Study of AZD4512 Monotherapy or in Combination With Anticancer Agents in Participants With Acute Lymphoblastic Leukemia

Официальное название

A Modular Phase I/II, Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Preliminary Efficacy of AZD4512 Monotherapy or in Combination With Anticancer Agent(s) in Participants With Acute Lymphoblastic Leukemia

Обзор

The study is intended to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of AZD4512 in patients with relapsed/refractory B-Cell acute lymphoblastic leukemia (r/r B-ALL).

Подробное описание

In this Phase I/II, open-label multi-center study AZD4512 will be administered to adult/young adult patients (Module 1: \>=16 years; Module 2: \>=12 years) with relapsed/refractory B-Cell acute lymphoblastic leukemia (B-ALL). This study will have 2 parts: Module 1 - Dose Escalation and Module 2 - Dose Optimization.

Вмешательства

• Комбинированный продукт AZD4512 monotherapy
  Patients will receive AZD4512 as monotherapy via intravenous infusion. AZD4512 is an antibody-drug conjugate targeting CD22

Первичные конечные точки

• Module 1 (Dose Escalation): Number of participants with dose-limiting toxicities (DLTs). [Срок оценки: From first dose up to 21 days (DLT period).]
• Module 1 (Dose Escalation): Frequency, duration and severity of treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs) [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 1 (Dose Escalation): Frequency of dose interruptions, modifications, delays, and discontinuations due to AEs [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 1 (Dose Escalation): Number of participants with clinically significant changes in laboratory values, ECGs, performance status, and vital signs [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 2 (Dose Optimization): Overall response rate (ORR) in participants with R/R Ph(-) B-ALL [Срок оценки: From date of first dose of AZD4512 up until end of study, up to 38 months]
• Module 2 (Dose Optimization): Frequency, duration and severity of treatment-emergent adverse events (TEAEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs) [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 2 (Dose Optimization): Frequency of dose interruptions, modifications, delays, and discontinuations due to AEs [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 2 (Dose Optimization): Number of participants with clinically significant changes in laboratory values, ECGs, performance status, and vital signs [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]

Вторичные конечные точки (12)

• Module 1 (Dose Escalation): Plasma PK parameters of AZD4512 [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 1 (Dose Escalation): Total antibody and total unconjugated payload [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 1 (Dose Escalation): Area Under Curve (AUC) [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 1 (Dose Escalation): Peak Plasma Concentration (Cmax) [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 1 (Dose Escalation): Time to max concentration (Tmax) [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 1 (Dose Escalation): Half life (T1/2) [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 1 (Dose Escalation): Clearance (CL) [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 1 (Dose Escalation): Volume of distribution (Vz) [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 1 (Dose Escalation): Number and percentage of participants who develop anti-drug antibodies (ADAs) [Срок оценки: From date of first dose of AZD4512 up until 30 days post last dose of AZD4512 (on average 6 months)]
• Module 1 (Dose Escalation): Objective Response Rate (ORR): proportion of participants with CR or CRh [Срок оценки: From date of first dose of AZD4512 up until end of study, up to 38 months]
• Module 1 (Dose Escalation): Composite Complete Remission (CRc) rate: proportion of participants with CR, CRh, or CRi [Срок оценки: From date of first dose of AZD4512 up until end of study, up to 38 months]
• Module 1 (Dose Escalation): Complete Remission (CR) rate [Срок оценки: From date of first dose of AZD4512 up until end of study, up to 38 months]

Критерии участия

Критерии включения

• 1\. Age:

• 16 years old in Module 1 (US only: ≥18year)
• 12 years old in Module 2

2\. Diagnosis: Known Diagnosis of CD22-positive B-ALL based on criteria established by WHO (Alaggio et al. 2022).

• Participants must have relapsed or refractory B-ALL ('relapsed' defined as bone marrow blasts > 5% or reappearance of blasts in PB)
• Module 1 (DE): Ph(-) B-ALL and Ph(+) B-ALL - R/R
• Backfill of Module 1 and Module 2 (DO): R/R Ph(-) B-ALL

3\. Performance status (ECOG ≤ 2; KPS ≥ 50; LPS ≥ 50)

4\. Peripheral lymphoblast count < 10,000/µL (may receive cytoreduction prior to C1D1 per protocol-specified criteria)

5\. At least 2 prior therapies with refractoriness or relapse, or 1 prior therapy with refractoriness or relapse and no standard options available. Participants who have received prior CD22 targeted therapies are eligible.

• Ph+ B-ALL (Module 1 DE only): intolerant to or have contraindications to TKI therapy or R/R disease despite treatment with at least 2 prior TKIs or at least one 3rd generation TKI

6\. Prior DLI >4 weeks, prior cell therapy or autoHSCT >8 weeks, alloHSCT >12 weeks

Критерии исключения

• Burkitt lymphoma and leukemia
• Isolated extramedullary disease; Active testicular or CNS (> CNS1) involvement
• Unresolved non-heme toxicities Grade ≥ 2 (except alopecia, stable Grade ≤ 2 neuropathy, vitiligo, endocrine disorders controlled with therapy)
• History of drug-induced non-infectious ILD/pneumonitis requiring oral or IV steroids or supplemental oxygen or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• Prior/concomitant therapy

• Cytotoxic treatment within 14 days (except ALL maintenance medications or cytoreduction)
• Biologic (immuno-oncology) treatment within 28 days or 5 half-lives (whichever is shorter)
• Non-CNS radiation within 2 weeks \& CNS radiation within 4 weeks
• Medications known to prolong QTc and/or associated with Torsades de Pointes within 5 half-lives
• Strong inhibitors of CYP 3A4 within 14 days or 5 half-lives (whichever is longer)
• Investigational agents or study interventions in the last 30 days or 5 half-lives prior to the first dose of AZD4512 whichever is longer. If the investigational product is an agent to treat B-ALL and meets the modality criteria, then a specific washout period must be adhered to instead.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 6 центров

• Research Site — Duarte
• Research Site — Jacksonville
• Research Site — Chicago
• Research Site — Iowa City
• Research Site — Franklin
• Research Site — Houston

Испания · 5 центров

• Research Site — Badalona(Barcelona)
• Research Site — Barcelona
• Research Site — Salamanca
• Research Site — Santander
• Research Site — Valencia

South Korea · 4 центра

• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul

Канада · 2 центра

• Research Site — Vancouver
• Research Site — Toronto

Китай · 2 центра

• Research Site — Гуанчжоу
• Research Site — Тяньцзинь

Япония · 2 центра

• Research Site — Bunkyō City
• Research Site — Chūōku

Тайвань · 2 центра

• Research Site — Taichung
• Research Site — Taipei

Великобритания · 2 центра

• Research Site — Bloomsbury
• Research Site — Manchester

Австралия · 1 центр

• Research Site — Melbourne

Идентификаторы

NCT: NCT07109219 · D9891C00001 · 2025-522372-93-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