A Modular, Phase I/II, Multicentre Study to Evaluate AZD4045, in Participants With Relapsed or Refractory Multiple Myeloma

Official title

A Modular, Phase I/II, Open-label, Multicentre Study to Evaluate the Safety, Tolerability, Cellular Kinetics, and Efficacy of AZD4045, an Allogeneic Chimeric Antigen Receptor-T Cell (CAR-T) Therapy Targeting B Cell Maturation Antigen (BCMA) in Participants With Relapsed or Refractory Multiple Myeloma

Overview

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

• Biological AZD4045
  Allogeneic Chimeric Antigen Receptor T cell (CAR-T) Therapy Targeting B Cell Maturation Antigen (BCMA)
• Drug Daratumumab
  Anti-CD38 monoclonal antibody
• Drug Aldesleukin
  Recombinant human IL-2

Primary outcome measures

• Adverse events (AEs) and serious AEs (SAEs) [Time frame: Through study completion, an average of 2 years]
• Dose-limiting toxicities (DLT) [Time frame: 28 days]

Secondary outcome measures (11)

• Efficacy - Objective Response Rate (ORR) [Time frame: Through study completion, an average of 2 years]
• Efficacy - Complete Response Rate (CRR) [Time frame: Through study completion, an average of 2 years]
• Efficacy - Duration of Response (DOR) [Time frame: Through study completion, an average of 2 years]
• Efficacy - Time to Response (TTR) [Time frame: Through study completion, an average of 2 years]
• Cellular kinetics - Quantification of CAR transgene levels [Time frame: Through study completion, an average of 2 years]
• Cellular kinetics - Tmax [Time frame: Through study completion, an average of 2 years]
• Cellular kinetics - Cmax [Time frame: Through study completion, an average of 2 years]
• Cellular kinetics - AUC0-28d [Time frame: 0 - 28 days]
• Cellular kinetics - Tlast [Time frame: Through study completion, an average of 2 years]
• Cellular kinetics - Clast [Time frame: Through study completion, an average of 2 years]
• Cellular kinetics - AUClast [Time frame: Through study completion, an average of 2 years]

Eligibility criteria

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:

• HIV (with exceptions)
• Chronic or active hepatitis B
• Active hepatitis C
• Participant has clinically significant cardiovascular disease, including but not limited to:

• Myocardial infarction within 6 months prior to eligibility confirmation, or an unstable or uncontrolled disease/condition related to or affecting cardiac function.
• Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities.
• Congestive heart failure Class III or IV.
• 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:

• Serious active or uncontrolled infection.
• Requirement of supplemental oxygen to maintain oxygen saturation.
• Active autoimmune disease or a history of autoimmune disease within 2 years.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 10 centers

• Research Site — Duarte
• Research Site — Denver
• Research Site — Tampa
• Research Site — Atlanta
• Research Site — St Louis
• Research Site — Hackensack
• Research Site — Cleveland
• Research Site — Nashville
• … and 2 more centers

Australia · 2 centers

• Research Site — Camperdown
• Research Site — East Melbourne

Identifiers

NCT: NCT07681596 · D7540C00001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