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

Phase 1

Active, not recruiting

Conditions: Relapsed or Refractory Classical Hodgkin Lymphoma

Interventions: Drug: Sabestomig (AZD7789)

Registration Number: NCT05216835

Lead Sponsor: AstraZeneca

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

Detailed Description: This is a Phase I/II, open-label multi-center study will have sabestomig 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.

The trial was intended to be Phase I/II trial (but the trial never moved forward to Phase 2). Hence, the study Phase was updated to Phase I.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 45

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 positron emission tomography (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 central nervous system (CNS) involvement or leptomeningeal disease.
History of allogeneic stem cell transplant or organ transplantation.
Any venous or arterial thromboembolic event within ≤ 6 months prior to the first dose of study intervention.
Active infection including Tuberculosis (TB), human immunodeficiency virus (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 uncontrol led 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort A: Dose Escalation	Sabestomig (AZD7789)	Patients with anti-PD-1/PD-L1 exposed r/r cHL will receive sabestomig to determine the recommended phase 2 dose (RP2D).
Cohort B1: Dose Expansion	Sabestomig (AZD7789)	Patients with anti-PD-1/PD-L1 exposed r/r cHL will receive sabestomig once the RP2D has been determined.
Cohort B2: Dose Expansion	Sabestomig (AZD7789)	Patients with anti-PD-1/PD-L1 naïve r/r cHL will receive sabestomig once the RP2D has been determined.

Primary Outcome Measures

Name	Time	Method
Part B (Dose Expansion): Number of Participants With AEs	Up to approximately 2 years 90 days	The safety and tolerability of sabestomig in participants with r/r cHL was planned to be assessed.
Part A (Dose Escalation): Number of Participants With Adverse Events (AEs)	From start of treatment [Cycle 1 Day 1 (C1D1) (each cycle was 28 days)] up to 90 days post last dose (approximately 2 years 5 months)	The safety and tolerability of sabestomig in participants with r/r cHL were assessed.
Part A (Dose Escalation): Number of Participants With Dose-limiting Toxicities (DLTs)	From first dose (C1D1) until 28 days for each participant [within 28 days DLT period]	DLT was defined as any ≥Grade 3 AE as per NCI CTCAE version 5 unless unequivocally due to underlying malignancy or an extraneous cause. The following conditions were considered as DLTs: * Any death not clearly due to the underlying disease or extraneous causes * Grade 4 imAE or anemia * Any ≥Grade 3 non-infectious pneumonitis or colitis of any duration * Specific liver transaminase elevation as per protocol * Any Grade 3 imAE, including rash, pruritus, or diarrhea, that does not downgrade to Grade 2 or less within 7 days * Grade 3 nausea, vomiting, or diarrhea that does not resolve to Grade 2 or less within 3 days of getting maximal supportive care * ≥Grade 3 neutropenia, without fever or systemic infection, that does not improve by at least one grade within 7 days * Grade 4 thrombocytopenia for more than 7 days or ≥Grade 3 thrombocytopenia along with Grade ≥2 bleeding * Grade 4 Cytokine Release Syndrome (CRS) of any duration or Grade 3 CRS not improving to Grade ≤2 within 72 hours
Part B (Dose Expansion): Cohort B1: Objective Response Rate (ORR)	Up to approximately 2 years 90 days	The anti-tumor activity of sabestomig in participants with r/r cHL was planned to be assessed. ORR was defined as the percentage of participants with an objective response \[Best Overall Response of a complete response (CR) or partial response (PR)\] as per modified Lugano criteria (Lugano 2014), with the denominator defined as the number of participants in the response-evaluable analysis set. Disease response was planned to be assessed according to Blinded Independent Central Review using modified Lugano criteria (Lugano 2014).
Part B (Dose Expansion): Cohort B2: Complete Response Rate (CRR)	Up to approximately 2 years 90 days	The anti-tumor activity of sabestomig in participants with r/r cHL was planned to be assessed. The CRR was defined as the percentage of participants with a CR as per modified Lugano criteria (Lugano 2014), with the denominator defined as the number of participants in the response-evaluable analysis set. Disease response was planned to be assessed according to Blinded Independent Central Review using modified Lugano criteria (Lugano 2014).

Secondary Outcome Measures

Name	Time	Method
Part A (Dose Escalation): Objective Response Rate (ORR)	From start of treatment [C1D1 (each cycle was 28 days)] until progression, or last evaluable assessment in the absence of progression (up to 2 years 5 months)	The anti-tumor activity of sabestomig in participants with r/r cHL was assessed. The ORR was defined as the percentage of participants with an objective response (Best Overall Response of CR or PR) as per modified Lugano criteria (Lugano 2014), as assessed by the Investigator, with the denominator defined as the number of participants in the response-evaluable analysis set. Disease response was assessed according to Investigator assessment using modified Lugano criteria (Lugano 2014).
Part A (Dose Escalation): Complete Response Rate (CRR)	From start of treatment [C1D1 (each cycle was 28 days)] until first documented disease progression, or last evaluable assessment in the absence of progression (up to 2 years 5 months)	The anti-tumor activity of sabestomig in participants with r/r cHL was assessed. The CRR was defined as the percentage of participants with a CR as per modified Lugano criteria (Lugano 2014) as assessed by the Investigator, with the denominator defined as the number of participants in the response-evaluable analysis set. Disease response was assessed according to Investigator assessment using modified Lugano criteria (Lugano 2014).
Part B (Dose Expansion): Duration of Response (DoR)	Up to approximately 2 years 90 days	The DoR of sabestomig in participants with r/r cHL was planned to be assessed.
Part A (Dose Escalation): Duration of Response (DoR)	From first documented response until date of first documented disease progression or death from any cause, or data cut-off or end of study (whichever came first, assessed up to 2 years 5 months)	The anti-tumor activity of sabestomig in participants with r/r cHL was assessed. The DoR was defined as the time from the date of first documented objective response (CR or PR), as assessed by Investigator, using the modified Lugano criteria (Lugano 2014), until the date of first documented disease progression or death (by any cause in the absence of disease progression). Disease response was assessed according to Investigator assessment using modified Lugano criteria (Lugano 2014).
Part A (Dose Escalation): Duration of Complete Response (DoCR)	From first documented complete response until date of first documented disease progression or death from any cause, or data cut-off or end of study (whichever came first, assessed up to 2 years 5 months)	The anti-tumor activity of sabestomig in participants with r/r cHL was assessed. The DoCR was defined as the time from first documented CR, as per modified Lugano criteria (Lugano 2014) as assessed by the Investigator, until the date of first documented relapse/progression or death due to any cause (in the absence of disease progression). Disease response was assessed according to Investigator assessment using modified Lugano criteria (Lugano 2014).
Part A (Dose Escalation): Progression-free Survival (PFS)	From start of treatment [C1D1 (each cycle was 28 days)] until date of first documented disease progression or data cut-off or end of study (whichever came first, assessed up to 2 years 5 months)	The anti-tumor activity of sabestomig in participants with r/r cHL was assessed. PFS was defined as the time from first dose until the earlier of the date of first documented disease progression, as per modified Lugano criteria (Lugano 2014) as assessed by the Investigator, or death (by any cause in the absence of disease progression or subsequent anticancer treatment). Disease response was assessed according to Investigator assessment using modified Lugano criteria (Lugano 2014).
Part A (Dose Escalation): Overall Survival (OS)	From start of treatment [C1D1 (each cycle was 28 days)] until date of death due to any cause or data cut-off or end of study (whichever came first, assessed up to 2 years 5 months)	The anti-tumor activity of sabestomig in participants with r/r cHL was assessed. The OS was defined as the time from the start of treatment until death due to any cause regardless of whether participant withdraws from treatment or receives another anti-lymphoma therapy.
Part A (Dose Escalation): Number of Participants With Positive Anti-drug Antibodies (ADA) Against Sabestomig in Serum	On C1D1, C2D1, and until end of study [up to 2 years 5 months (each cycle was 28 days)]	The presence of ADA for sabestomig in treated participants with r/r cHL was assessed.
Part A (Dose Escalation): Maximum Observed Concentration (Cmax)	From C1D1 [before start of infusion (SOI) and at end of infusion (EOI)] to end of study [up to 2 years 5 months (each cycle was 28 days)]	The Cmax of sabestomig in participants with r/r cHL was assessed.
Part A (Dose Escalation): Area Under the Concentration-time Curve (AUC)	From C1D1 (before SOI and at EOI) to end of study [up to 2 years 5 months (each cycle was 28 days)]	The AUC of sabestomig in participants with r/r cHL was assessed.
Part A (Dose Escalation): Clearance (CL)	From C1D1 (before SOI and at EOI) to end of study [up to 2 years 5 months (each cycle was 28 days)]	The CL of sabestomig in participants with r/r cHL was assessed.
