A Phase I/II Study of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Advanced Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This study evaluates the safety, tolerability, PK, and preliminary efficacy of AZD0466 as monotherapy or in combination with other anticancer agents in patients with advanced NHL

Detailed Description
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This is a modular Phase I/II, open-label, dose escalation and expansion, multicentre Study. The study consists of individual modules, each evaluating the safety and tolerability of AZD0466 as monotherapy or with a specific combination treatment. The initial components are the core protocol, which contains information applicable to all modules, and Module 1. Module 1 will evaluate the safety, tolerability, PK, and preliminary efficacy of AZD0466 monotherapy and will include 2 parts. Part A dose escalation and Part B dose expansion cohorts. Part A will enrol patients with advanced B-NHL and once the RP2D has been determined, Part B may open to further explore the preliminary anticancer efficacy of AZD0466 monotherapy in patients with selected lymphoid malignancies. Part A: Phase 1 dose setting to assess the safety and tolerability and determine dose(s) and schedule(s) to be evaluated in Part B. Part B: Phase 1b/2a dose expansion to assess the efficacy of AZD0466 in 3 select patient populations: relapsed/refractory (R/R) mantle cell lymphoma (MCL) (Cohort B1), R/R follicular lymphoma (FL) or marginal zone lymphoma (MZL) (Cohort B2), and R/R diffuse large B-cell lymphoma (DLBCL) (Cohort B3).

Official Title
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A Modular Phase I/II, Open-label, Dose Escalation and Expansion, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of AZD0466 as Monotherapy or in Combination With Anticancer Agents in Patients With Advanced Non-Hodgkin Lymphoma.

Conditions
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Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: AZD0466


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria- Core Patient must be aged ≥ 18 years at the time of signing the informed consent. In some countries, parental consent may be required in addition to an assent form for patients who are 18 years of age. Patient must have histologically documented diagnosis of B-cell non-Hodgkin lymphoma (B-NHL) as defined by a B-cell neoplasm in the World Health Organisation classification scheme except as noted in the exclusion criteria. Patient has relapsed after or failed to respond to at least 2 but no more than 5 prior systemic treatment regimens (including investigational therapy) and for whom there is no available therapy expected to improve survival (eg, standard chemotherapy, autologous stem cell transplantation (SCT), chimeric antigen receptor T cell (CAR-T) cell therapy). Documented active disease requiring treatment that is relapsed or refractory defined as: Recurrence/relapse of disease after response to prior line(s) of therapy. Progressive disease (refractory) on/after completion of the treatment regimen preceding entry into the study. Must have at least one measurable, fluorodeoxyglucose positron emission tomography (FDG-PET) avid lesion (except for MZL), based on bi-dimensional assessment on PET and computed tomography (CT)/magnetic resonance imaging (MRI) scan. A measurable lesion is defined as: For nodal lesions: longest diameter > 1.5 cm For extranodal lesions: longest diameter > 1 cm Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2. Performance status must not have deteriorated by ≥ 2 levels within 2 weeks after providing informed consent. Adequate haematologic, hepatic, and renal function Adequate cardiac function as demonstrated by left ventricular ejection fraction > 50% on screening cardiac multigated acquisition, magnetic resonance imaging, or echocardiogram. Women of childbearing potential and men should use protocol defined contraceptive measures. Willing and able to participate in all required study evaluations and procedures including receiving IV administration of study intervention and admission to the hospital, when required, for administration of study treatment and monitoring. All patients must be willing to undergo an incisional or excisional lymph node or tissue biopsy or to provide a lymph node or tissue biopsy from the most recent available archival tissue. For inclusion in the genetic component of the study, patients must fulfil protocol defined criteria. Inclusion Criteria- Module 1 Additional Inclusion Criteria for Cohort B1 (R/R mantle cell lymphoma [MCL]): Histologically confirmed MCL, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1, as assessed by Investigator or local pathologist. Must have relapsed after or failed to respond to at least 2 prior lines of treatment, including one anti-CD20 monoclonal antibody (mAb) and a Bruton's tyrosine kinase inhibitor. Additional Inclusion Criteria for Cohort B2 (R/R FL or MZL): Histologically confirmed diagnosis of FL Grade 1, 2, or 3a OR histologically confirmed MZL including splenic, nodal, and extranodal subtypes, as assessed by Investigator or local pathologist. For FL patients: Previously received at least 2 prior systemic treatment regimens (including anti-CD20 mAb and an alkylating agent). For MZL patients: Previously received at least 2 prior lines of systemic therapy including at least one anti-CD20 mAb-directed regimen either as monotherapy or as chemoimmunotherapy (Helicobacter pylori eradication and radiation therapy alone will not be considered a systemic treatment regimen). Additional Inclusion Criteria for Cohort B3 (R/R DLBCL): Histologically confirmed DLBCL (including transformed FL) OR FL Grade 3b. Must have received 2 lines of systemic therapy including at least one anti-CD20 mAb-directed regimen and must have failed or are ineligible for stem cell transplantation (if indicated per local institutional guidelines). Exclusion Criteria- Core Diagnosis of post-transplant lymphoproliferative disease, Richter's