Lymphoma, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, Peripheral T-cell Lymphoma (PTCL), PTCL-NOS, ALCL, AITL
Conditions
Keywords
Haematologic Malignancies, Hodgkin lymphoma, Peripheral T-cell lymphoma (PTCL), Methylthioadenosine Phosphorylase (MTAP) deficient, Protein Arginine Methyltransferase 5 (PRMT5)
Brief 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.
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 )
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Core Inclusion criteria: 1. Adequate adult (ECOG) or adolescent (Karnofsy or Lanksy) Performance Score assessments 2. Adequate organ and bone marrow function. Module 1 Cohort 1: 1. Age: 1. Part A (dose escalation): aged ≥ 18 years at the time of signing the informed consent. 2. Part B (optimization): aged ≥ 12 years of age. Adolescent participants must weigh ≥ 40 kg. 2. Histologically confirmed diagnosis of cHL based on WHO criteria 3. Previous treatment with at least 2 prior lines of therapy for the treatment of cHL (including at least 2 cycles of BV and anti-PD1) and have documented r/r active disease requiring treatment. 4. Participants must provide FFPE baseline tumour tissue. 5. At least 1 radiographically measurable, and/or FDG-avid lymphoma lesion ( \>1.5 cm for nodal lesion and \>1 cm for extranodal lesion). Module 1 Cohort 2: 1. Participants must be at least 50 years of age or older at study entry. 2. Histologically confirmed diagnosis of cHL based on WHO criteria 3. Ann Arbor stages III or IV. 4. Participant must have previously received at least 4 cycles of SoC combination therapy with A-AVD, N-AVD, AVD, or ABVD (based on regional SOC, per investigator) as finite first-line induction therapy, and achieved at least a PR post-induction therapy. 5. Participants must provide FFPE baseline tumour tissue. Module 1 Cohort 3: 1. Participants must be aged ≥ 18 years at the time of signing the informed consent. 2. Histologically confirmed diagnosis of PTCL NOS, systemic ALCL, or AITL based on WHO criteria. 3. Participants must have received at least 1 prior line of therapy for the treatment of PTCL and have exhausted all available therapies with demonstrated clinical benefit. Participants with ALCL must have received prior BV treatment. 4. Participants must provide FFPE baseline tumour tissue a. Ability to provide an on-treatment biopsy (if the tumour is suitable for biopsy). 5. At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (\> 1.5 cm for nodal lesion and \>1 cm for extranodal lesion). Module 2 Cohort 1: 1. Participants must be aged ≥ 18 years at the time of signing the informed consent. 2. Histologically confirmed diagnosis of cHL based on WHO criteria 3. At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (\> 1.5 cm for nodal lesion and \>1 cm for extranodal lesion). 4. Participant must have received at least 1 prior line of therapy for the treatment of cHL and have documented r/r active disease requiring treatment. 5. Participants must provide FFPE baseline tumour tissue.
Exclusion criteria
Core
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) | From Screening continuously until 28 days after the last dose of study medication. | 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. |
| Incidence of DLTs (Dose Escalation Cohorts only) | From first dose of AZD3470 to end of Cycle 1 (each cycle is 21 days). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response endpoints as assessed by the investigator according to the Lugano Classification: Objective Response Rate (ORR)/Complete Response Rate (CRR) | 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. | 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 |
| Response Endpoints as assessed by investigator according to the Lugano Classification: Conversation rate of Partial Response (PR) to Complete Response (CR) | 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. | 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. |
| Response endpoints as assessed by the investigator according to the Lugano Classification: Duration of Response (DoR) | From date of first objective response until documented progression or death due to any cause or censoring (if progression or death have not occurred) | 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). |
| Response endpoints as assessed by the investigator according to the Lugano Classification for CHL: The rate of durable CR | From date of first complete response until documented progression or death due to any cause or censoring (if progression or death have not occurred) | 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. |
| Response Endpoints as assessed by the investigator according to the Lugano Classification: Progression-free Survival (PFS) | 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 | 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. |
| Response Endpoints as assessed by the investigator according to the Lugano Classification: Overall Survival (OS) | 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 | 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. |
| Measurement of Plasma PK parameters: AUC, Cmax, tmax, Ctrough, t1/2 λz, CL/F, and Vz/F | From Cycle 1 Day 1 (each cycle is 21 days) to EoT, at predefined intervals throughout the treatment period. | Applicable to all cohorts: Assessed to characterize the plasma PK profile of AZD3470. |
| Measurement of Plasma PK parameters under fed or fasted conditions: Ratio of Cmax, Tmax, and AUCtau | From Cycle 1 Day 1 to Cycle 2 Day 1 at predefined intervals (each cycle is 21 days). | 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. |
| Urine PK parameters including Cumulative percentage of unchanged drug in urine (Ae,tau) during dosing interval and renal clearance | From Cycle 1 Day 1 to end of Cycle 1 at predefined intervals throughout the cycle (each cycle is 21 days). | Applicable to Module 1 Cohort 1 Part A: Assessed to characterize the urine PK profile of AZD3470. |
| Percentage change from baseline tumour SDMA mesaured by IHC. | From Screening to EoT, at predefined intervals throughout the treatment period. | Applicable to Module 1 Cohort 3: To asses the inhibition of PRMT5 in tumour |
Countries
Australia, China, France, Germany, Italy, Japan, South Korea, Spain, United Kingdom, United States
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed