Safety and Preliminary Efficacy Assessment of AZD7789 in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma

Study Overview
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Brief Summary
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The study is intended to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of AZD7789 in patients with relapsed/refractory classical Hodgkin Lymphoma (r/r cHL).

Detailed Description
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This is a Phase I/II, open-label multi-center study will have AZD7789 administered via intravenous infusion on Cycle 1 Day 1 to adult/young adult patients with relapsed/refractory classical Hodgkin Lymphoma (r/r cHL). This study will have 2 parts: Phase 1 (Part A) Dose Escalation and Phase 2 (Part B) Dose Expansion. Patients will be treated with study intervention for a maximum of 35 cycles, or until disease progression, unacceptable toxicity, withdrawal of consent, or if other reasons to discontinue treatment occur.

Official Title
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A Phase I/II Open-label, Multi-center Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD7789, an Anti-PD-1 and Anti-TIM-3 Bispecific Antibody, in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma.

Conditions
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Relapsed or Refractory Classical Hodgkin Lymphoma

Intervention / Treatment
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* Drug: AZD7789


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 16 years of age at the time of obtaining informed consent Eastern Cooperative Oncology Group performance status of 0 or 1 at screening At least one PET-avid measurable lesion according to Modified Lugano Criteria after the last line of therapy. Confirmed histological diagnosis of active relapse/refractory cHL Failed at least 2 prior lines of systemic therapy. No previous treatment with anti-TIM-3. Adequate organ and bone marrow function Non-pregnant women and willingness of female patients to avoid pregnancy or male participants willing to avoid fathering children through highly effective methods of contraception Minimum body weight ≥ 40 kg for all participants. Exclusion Criteria: Unresolved toxicities of ≥ Grade 2 from prior therapy Any prior ≥ Grade 3 imAE while receiving prior checkpoint inhibitor immunotherapy Patients with CNS involvement or leptomeningeal disease. History of organ transplantation (e.g., stem cell or solid organ transplant). Any venous or arterial thromboembolic event within ≤ 6 months prior to the first dose of study intervention. Active infection including TB, HIV, hepatitis A, chronic or active hepatitis B, chronic or active hepatitis C, active COVID-19 infection History of arrhythmia which is requires treatment, symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia Uncontrolled intercurrent illness. Active or prior documented pathologically confirmed autoimmune or inflammatory disorders. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD Other invasive malignancy within 2 years prior to screening Congenital long QT syndrome or history of QT prolongation associated with other medications that cannot be changed or discontinued based on a cardiologist assessment Current or prior use of immunosuppressive medication within 14 days prior to the first dose of study intervention Any concurrent chemotherapy, radiotherapy, investigational, biologic, or hormonal therapy for cancer treatment.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 101 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: Cohort A: Dose Escalation<br>Patients with anti-PD-1/PD-L1 exposed r/r cHL will receive AZD7789. | Drug: AZD7789<br>* Patients will receive AZD7789 (PD-1/TIM-3 bispecific monoclonal antibody) via intravenous infusion.<br>|
| Experimental: Cohort B1: Dose Expansion<br>Patients with anti-PD-1/PD-L1 exposed r/r cHL will receive AZD7789 once the recommended phase 2 dose (RP2D) has been determined. | Drug: AZD7789<br>* Patients will receive AZD7789 (PD-1/TIM-3 bispecific monoclonal antibody) via intravenous infusion.<br>|
| Experimental: Cohort B2: Dose Expansion<br>Patients with anti-PD-1/PD-L1 naïve r/r cHL will receive AZD7789 once the RP2D has been determined. | Drug: AZD7789<br>* Patients will receive AZD7789 (PD-1/TIM-3 bispecific monoclonal antibody) via intravenous infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A (Dose Escalation): Number of incidence of adverse events (AEs) | To assess safety and tolerability of AZD7789 in patients with r/r cHL. | Approximately up to 2 years 90 days | 
| Part A (Dose Escalation): Number of patients with dose-limiting toxicities (DLTs) | To determine the maximum tolerated dose (MTD). To determine the incidence of DLT. | From first dose until 28 days from the last patient first dose [within 28 days DLT period] | 
| Part B (Dose Expansion): Cohort B1: Objective response rate (ORR) | To assess anti-tumor activity of AZD7789 in patients with r/r cHL. ORR defined as CR + PR as per modified Lugano criteria (Lugano 2014). | Up to 2 years of treatment | 
| Part B (Dose Expansion): Cohort B2: Complete response rate (CRR) | To assess anti-tumor activity of AZD7789 in patients with r/r cHL. CRR is defined as CR as per modified Lugano criteria (Lugano 2014). | Up to 2 years of treatment | 
| Part B (Dose Expansion): Number of incidence of adverse events (AEs) | To assess safety and tolerability of AZD7789 in patients with r/r cHL. | Approximately up to 2 years 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A (Dose Escalation): Complete Response Rate (CRR) | To assess anti-tumor activity of AZD7789 in patients with r/r cHL. CRR is defined as CR as per modified Lugano criteria (Lugano 2014). | Up to 2 years of treatment | 
| Part A (Dose Escalation): Objective Response Rate (ORR) | To assess anti-tumor activity of AZD7789 in patients with r/r cHL. ORR defined as CR + PR as per modified Lugano criteria (Lugano 2014). | Up to 2 years of treatment | 
| Part A (Dose Escalation): Duration of Response (DoR) | To assess DoR of AZD7789 in patients with r/r cHL. | Up to approximately 5 years | 
| Part A (Dose Escalation): Duration of Complete Response (DoCR) | To assess DoCR of AZD7789 in patients with r/r cHL | Up to approximately 5 years | 
| Part A (Dose Escalation): Progression-free Survival (PFS) | To assess anti-tumor activity of AZD7789 in patients with r/r cHL. | Up to approximately 5 years | 
| Part A (Dose Escalation): Overall Survival (OS) | To assess anti-tumor activity of AZD7789 in patients with r/r cHL. | Up to approximately 5 years | 
| Part A (Dose Escalation): Number of patients with positive anti-drug antibodies against AZD7789 in serum | To assess the presence of anti-drug antibodies for AZD7789 in treated patients with r/r cHL. | Up to 2 years | 
| Part A (Dose Escalation): Maximum observed concentration (Cmax) | To assess the Cmax of AZD7789 in patients with r/r cHL. | Up to 2 years | 
| Part A (Dose Escalation): Area under the concentration-time curve (AUC) | To assess AUC of AZD7789 in patients with r/r cHL. | Up to 2 years | 
| Part A (Dose Escalation): Terminal elimination half-life (t½) | To assess t½ of AZD7789 in patients with r/r cHL. | Up to 2 years | 
| Part B (Dose Expansion): Duration of Response (DoR) | To assess DoR of AZD7789 in patients with r/r cHL. | Up to approximately 5 years | 
| Part B (Dose Expansion): Duration of Complete Response (DoCR) | To assess DoCR of AZD7789 in patients with r/r cHL | Up to approximately 5 years | 
| Part B (Dose Expansion): Progression-free Survival (PFS) | To assess anti-tumor activity of AZD7789 in patients with r/r cHL. | Up to approximately 5 years | 
| Part B (Dose Expansion): Overall Survival (OS) | To assess anti-tumor activity of AZD7789 in patients with r/r cHL. | Up to approximately 5 years | 
| Part B (Dose Expansion): Number of patients with positive anti-drug antibodies against AZD7789 in serum | To assess the presence of anti-drug antibodies for AZD7789 in treated patients with r/r cHL. | Up to 2 years | 
| Part B (Dose Expansion): Maximum observed concentration (Cmax) | To assess the Cmax of AZD7789 in patients with r/r cHL. | Up to 2 years | 
| Part B (Dose Expansion): Area under the concentration-time curve (AUC) | To assess AUC of AZD7789 in patients with r/r cHL. | Up to 2 years | 
| Part B (Dose Expansion): Terminal elimination half-life (t½) | To assess t½ of AZD7789 in patients with r/r cHL. | Up to 2 years | 
| Part B (Dose Expansion): Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) | Proportion of participants reporting different levels of presence/magnitude/interference (as applicable) of diarrhea, rash, and fatigue over time based on PRO-CTCAE will be evaluated. | Up to 2 years of treatment | 
| Part B (Dose Expansion): Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (Peds-PRO-CTCAE) | Proportion of participants reporting different levels of presence/magnitude/interference (as applicable) of diarrhea, rash, and fatigue over time based on peds-PRO-CTCAE will be evaluated. | Up to 2 years of treatment | 
| Part B (Dose Expansion): Patient Global Impression of Treatment Tolerability (PGI-TT) | Proportion of participants reporting different levels of overall side-effect bother over time based on the PGI-TT. | Up to 2 years of treatment | 
| Part B (Dose Expansion): European Organization for Research and Treatment of Cancer (EORTC) Item List (IL)XX QL2 (2-item global health-related quality of life (HRQoL)) | Proportion of participants reporting different levels of quality of life/health over time based on the European Organization for Research and Treatment of Cancer Item List (EORTC) ILXX QL2 items will be evaluated. | Up to 2 years of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T cell immunoglobulin and mucin domain-containing protein-3(TIM-3), Modified toxicity probability interval-2 (mTPI-2), Bispecific antibody, Immunotherapy, Dose Expansion, Pharmacokinetics, Classical Hodgkin Lymphoma (cHL), Dose escalation, r/r cHL, programmed cell death protein-1 (PD-1), Accelerated titration design (ATD)