transformation, Burkitt's lymphoma, Burkitt-like lymphoma, lymphoblastic lymphoma/leukaemia, chronic lymphocytic leukaemia, small lymphocytic lymphoma. High risk of TLS according to Howard modification of Cairo-Bishop criteria and/or the presence of bulky disease. Unresolved toxicity from prior anticancer therapy. Patients with Grade 2 neuropathy or Grade 2 alopecia are eligible. Active idiopathic thrombocytopenic purpura. Active central nervous system (CNS) involvement by lymphoma, leptomeningeal disease or spinal cord compression. Known history of infection with human immunodeficiency virus. Known serologic status reflecting active hepatitis B or C infection; concurrent infection with cytomegalovirus (CMV). Patients must be tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and those with active infection in accordance with local testing guidelines will be excluded. Any evidence of severe or uncontrolled systemic diseases; current unstable or uncompensated respiratory or cardiac conditions; uncontrolled hypertension; history of, or active, bleeding diatheses; uncontrolled active systemic fungal, bacterial, or other infection. Any of the following cardiac criteria at screening: patients with a history of myocarditis within one year of study entry, or heart failure; mean resting corrected QT interval (QTcF) ≥ 470 msec obtained from 3 electrocardiograms (ECGs), in the absence of a cardiac pacemaker; any factors that increase the risk of QTc prolongation or risk of arrhythmic events; any clinically important abnormalities in rhythm, conduction or morphology of resting ECG. History of another life-threatening malignancy ≤ 2 years prior to first dose of study intervention. Any of the following currently or in the 6 months prior to the first dose of study intervention: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other CNS bleeding. Treatment with any of the following: radiotherapy less than 2 weeks prior to the first dose of study intervention; any investigational agents or study drugs from a previous clinical study within ≤ 14 days or 5 half-lives prior to the first dose of study intervention; any other chemotherapy, immunotherapy, immunosuppressant medication or anticancer agents within 21 days of the first dose of study intervention; Prior allogenic haematopoietic stem cell transplantation (HSCT) within 6 months from the first dose of study intervention (patients > 6 months after allogenic HSCT are eligible in the absence of active graft-versus host disease and concomitant immune-suppressive therapy). Eligible patients must have stopped immunosuppression at least 2 months prior to study entry; prior cellular therapies such as CAR-T and/or autologous HSCT within 3 months prior to the first dose of study intervention; major surgery ≤ 21 days, or minor surgical procedures ≤ 7 days, prior to the first dose of study intervention; prescription or non-prescription drugs or other products known to be sensitive substrates of BCRP, OCT2, OAT3, OATP1B1, OATP1B3, CYP2B6, CYP2C8, CYP2C9 or CYP2D6, or reversible moderate or strong cytochrome 3A (CYP3A) inhibitors, which cannot be discontinued within 5 half-lives of the first dose of study intervention and withheld throughout the study until 14 days after the last dose of AZD0466; moderate or strong mechanism-based inhibitors or inducers of CYP3A4 which cannot be discontinued within 5 half-lives plus 12 days of the drug prior to the first dose of study intervention and withheld until 14 days after the last dose of AZD0466; concurrent anticoagulation therapy, including aspirin, which cannot be stopped; medications with known risk of Torsades de Pointes within 5 half-lives of the first dose of study intervention and continuing until 5 half-lives after the last dose of AZD0466. Administration of a live, attenuated vaccine within 4 weeks before first dose of study intervention. Administration of inactivated vaccines or protein/RNA immunogen vaccines. Patients with a known hypersensitivity to polyethylene glycol, pegylated products, or drugs with a similar chemical structure or class to AZD0466 or other BH3 mimetic. Exclusion Criteria- Module 1 Additional Exclusion Criteria for Cohort B1: - Patients with known blastoid or pleiomorphic variant at study entry/most recent relapse. Additional Exclusion Criteria for Cohort B2: Histologically confirmed diagnosis of FL grade 3B. Known transformation to aggressive lymphoma, eg, large cell lymphoma.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A (Dose Escalation): Dose Level (DL)-1<br>Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first. | Drug: AZD0466<br>* All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.<br>|
| Experimental: Part A (Dose Escalation): DL1<br>Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first. | Drug: AZD0466<br>* All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.<br>|
| Experimental: Part A (Dose Escalation): DL2<br>Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first. | Drug: AZD0466<br>* All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.<br>|
| Experimental: Part A (Dose Escalation): DL3<br>Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first. | Drug: AZD0466<br>* All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.<br>|
| Experimental: Part A (Dose Escalation): DL4<br>Participants with advanced R/R B-NHL will receive AZD0466 on day 1 , day 4, day 8 day 15, day 22 of cycle 1 and day 1, day 8 day 15, day 22 of cycle 2 and beyond until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first. | Drug: AZD0466<br>* All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.<br>|
| Experimental: Part B (Dose Expansion): Cohort B1 (R/R MCL)<br>Participants with advanced R/R MCL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first. | Drug: AZD0466<br>* All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.<br>|
| Experimental: Part B (Dose Expansion): Cohort B2 (R/R FL or MZL)<br>Participants with advanced R/R FL or MZL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first. | Drug: AZD0466<br>* All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.<br>|
