Newly Diagnosed Multiple Myeloma
Conditions
Keywords
Newly Diagnosed Multiple Myeloma (NDMM), Multiple Myeloma, AZD0120, Cell Therapy, CAR-T, DURGA-5, BCMA, CD19, ASCT ineligible, Transplant ineligible
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.
Interventions
BIOLOGICALAZD0120
AZD0120, is a BCMA/CD19 dual CAR T-cell product, which is administered intravenously.
BIOLOGICALDaratumumab
Induction, optional bridging and continuous therapy.
DRUGDexamethasone
Induction, optional bridging and continuous therapy.
BIOLOGICALIsatuximab
Induction, optional bridging and continuous therapy.
DRUGLenalidomide
Induction, optional bridging and continuous therapy.
DRUGBortezomib
Induction therapy.
DRUGCyclophosphamide
Lymphodepletion
DRUGFludarabine
Lymphodepletion
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a randomised, multicentre, controlled, open-label, Phase III global study comparing the efficacy and safety of AZD0120 versus standard regimens (IsaVRd and DRd) in participants with NDMM who are ineligible to receive ASCT as initial therapy.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants must be 18 years or older, at the time of signing the ICF. 2. Participant must have documented diagnosis of MM according to the IMWG diagnostic criteria. 3. 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. 4. Participant must be deemed ineligible for ASCT while also having adequate organ function for CAR-T cell treatment. 5. Participant is a candidate to receive at least one of the regimens (IsaVRd or DRd) as determined by the Investigator. 6. ECOG performance status Grade of 0 to 2. 7. Participant must have adequate organ and bone marrow function.
Exclusion criteria
1. Participant has active or prior CNS or meningeal involvement of MM. 2. Participant has primary amyloidosis, active plasma cell leukemia (≥5% circulating plasma cells), Waldenström macroglobulinemia, or POEMS syndrome. 3. Participant has significant neurological or psychiatric condition posing risk or impairing evaluation. 4. Participant has any other significant medical condition that increases unacceptable risk, interferes with therapy delivery, or confounds evaluation. 5. 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. 6. Participant has a history of haematologic malignancies, other than MM, regardless of remission status. 7. Participant is positive for any of the following: 1. HIV: Known to be seropositive for HIV (including any history of HIV). 2. Chronic or active hepatitis B. 3. Active hepatitis C: Hepatitis C infection. 4. Additional local requirements for the testing for infectious diseases and exclusions of applicable participants should be followed per local regulations. 8. Participant has clinically significant cardiovascular disease. 9. Participant has COPD with an FEV1 \< 50% of predicted normal. 10. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | Up to 9 years. | The proportion of participants who achieved CR or better according to IMWG 2016 criteria, as assessed by BICR |
| Overall Survival | Up to 9 years. | Time from randomisation until date of death due to any cause |
| Number and percentage of participants with adverse events as graded by CTCAE v6 and ASTCT Consensus Grading criteria | Up to 9 years. | Adverse Event Incidence |
| Concentration of Circulating CAR-T+ Cells in Peripheral Blood | Up to 9 years. | Quantification of circulating CAR-T+ cell levels by measuring CAR transgene in peripheral blood and CK parameters of AZD0120 will be measured to characterise the cellular kinetics of AZD0120 in blood. |
| Number and percentage of participants with incidence of ADAs against AZD0120 | Up to 9 years. | Assessment humoral immunogenicity of AZ0120 based on incidence of ADAs. |
| Patient Reported Outcomes | Up to 9 years. | Change from baseline in bone pain severity measured by the European Organisation for Research and Treatment of Cancer Item Library 469 single bone pain item (EORTC IL469 - score range 0 - 100, with higher scores indicating worse bone pain) in participants with newly diagnosed multiple myeloma ineligible for autologous stem cell transplantation as initial therapy. |
| Overall Response Rate | Up to 9 years | Proportion of participants who achieved PR or better according to IMWG 2016 criteria |
| Duration of Response | Up to 9 years | Time from first documented confirmed response (PR or better) until date of documented PD per IMWG 2016 criteria or death due to any cause, whichever occurs first. |
| Time to Response | Up to 9 years | Time from randomisation until the date of first documented objective response (PR or better), as assessed per IMWG 2016 criteria. |
| MRD negative CR rate | Up to 9 years | Proportion of participants who have MRD negative status and have a response of CR or sCR (according to the IMWG 2016 criteria) at any time after the date of randomisation and before initiation of subsequent therapy. |
| Rate of sustained MRD negative CR | Up to 9 years | Proportion of participants who have achieved MRD negative status and have a response of CR or sCR |
| Progression Free Survival 2 (PFS2) | Up to 9 years | Time from randomisation to progression on next line of therapy, as assessed by Investigator, or death due to any cause, whichever occurs first |
Countries
Australia, Brazil, Canada, Denmark, France, Germany, Italy, Japan, Poland, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
STUDY_DIRECTORJen Brudno, MD
AstraZeneca
Outcome results
None listed