A Modular Phase I/II, Open-label, Multicentre Study to Evaluate the Safety, Tolerability, and Efficacy of AZD3470, a PRMT5 Inhibitor, as Monotherapy or in Combination With Anticancer Agent(s) in Participants With Haematologic Malignancies
Summary
This study is designed to evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy following oral administration of AZD3470 as a monotherapy, and in combination with other anticancer agents in participants with haematologic malignancies.
Detailed description
This is a modular, Phase I/II, open-label, multicentre study of AZD3470 in participants with haematologic malignancies. The study consists of several study modules, each evaluating the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of orally administered AZD3470 as a monotherapy and in combination with other anticancer agent(s). Module 1 Cohort 1 will evaluate AZD3470 monotherapy in adults and adolescents with r/r cHL who have received at least 2 prior lines of anticancer therapy. Part A (dose escalation) will assess AZD3470 at increasing doses to determine Maximum Tolerated Dose and Recommended Dose for Expansion in participants aged 18 years or older. Part B (dose optimization/expansion) will include participants to selected dose levels that were evaluated in Part A to support the recommended phase II dose (RP2D). Safety, tolerability, PK, preliminary efficacy, and food effect will be assessed. Adolescent participants (aged 12 years and older) will only be enrolled in Part B once sufficient supportive adult safety/PK data is reviewed and agreed upon with Safety Review Committee. Module 1 Cohort 2 will evaluate AZD3470 monotherapy as a consolidation therapy in advanced stage (Stage III/IV) cHL participants aged 50 years or older, who have achieved a response (CR or PR) after at least 4 cycles of frontline standard of care therapy. Safety and tolerability, PK, Pharmacodynamics and preliminary efficacy will be evaluated. Module 1 Cohort 3 will evaluate AZD3470 monotherapy in participants with r/r PTCL (PTCL NOS, ALCL, AITL) aged 18 years or older, who have received at least one prior anticancer therapy. Safety and tolerability, PK, Pharmacodynamics, and preliminary efficacy will be evaluated. Module 2 Cohort 1 will evaluate AZD3470 in combination with pembrolizumab in r/r cHL participants aged 18 years or older, who have received at least one prior anticancer therapy. Part A (dose escalation) will include participants at select dose levels below or at the highest tolerable monotherapy dose in Module 1 Cohort 1. Part B (dose optimization/expansion) will include participants to selected dose levels that were evaluated in Part A to support the recommended combination phase II dose (RP2D). Safety, tolerability, PK, Pharmacodynamics and preliminary efficacy, will be evaluated. The protocol may be amended in the future to incorporate additional cohorts in combination with pembrolizumab or new modules evaluating AZD3470 in combination with other anticancer agents in haematologic malignancies.
Arms & interventions
- DrugAZD3470
AZD3470 is a novel, potent and selective, second-generation, Methylthioadenosine (MTA)-selective, small molecule inhibitor of PRMT5.
- DrugPembrolizumab
Pembrolizumab (CAS nr: 1374853-91-4 )
Outcome measures
Primary
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
AEs: Number of patients with adverse events by system organ class and preferred term. SAEs: Number of patients with serious adverse events by system organ class and preferred term.
Time frame: From Screening continuously until 28 days after the last dose of study medication.
Incidence of DLTs (Dose Escalation Cohorts only)
In the Dose Escalation cohorts in Part A, the number of participants with at least 1 dose-limiting toxicity (DLT), which is any toxicity defined as a DLT in the Clinical Study Protocol.
Time frame: From first dose of AZD3470 to end of Cycle 1 (each cycle is 21 days).
Secondary
Response endpoints as assessed by the investigator according to the Lugano Classification: Objective Response Rate (ORR)/Complete Response Rate (CRR)
Time frame: From first dose (Cycle 1 Day 1, each cycle is 21 days) until disease progression or the last evaluable assessment in the absence of progression.
Response Endpoints as assessed by investigator according to the Lugano Classification: Conversation rate of Partial Response (PR) to Complete Response (CR)
Time frame: From First dose (Cycle 1 Day 1, each cycle is 21 days) until disease progression or the last evaluable assessment in the absence of progression.
Response endpoints as assessed by the investigator according to the Lugano Classification: Duration of Response (DoR)
Time frame: From date of first objective response until documented progression or death due to any cause or censoring (if progression or death have not occurred)
Response endpoints as assessed by the investigator according to the Lugano Classification for CHL: The rate of durable CR
Time frame: From date of first complete response until documented progression or death due to any cause or censoring (if progression or death have not occurred)
Response Endpoints as assessed by the investigator according to the Lugano Classification: Progression-free Survival (PFS)
Time frame: From first dose (each cycle is 21 days)/from randomisation (for non-randomized & randomized study parts respectively) until disease progression or death, or censoring (if progression or death have not occurred) whichever is first
Response Endpoints as assessed by the investigator according to the Lugano Classification: Overall Survival (OS)
Time frame: From first dose (each cycle is 21 days)/from randomisation (for non-randomized & randomized study parts respectively) until disease progression or death, or censoring (if progression or death have not occurred) whichever is first
Measurement of Plasma PK parameters: AUC, Cmax, tmax, Ctrough, t1/2 λz, CL/F, and Vz/F
Time frame: From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period.
Measurement of Plasma PK parameters under fed or fasted conditions: Ratio of Cmax, Tmax, and AUCtau
Time frame: From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days).
Urine PK parameters including Cumulative percentage of unchanged drug in urine (Ae,tau) during dosing interval and renal clearance
Time frame: From Cycle 1 Day 1 to end of Cycle 1 at predefined intervals throughout the cycle (each cycle is 21 days).
Percentage change from baseline tumour SDMA mesaured by IHC.
Time frame: From Screening to EoT, at predefined intervals throughout the treatment period.
Eligibility criteria
Study locations (7)
Research Site
Duarte, California, 91010
Research Site
Miami, Florida, 33136
Research Site
Atlanta, Georgia, 30322
Research Site
Boston, Massachusetts, 02215
Research Site
New York, New York, 10016
Research Site
Philadelphia, Pennsylvania, 19104
Research Site
Houston, Texas, 77030