Multiple Myeloma
Conditions
Keywords
GPRC5D, ADC, AZD0305, Multiple Myeloma, MM, MMAE
Brief summary
This is a Phase I/II, modular, open-label, multicenter, dose escalation, and dose expansion/optimization study to evaluate the safety, tolerability, PK, immunogenicity, pharmacodynamics and efficacy of AZD0305 as monotherapy and in combination with other anticancer agents in participants with MM.
Detailed description
This study will follow a modular protocol design evaluating AZD0305 as monotherapy and in combination with other anticancer agents. The protocol may be amended in the future to incorporate further monotherapy expansion at the recommended Phase 2 dose (RP2D) in Phase II, and/or additional modules investigating AZD0305 in combination with other anticancer agents. The study consists of 3 modules: * Module 1 (AZD0305 monotherapy), * Module 2 (AZD0305 in combination with elranatamab) * Module 3 (AZD0305 in combination with pomalidomide and dexamethasone \[Pd\])
Interventions
DRUGAZD0305
AZD0305 Investigational product
DRUGElranatamab
Module 2 Investigational product
DRUGPomalidomide
Module 3 Standard of Care (background treatment)
DRUGDexamethasone
Module 3 Standard of Care (background treatment)
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
No Masking
Intervention model description
This protocol has a modular design, with 3 treatment arms/modules. Module 1 will include Phase Ia (Dose escalation), and Phase Ib (Dose expansion/optimization). Module 2 will evaluate AZD0305 in combination with elranatamab at selected dose levels. Module 3 will evaluate AZD0305 in combination with pomalidomide and dexamethasone at selected dose levels.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Participants must be at least 18 years of age or the legal age of consent in the jurisdiction * in which the study is taking place; * Eastern Cooperative Oncology Group performance status of ≤ 2 in module 1, or 0 or 1 in modules 2 and 3; * Documentation of Multiple Myeloma (MM) as defined by International Myeloma Working Group (IMWG) Diagnostic Criteria for Multiple Myeloma. Site should ensure that Multiple Myeloma diagnosis is confirmed in accordance with the IMWG Diagnostic Criteria; * Participants must have one or more measurable disease criteria for Serum M-Protein, Urine M-protein, and Serum immunoglobulin free light chains as specified in the relevant module of the CSP; * Adequate organ and bone marrow function assessment at screening according to the hematological, hepatic, and renal parameters listed in the CSP as relevant to each module; * Participants must have received at least 3 prior lines of treatment in module 1, or 1-3 prior lines in modules 2 and 3, with additional module-specific requirements related to prior lines of therapy The above is a summary of key criteria, other inclusion criteria details may apply Key
Exclusion criteria
* Amyloidosis, plasma cell leukemia, Waldenstrom Macroglobulinemia, Polyneuropathy Organomegaly Endocrinopathy M-protein and Skin Syndrome, or Smoldering Multiple Myeloma (compliant with WHO criteria); * Participants exhibiting clinical signs of central nervous system involvement of MM; * Participants with known COPD, or previous history of ILD/pneumonitis; * Participants with known moderate or severe persistent asthma within the past 5 years, or uncontrolled asthma of any classification; * Participants who have severe cardiovascular disease which is not adequately controlled; * Participants who have a history of immunodeficiency disease; * Participants with peripheral neuropathy ≥ Grade 2; * Primary refractory MM; * Participants who have previously received anti-GPRC5D or MMAE-containing treatment; * Participants who have previously received allogenic stem cell transplant, or participant has received autologous stem cell transplant within 3 months before the first dose of study intervention; * Participants with a history of prior malignancy other than MM within 3 years prior to first dose of study intervention. some exceptions apply; * Participants with previous history of active JC virus infection resulting in PML; * Participants with a known hypersensitivity to AZD0305 or any of the excipients of the product or to any of the drugs included in the respective modules or who experienced Grade 3 or higher hypersensitivity to prior monoclonal antibody therapy; * Participants who have uncontrolled severe illness including but not limited to ongoing active infection requiring therapeutic antibiotics and/or other administration The above is a summary of key criteria, other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of dose-limiting toxicity (DLT), as defined in the protocol (Phase Ia dose escalation only) | From first dose of AZD0305 until the end of Cycle 1. Cycle 1 (the DLT assessment period is 21 days for Module 1 Group A and 28 days for Module 1 Group B, Module 2, and Module 3) | A DLT is any toxicity occuring from the first dose of AZD0305 up to and including the planned end of Cycle 1 (the DLT assessment period) that is assessed as unrelated to the disease or disease-related processes under investigation and which includes, any death not clearly due to the underlying disease or extraneous causes, pre-defined haematological and non-haematological toxicities |
| Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) | From time of Informed consent to 30 days post end of treatment | Number of patients with adverse events and serious adverse events by system organ class and preferred term |
| Frequency of dose modifications, dose delays, and treatment discontinuations due to AEs (Module 2 and Module 3) | From first dose of study treatment until End of treatment (EOT), assessed up to approximately 2 years (each cycle is 28 days) | Number and percentage of participants with dose modifications, dose delays, and permanent discontinuations due to adverse events (for AZD0305 and combination agent\[s\], as applicable), per protocol-defined dose modification rules. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ia: Objective Response Rate (ORR) | From first dose of AZD0305 to progressive disease or Initiation of subsequent MM therapy (approximately 2 years) | The percentage of patients with a confirmed investigator assessed sCR, CR, VGPR or PR according to IMWG criteria |
| Phase Ia: Duration of response (DoR) | From the first documented response to confirmed progressive disease or death (approximately 2 years) | The time from the date of first response until date of disease progression or death in the absence of disease progression |
| Phase Ia: Progression free Survival (PFS) | From first dose of AZD0305 to progressive disease or death in the absence of disease progression (approximately 2 years) | The time from first dose until IMWG defined disease progression or death |
| Phase Ia: Overall Survival (OS) | From first dose of AZD0305 to death (approximately 2 years) | The time from the date of the first dose of study treatment until death due to any cause |
| Phase Ia: Pharmacokinetics of AZD0305: Area Under the concentration-time curve (AUC) | From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years) | Area under the plasma concentration-time curve |
| Phase Ia: Pharmacokinetics of AZD0305: Maximum plasma concentration of the study drug (Cmax) | From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years) | Maximum observed plasma concentration of the study drug |
| Phase Ia: Pharmacokinetics of AZD0305: Time to maximum plasma concentration of the study drug (tmax) | From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years) | Time to maximum observed plasma concentration of the study drug |
| Phase Ia: Pharmacokinetics of AZD0305: Clearance | From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years) | A pharmacokinetic measurement of the volume of plasma from which the study drug is completely removed per unit time |
| Phase Ia: Pharmacokinetics of AZD0305: Terminal elimination half-life (t 1/2) | From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years) | Terminal elimination half-life |
| Phase Ia: Immunogenicity of AZD0305 | From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years) | The number and percentage of participants who develop ADAs |
| Phase Ia: Immunogenicity of elranatamab | From the first dose, at predefined intervals until Cycle 24 administration of elranatamab(approximately 2 years) | The number and percentage of participants who develop ADAs |
| Phase Ia: MRD negative CR rate | From first dose of AZD0305 to progressive disease or death in the absence of disease progression (approximately 2 years) | The percentage of patients who achieve a complete response (CR) and have minimal residual disease (MRD) negativity in bone marrow. |
| Phase Ib: Objective Response Rate (ORR) | From randomization/cohort assignment to progressive disease or Initiation of subsequent MM therapy (approximately 2 years) | The percentage of patients with a confirmed investigator assessed sCR, CR, VGPR or PR according to IMWG criteria |
| Phase Ib: Duration of response (DoR) | From randomization/cohort assignment to confirmed progressive disease or death (approximately 2 years) | The time from date of first response until date of disease progression or death in the absence of disease progression |
| Phase Ib: Progression free Survival (PFS) | From randomization/cohort assignment to progressive disease or death in the absence of disease progression (approximately 2 years) | The time from randomization until IMWG defined disease progression or death |
| Phase Ib: Overall Survival (OS) | From randomization/cohort assignment to death (approximately 2 years) | The time from randomization until death due to any cause |
| Phase Ib: Pharmacokinetics of AZD0305: Area Under the concentration-time curve (AUC) | From randomization/cohort assignment , at predefined intervals throughout the administration of AZD0305 (approximately 2 years) | Area under the plasma concentration-time curve |
| Phase Ib: Pharmacokinetics of AZD0305: Maximum plasma concentration of the study drug (Cmax) | From randomization/cohort assignment , at predefined intervals throughout the administration of AZD0305 (approximately 2 years) | Maximum observed plasma concentration of the study drug |
| Phase Ib: Pharmacokinetics of AZD0305: Time to maximum plasma concentration of the study drug (tmax) | From randomization/cohort assignment , at predefined intervals throughout the administration of AZD0305 (approximately 2 years) | Time to maximum observed plasma concentration of the study drug |
| Phase Ib: Pharmacokinetics of AZD0305: Clearance | From randomization/cohort assignment , at predefined intervals throughout the administration of AZD0305 (approximately 2 years | A pharmacokinetic measurement of the volume of plasma from which the study drug is completely removed per unit time |
| Phase Ib: Pharmacokinetics of AZD0305: Terminal elimination half-life (t 1/2) | From randomization/cohort assignment, at predefined intervals throughout the administration of AZD0305 (approximately 2 years) | Terminal elimination half-life |
| Phase Ib: Immunogenicity of AZD0305 | From randomization/cohort assignment, at predefined intervals throughout the administration of AZD0305 (approximately 2 years) | The number and percentage of participants who develop ADAs |
| Phase Ib: Immunogenicity of elranatamab | From the first dose, at predefined intervals until Cycle 24 administration of elranatamab(approximately 2 years) | The number and percentage of participants who develop ADAs |
| Phase 1b: MRD negative CR rate | From first dose of AZD0305 to progressive disease or death in the absence of disease progression (approximately 2 years) | The percentage of patients who achieve a complete response (CR) and have minimal residual disease (MRD) negativity in bone marrow. |
| Complete Response Rate (CRR) - Mod2&3 only | From first dose of combination treatment to progressive disease or initiation of subsequent multiple myeloma therapy (approximately 2 years) | Percentage of participants achieving a confirmed CR or sCR per IMWG criteria. |
| Pre-Dose Plasma Concentration of Elranatamab (pharmacokinetics - Module 2 only) | From the first dose of study intervention, at predefined intervals until Cycle 24 administration of elranatamab(approximately 2 years; 1 cycle = 28 days) | Pre-dose Plasma concentrations for elranatamab. |
Countries
Australia, Brazil, Canada, China, France, Germany, Japan, Spain, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed