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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
161
AZD3470 is a novel, potent and selective, second-generation, Methylthioadenosine (MTA)-selective, small molecule inhibitor of PRMT5.
Pembrolizumab (CAS nr: 1374853-91-4 )
Research Site
Duarte, California, United States
NOT_YET_RECRUITINGResearch Site
Miami, Florida, United States
RECRUITINGResearch Site
Atlanta, Georgia, United States
WITHDRAWNResearch Site
Boston, Massachusetts, United States
RECRUITINGIncidence 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).
Response endpoints as assessed by the investigator according to the Lugano Classification: Objective Response Rate (ORR)/Complete Response Rate (CRR)
Applicable to Module 1 Cohort 1 and 3, and Module 2 Cohort 1: ORR is defined as the proportion of participants who have a CR or PR and CRR is defined as the proportion of participants who have a CR. Assessment of ORR/CRR will be done according to the Lugano Classification for cHL and PTCL
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)
Applicable to Module 1 Cohort 2: PR to CR conversion rate is defined as the proportion of participants who have a PR at baseline after induction therapy, who subsequently achieve a CR. PR and CR are assessed by investigators according to Lugano classification for lymphoma.
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)
Applicable to Module 1 Cohort 1 and Cohort 3 and Module 2 Cohort 1: For the patients who have achieved an objective response (CR or PR), the time from the date of first documented response until the date of documented progression as assessed by the investigator according to the Lugano classification for cHL and PTCL, or death due to any cause (in absence of disease progression).
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
Applicable to Module 2 Cohort 1: Rate of durable complete response is defined as the proportion of participants who have a CR with a duration according to CSP-defined timelines.
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)
Applicable to all cohorts: Time from date of first dose (non- randomised study parts) or date of randomization (randomised study parts) until progression as assessed by the investigator according to the Lugano Classification for cHL and PTCL, or death, due to any cause.
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)
Applicable to all cohorts: Time from date of first dose (non-randomised study parts) or date of randomization (randomised study parts) until the date of death due to any cause.
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
Applicable to all cohorts: Assessed to characterize the plasma PK profile of AZD3470.
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
Applicable to Module 1 Cohort 1 Part B: Preliminary food effect on plasma PK of AZD3470 administered as a monotherapy in participants enrolled in dose expansion.
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
Applicable to Module 1 Cohort 1 Part A: Assessed to characterize the urine PK profile of AZD3470.
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.
Applicable to Module 1 Cohort 3: To asses the inhibition of PRMT5 in tumour
Time frame: From Screening to EoT, at predefined intervals throughout the treatment period.
AstraZeneca Clinical Study Information Center
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Research Site
New York, New York, United States
NOT_YET_RECRUITINGResearch Site
Philadelphia, Pennsylvania, United States
RECRUITINGResearch Site
Houston, Texas, United States
RECRUITINGResearch Site
Adelaide, Australia
WITHDRAWNResearch Site
Birtinya, Australia
WITHDRAWNResearch Site
Fitzroy, Australia
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