| Experimental: Part B (Dose Expansion): Cohort B3 (R/R DLBCL)<br>Participants with advanced R/R DLBCL will receive AZD0466 at the recommended phase 2 dose (RP2D) until maximum 2 years or until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study intervention, whichever occurs first. | Drug: AZD0466<br>* All patients will receive treatment with the investigational product AZD0466 via intravenous infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Incidence of adverse events (AEs) and dose-limiting toxicities (DLTs) | To assess the safety and tolerability and identify the MTD and/or RP2D of AZD0466 as monotherapy or in combination with anticancer agents in patients with R/R B-NHL | From Screening until for 28 days Post-treatment follow-up visit (upto 2 years) | 
| Part B: Objective Response Rate (ORR) | To assess the preliminary efficacy of AZD0466 as monotherapy or in combination with other anticancer agents in patients with R/R B-NHL. ORR is defined as the proportion of participants who have a tumour response (complete Response [CR] and partial response [PR]). | From Screening until for 28 days Post-treatment follow-up visit (upto 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Incidence of adverse events (AEs) and serious adverse events (SAEs) | Assessment of the safety and tolerability of AZD0466 as monotherapy or in combination with anticancer agents in patients with R/R B-NHL | From screening until for 28 days Post-treatment follow-up visit and every 3 month (Q3M) after post-treatment follow-up visit (upto 2 years) | 
| Part B: Complete Response (CR) Rate | To assess the efficacy of AZD0466 as monotherapy or in combination with anticancer agents by evaluation of tumour response and OS in patients with R/R B-NHL | From screening until for 28 days Post-treatment follow-up visit and the Q3M after post-treatment follow-up visit (upto 2 years) | 
| Part B: Duration of Response (DoR) | To assess the efficacy of AZD0466 as monotherapy or in combination with anticancer agents by evaluation of DoR defined as the time from the date of first documented response until the date of documented progression or death due to any cause in the absence of disease progression. | From screening until for 28 days Post-treatment follow-up visit and the Q3M after post-treatment follow-up visit (upto 2 years) | 
| Part B: Time to Response (TTR) | To assess the efficacy of AZD0466 as monotherapy or in combination with anticancer agents by evaluation of TTR defined as the time from date of first dose until the date of first documented objective response. | From screening until for 28 days Post-treatment follow-up visit and the Q3M after post-treatment follow-up visit (upto 2 years) | 
| Part B: Progression-free Survival (PFS) | To assess the efficacy of AZD0466 as monotherapy or in combination with anticancer agents by evaluation of PFS is defined as the time from date of first dose to date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from treatment or receives another anti-lymphoma therapy prior to progression. | From screening until for 28 days Post-treatment follow-up visit and the Q3M after post-treatment follow-up visit (upto 2 years) | 
| Part B: Overall Survival (OS) | To assess the efficacy of AZD0466 as monotherapy or in combination with anticancer agents by evaluation of OS defined as the time from date of first dose until death due to any case regardless of whether patient withdraws from treatment or receives another anti-lymphoma therapy. | From screening until for 28 days Post-treatment follow-up visit and the Q3M after post-treatment follow-up visit (upto 2 years) | 
| Part A and Part B: Maximum observed plasma (peak) drug concentration (Cmax) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 
| Part A and Part B: Time to reach peak or maximum observed concentration or response following drug administration (tmax) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 
| Part A and Part B: Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 
| Part A and Part B: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2λz) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 
| Part A and Part B: Partial area under the plasma concentration-time curve from time 0 to 24 hours after the start of infusion (AUC0-24) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 
| Part A and Part B: Partial area under the plasma concentration-time curve from time 0 to 72 hours after the start of infusion (AUC0-72) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 
| Part A and Part B: Area under the plasma concentration-curve from time 0 to the last quantifiable concentration (AUClast) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 
| Part A and Part B: Time of last observed (quantifiable) concentration (tlast) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 
| Part A and Part B: Concentration prior to dosing (Ctrough) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 
| Part A and Part B (total AZD4320 only): Area under the plasma concentration-time curve from time 0 to time of last quantifiable analyte concentration divided by the dose administered (Dose normalised AUClast) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 
| Part A and Part B (total AZD4320 only): Area under the plasma concentration-time curve from time 0 to 72 hours after the start of infusion (Dose normalised AUC0-72) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 
| Part A and Part B (total AZD4320 only): Maximum observed plasma (peak) drug concentration divided by the dose administered (Dose normalised Cmax) | Assessment of AZD4320 to characterise the PK profile of AZD0466 | Cycle 1 Days 1, 4, 8, 9 and Cycle 1 days 10, 11 only for part A; Cycle 2 Day 1, Cycle 3 Day 1, Cycle 5 Day 1 (cycle length 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multicentre Study, Open-label,, Dose Escalation, Dose Expansion,, Anticancer, Pegylated poly-L-lysine dendrimer