Relapsed or Refractory Multiple Myeloma
Conditions
Keywords
Multiple myeloma, Relapsed or refractory multiple myeloma, RRMM, Relapsed multiple myeloma, Refractory multiple myeloma, AZD4045, CAR-T, CART, Allogeneic
Brief summary
The purpose of this study is to assess the safety, tolerability, preliminary efficacy, cellular kinetics, and other exploratory endpoints of AZD4045 as a monotherapy and in association with daratumumab and aldesleukin for the treatment of adult participants with RRMM.
Detailed description
This modular study aims to evaluate the safety, tolerability, preliminary efficacy, and cellular kinetics of AZD4045 in participants with relapsed or refractory multiple myeloma (RRMM), and determine the recommended Phase 2 dose of AZD4045. Module 1 consists of AZD4045 as a monotherapy and in association with daratumumab and aldesleukin.
Interventions
BIOLOGICALAZD4045
Allogeneic Chimeric Antigen Receptor T cell (CAR-T) Therapy Targeting B Cell Maturation Antigen (BCMA)
DRUGDaratumumab
Anti-CD38 monoclonal antibody
DRUGAldesleukin
Recombinant human IL-2
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must be 18 years or older at the time of signing the informed consent form. * Participants must have documented diagnosis of MM according to the IMWG diagnostic criteria. * Participant must have one or more of the following measurable disease criteria: * Serum M-protein level ≥ 1.0 g/dL. * Urine M-protein ≥ 200 mg/24 h. * Serum immunoglobulin free light chain ≥ 10 mg/dL (100 mg/L) and abnormal serum immunoglobulin kappa lambda free light chain ratio. * ECOG performance score of 0 to 1. * Participant must have screening bone marrow aspirate and/or archival sample adequate for clonal sequence calibration for MRD. An archival sample obtained from any time prior is acceptable. * Participant must have adequate organ and bone marrow function. * Participant must have received at least 3 prior classes of therapy, including a PI, an IMiD, and an anti-CD38 antibody * Participant must have documented evidence of PD by IMWG 2016 criteria based on Investigator's determination during or after the most recent line of therapy
Exclusion criteria
* Participant has a history of any grade IEC-HS and/or history of Grade ≥ 3 CRS and/or Grade ≥ 2 neurotoxicities during prior CAR-T cell therapy or T cell engaging therapy. * Participant has ongoing toxicity from previous anti-cancer therapy that did not resolve to baseline levels or to Grade ≤ 1 with the exception of alopecia or peripheral neuropathy. * Participant has a known active, or prior history of CNS involvement or exhibits clinical signs of meningeal involvement of MM. * Participant has systemic immunoglobulin light chain amyloidosis, active plasma cell leukaemia (presence of ≥ 5% of circulating plasma cells on a conventional peripheral blood smear) at time of screening, Waldenstrom macroglobulinemia or Polyneuropathy Organomegaly Endocrinopathy M-protein and Skin (POEMS) syndrome. * Participant has a history of haematologic malignancies, other than MM, regardless of remission status. * 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 significant neurological or psychiatric condition (active or history of). * Participant is positive for any of the following: 1. HIV (with exceptions) 2. Chronic or active hepatitis B 3. Active hepatitis C * Participant has clinically significant cardiovascular disease, including but not limited to: 1. Myocardial infarction within 6 months prior to eligibility confirmation, or an unstable or uncontrolled disease/condition related to or affecting cardiac function. 2. Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities. 3. Congestive heart failure Class III or IV. 4. Impaired cardiac function (LVEF \< 45%). * Participant has any other significant medical condition which, in the opinion of the Investigator, places the participant at an unacceptable risk for treatment-related complications, could interfere with the successful or safe delivery of therapy, or could interfere with evaluation of study intervention or interpretation of participant safety or study results. These include but are not limited to: 1. Serious active or uncontrolled infection. 2. Requirement of supplemental oxygen to maintain oxygen saturation. 3. Active autoimmune disease or a history of autoimmune disease within 2 years. 4. Inflammatory bowel disease requiring treatment within the past 5 years or other clinically significant gastrointestinal condition. * Participant received live, attenuated vaccine within 28 days prior to eligibility confirmation * Participant has undergone major surgery within 28 days prior to eligibility confirmation * Concurrent enrolment in another clinical study (unless the study is observational, or the participant is in the follow-up period of an interventional study). * Participant has a known life-threatening allergy, hypersensitivity, intolerance, or a contraindication to any study intervention or their excipients. * Participant received any prior CAR-T or CAR-NK therapy directed at any target within 6 months prior to eligibility confirmation. * Participant received any prior TCE therapy directed at any target within 6 months prior to eligibility confirmation. * Participant received any prior BCMA-targeted treatment within 6 months prior to eligibility confirmation. * Participant with a history of refractoriness to the most recent BCMA-targeted treatment received as defined as PD on or within 60 days of last dose or non-responsiveness (ie, did not achieve at least minimal response) on therapy. * Participant received prior allogeneic stem cell transplant at any time. * Participant received autologous stem cell transplant within 3 months prior to eligibility confirmation. * Participant received radiation therapy for treatment of plasmacytoma within 14 days before eligibility confirmation. * Participant received prior anti-tumour therapy as follows prior to the first dose of lymphodepletion: a) Within 7 days: * Immunomodulatory or cereblon E3 ligase modulatory drugs. b) Within 14 days: * PI therapy. * Monoclonal antibody treatment for MM. * Cytotoxic therapy. * Other systemic anti-myeloma therapy. * Radiation. c) Within 14 days or at least 5 half-lives, whichever is longer: * Targeted therapy, epigenetic therapy, investigational drug or used an invasive investigational medical device.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events (AEs) and serious AEs (SAEs) | Through study completion, an average of 2 years | Incidence and severity of adverse events (AEs) and serious AEs (SAEs) |
| Dose-limiting toxicities (DLT) | 28 days | Incidence and severity of dose-limiting toxicity (DLT) events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cellular kinetics - Tlast | Through study completion, an average of 2 years | Time to last quantifiable concentration of AZD4045 level |
| Efficacy - Objective Response Rate (ORR) | Through study completion, an average of 2 years | Defined as proportion of participants who achieve an overall response of PR or better according to the IMWG 2016 criteria |
| Efficacy - Complete Response Rate (CRR) | Through study completion, an average of 2 years | Defined as proportion of participants who achieve a CR/sCR response according to the to the IMWG 2016 criteria |
| Efficacy - Duration of Response (DOR) | Through study completion, an average of 2 years | Defined as the time from first documented confirmed response until date of documented PD per IMWG 2016 criteria or death due to any cause, whichever occurs first |
| Efficacy - Time to Response (TTR) | Through study completion, an average of 2 years | Defined as the time from infusion until the date of first documented objective response, as assessed per IMWG 2016 criteria |
| Cellular kinetics - Quantification of CAR transgene levels | Through study completion, an average of 2 years | Determination of transgene level |
| Cellular kinetics - Tmax | Through study completion, an average of 2 years | Time to reach maximum AZD4045 level |
| Cellular kinetics - Cmax | Through study completion, an average of 2 years | Maximum AZD4045 level |
| Cellular kinetics - Clast | Through study completion, an average of 2 years | Observed concentration of AZD4045 at last quantifiable concentration |
| Cellular kinetics - AUC0-28d | 0 - 28 days | Area under the concentration time-curve of AZD4045 level |
| Cellular kinetics - AUClast | Through study completion, an average of 2 years | Area under the concentration time-curve of AZD4045 level |
Countries
Australia, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed