible to receive ASCT as initial therapy.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participants must be 18 years or older, at the time of signing the ICF.
- •Participant must have documented diagnosis of MM according to the IMWG diagnostic criteria.
- •Participant must have one or more of the following measurable disease criteria: (a) Serum M-protein level ≥1.0 g/dL, (b) Urine M-protein level ≥ 200 mg/24 h, (c)Serum immunoglobulin FLC ≥ 10 mg/dL (100 mg/L) and abnormal serum immunoglobulin kappa lambda FLC ratio.
- •Participant must be deemed ineligible for ASCT while also having adequate organ function for CAR-T cell treatment.
- •Participant is a candidate to receive at least one of the regimens (IsaVRd or DRd) as determined by the Investigator.
- •ECOG performance status Grade of 0 to
- •Participant must have adequate organ and bone marrow function.
Exclusion Criteria
- •Participant has active or prior CNS or meningeal involvement of MM.
- •Participant has primary amyloidosis, active plasma cell leukemia (≥5% circulating plasma cells), Waldenström macroglobulinemia, or POEMS syndrome.
- •Participant has significant neurological or psychiatric condition posing risk or impairing evaluation.
- •Participant has any other significant medical condition that increases unacceptable risk, interferes with therapy delivery, or confounds evaluation.
- •Participant has a history of a prior non-haematologic malignancy unless the participant has been disease-free with no evidence of recurrence for ≥ 2 years.
- •Participant has a history of haematologic malignancies, other than MM, regardless of remission status.
- •Participant is positive for any of the following:
- •HIV: Known to be seropositive for HIV (including any history of HIV).
- •Chronic or active hepatitis B.
- •Active hepatitis C: Hepatitis C infection.
- •Additional local requirements for the testing for infectious diseases and exclusions of applicable participants should be followed per local regulations.
- •Participant has clinically significant cardiovascular disease.
- •Participant has COPD with an FEV1 < 50% of predicted normal.
- •Additional exclusion for participants who are planned to receive IsaVRd as induction: Participant has peripheral neuropathy Grade 4, Grade 3, Grade 2, or Grade 1 with pain.
Arms & Interventions
Arm B: Control Arm
Arm B is the standard therapy induction with IsaVRd or DRd, followed by continuous IsaRd or DRd until disease progression or intolerable toxicity.
Intervention: Lenalidomide (Drug)
Arm A: Investigational Arm
Arm A is the sequence of induction with IsaVRd or DRd, apheresis, optional bridging therapy, lymphodepletion (cyclophosphamide and fludarabine), and AZD0120.
Intervention: AZD0120 (Biological)
Arm B: Control Arm
Arm B is the standard therapy induction with IsaVRd or DRd, followed by continuous IsaRd or DRd until disease progression or intolerable toxicity.
Intervention: Dexamethasone (Drug)
Arm A: Investigational Arm
Arm A is the sequence of induction with IsaVRd or DRd, apheresis, optional bridging therapy, lymphodepletion (cyclophosphamide and fludarabine), and AZD0120.
Intervention: Dexamethasone (Drug)
Arm B: Control Arm
Arm B is the standard therapy induction with IsaVRd or DRd, followed by continuous IsaRd or DRd until disease progression or intolerable toxicity.
Intervention: Daratumumab (Biological)
Arm A: Investigational Arm
Arm A is the sequence of induction with IsaVRd or DRd, apheresis, optional bridging therapy, lymphodepletion (cyclophosphamide and fludarabine), and AZD0120.
Intervention: Daratumumab (Biological)
Arm A: Investigational Arm
Arm A is the sequence of induction with IsaVRd or DRd, apheresis, optional bridging therapy, lymphodepletion (cyclophosphamide and fludarabine), and AZD0120.
Intervention: Isatuximab (Biological)
Arm A: Investigational Arm
Arm A is the sequence of induction with IsaVRd or DRd, apheresis, optional bridging therapy, lymphodepletion (cyclophosphamide and fludarabine), and AZD0120.
Intervention: Cyclophosphamide (Drug)
Arm B: Control Arm
Arm B is the standard therapy induction with IsaVRd or DRd, followed by continuous IsaRd or DRd until disease progression or intolerable toxicity.
Intervention: Bortezomib (Drug)
Arm A: Investigational Arm
Arm A is the sequence of induction with IsaVRd or DRd, apheresis, optional bridging therapy, lymphodepletion (cyclophosphamide and fludarabine), and AZD0120.
Intervention: Bortezomib (Drug)
Arm A: Investigational Arm
Arm A is the sequence of induction with IsaVRd or DRd, apheresis, optional bridging therapy, lymphodepletion (cyclophosphamide and fludarabine), and AZD0120.
Intervention: Lenalidomide (Drug)
Arm A: Investigational Arm
Arm A is the sequence of induction with IsaVRd or DRd, apheresis, optional bridging therapy, lymphodepletion (cyclophosphamide and fludarabine), and AZD0120.
Intervention: Fludarabine (Drug)
Arm B: Control Arm
Arm B is the standard therapy induction with IsaVRd or DRd, followed by continuous IsaRd or DRd until disease progression or intolerable toxicity.
Intervention: Isatuximab (Biological)
Outcomes
Primary Outcomes
PFS in NDMM who are ineligible to receive ASCT is measured to demonstrate the superiority of IsaVRd or DRd induction followed by AZD0120 compared to IsaVRd or DRd induction followed by continuous DRd or IsaRd.
Time Frame: Up to 9 years.
PFS: defined as time from randomisation until progression according to IMWG 2016 criteria as assessed by BICR, or death due to any cause, whichever occurs first.
MRD negative CR rate at 9M in NDMM who are ineligible to receive ASCT is measured to demonstrate the superiority of IsaVRd or DRd induction followed by AZD0120 compared to IsaVRd or DRd induction followed by continuous DRd or IsaRd
Time Frame: Up to 9 years.
MRD negative CR rate at 9 months: defined as the proportion of participants with MRD negative status (at threshold of 10-5) and have a response of CR or sCR (according to the IMWG 2016 criteria) as assessed by BICR at 9 months (± 3 months) from randomisation before initiation of subsequent anti-myeloma therapy.
Secondary Outcomes
- Complete Response Rate(Up to 9 years.)
- Overall Survival(Up to 9 years.)
- Number and percentage of participants with adverse events as graded by CTCAE v6 and ASTCT Consensus Grading criteria(Up to 9 years.)
- Concentration of Circulating CAR-T+ Cells in Peripheral Blood(Up to 9 years.)
- Number and percentage of participants with incidence of ADAs against AZD0120(Up to 9 years.)
- Patient Reported Outcomes(Up to 9 years.)
- Overall Response Rate(Up to 9 years)
- Duration of Response(Up to 9 years)
- Time to Response(Up to 9 years)
- MRD negative CR rate(Up to 9 years)
- Rate of sustained MRD negative CR(Up to 9 years)
- Progression Free Survival 2 (PFS2)(Up to 9 years)