Part A (Dose Escalation): Terminal Elimination Half-life (t½λz)	From C1D1 (before SOI and at EOI) to end of study [up to 2 years 5 months (each cycle was 28 days)]	The t½λz of sabestomig in participants with r/r cHL was assessed.
Part B (Dose Expansion): Duration of Complete Response (DoCR)	Up to approximately 2 years 90 days	The DoCR of sabestomig in participants with r/r cHL was planned to be assessed.
Part B (Dose Expansion): Progression-free Survival (PFS)	Up to approximately 2 years 90 days	The anti-tumor activity of sabestomig in participants with r/r cHL was planned to be assessed.
Part B (Dose Expansion): Overall Survival (OS)	Up to approximately 2 years 90 days	The anti-tumor activity of sabestomig in participants with r/r cHL was planned to be assessed.
Part B (Dose Expansion): Number of Participants With Positive ADA Against Sabestomig in Serum	Up to approximately 2 years 90 days	The presence of ADA for sabestomig in treated participants with r/r cHL was planned to be assessed.
Part B (Dose Expansion): Maximum Observed Concentration (Cmax)	Up to approximately 2 years 90 days	The Cmax of sabestomig in participants with r/r cHL was planned to be assessed.
Part B (Dose Expansion): Area Under the Concentration-time Curve (AUC)	Up to approximately 2 years 90 days	The AUC of sabestomig in participants with r/r cHL was planned to be assessed.
Part B (Dose Expansion): Terminal Elimination Half-life (t½λz)	Up to approximately 2 years 90 days	The t½λz of sabestomig in participants with r/r cHL was planned to be assessed.
Part B (Dose Expansion): Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)	Up to approximately 2 years 90 days	Proportion of participants reporting different levels of presence/magnitude/interference (as applicable) of diarrhea, rash, and fatigue over time based on PRO-CTCAE was planned to be evaluated. PRO-CTCAE was a PRO measurement system developed to evaluate symptomatic toxicity in participants on cancer clinical trials. The PRO-CTCAE Item Library included 124 items representing 78 symptomatic toxicities drawn from the CTCAE. PRO-CTCAE items were planned to evaluate the symptom attributes of frequency, severity, interference, amount, presence/absence. Each symptomatic AE was planned to be assessed by 1 to 3 attributes. Conditional branching logic was planned to be used with electronic data capture, thereby reducing respondent burden. The recall period was planned as the past 7 days and PRO-CTCAE responses were planned to score from 0 to 4 (or 0/1 for absent/present).
Part B (Dose Expansion): Pediatric Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (Peds-PRO-CTCAE)	Up to approximately 2 years 90 days	Proportion of participants reporting different levels of presence/magnitude/interference (as applicable) of diarrhea, rash, and fatigue over time based on peds-PRO-CTCAE was planned to be evaluated. The pediatric module included 130 items representing 62 symptomatic toxicities and permitted self-reporting by children and adolescents aged 7 to 17 years. In this study, 17 symptomatic toxicities were planned for selection. Thus, the total number of questions that participants would have answered ranged from 17 (assuming that no branching questions were triggered, ie, the participant answered '0' to the initial question for each symptom) to 42 items (assuming that all possible branching questions were triggered for every symptom posed to the participant).
Part B (Dose Expansion): Patient Global Impression of Treatment Tolerability (PGI-TT)	Up to approximately 2 years 90 days	Proportion of participants reporting different levels of overall side-effect bother over time based on the PGI-TT was planned to be evaluated. For adult participants only, the PGI-TT item was included to assess how a participant perceived the overall burden of treatment-related side effects of cancer treatment over the past 7 days. Participants were planned to be asked to choose the response that best described the level of burden by the side effect of their cancer treatment over the past week. The planned response options were:"not at all", "a little bit", "somewhat", "quite a bit", and "very much".
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)]	Up to approximately 2 years 90 days	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 was planned to be evaluated. EORTC QLQ-C30 was a 30-item self-administered questionnaire designed for all cancer types. Questions were grouped into 5 multi-item functional scales (physical, role, emotional, cognitive, and social), 3 multi-item symptom scales (fatigue, pain, and nausea/vomiting), 2-item global HRQoL (QL2) scale, 5 single items assessing additional symptoms commonly reported by participants with cancer (dyspnea, loss of appetite, insomnia, constipation, and diarrhea), and 1 item on the financial impact of the disease. Participants were planned to answer QLQ-C30 questions in reference to how they had been over the past week. Final scores were planned to transform to range from 0 to 100, where higher scores indicated better functioning, better HRQoL, or greater level of symptoms.