A Phase 1 Study of AJ1-11095 in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) Who Have Been Failed by a Type I JAK2 Inhibitor (JAK2i)

Официальное название

A Multicenter, Open-Label, Phase 1 Study of AJ1-11095 Administered as Oral Monotherapy in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) Who Have Been Failed by a Type I JAK2 Inhibitor (JAK2i)

Обзор

AJX-101 is a first-in-human (FIH), phase 1, non-randomized, multi-center, open-label clinical trial designed to investigate the safety, tolerability, pharmacokinetics (PK), clinical activity and changes in biomarkers of an orally administered type II JAK2 inhibitor, AJ1-11095, in subjects with primary or secondary myelofibrosis previously treated with at least one type I JAK2 inhibitor.

Подробное описание

This is a phase 1, non-randomized, open-label study utilizing a 3+3 sequential dose escalation design followed by an expansion phase. The primary objective will be to evaluate the safety and tolerability of AJ1-11095, and establish a Maximally Tolerated Dose (MTD) and/or inform the establishment of a candidate Recommended Phase 2 dose (RP2D). The RP2D may be the maximally tolerated dose (MTD) or may be a dose below the MTD. The candidate RP2D will be based on AE pattern, PK and biomarker information, in addition to all available safety and efficacy data. Expansion cohorts will be enrolled to gather additional safety and efficacy information and to further refine input for future RP2D discussions. Eligible participants will have PMF, PPV-MF or PET-MF and will have either have relapsed after a response, or be refractory to, at least one prior type I JAK2 inhibitor therapy, either administered as monotherapy or in combination with another drug.

Вмешательства

• Препарат AJ1-11095
  Type II JAK2 Inhibitor

Первичные конечные точки

• Number of patients with treatment-emergent adverse events as assessed by CTCAE v 5.0. [Срок оценки: Baseline through study completion, an average of 1 year]
• Number of patients with Dose Limiting Toxicities (DLTs) [Срок оценки: Baseline through study completion, an average of 1 year]
• To establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of AJ1-11095 [Срок оценки: Baseline through study completion, an average of 1 year]

Вторичные конечные точки (8)

• To assess clinical response to AJ1-11095 evaluated by the Total Symptom Score (TSS). [Срок оценки: Baseline through Week 24]
• To assess clinical response to AJ1-11095 evaluated by spleen volume assessments. [Срок оценки: Baseline through Week 24]
• To assess clinical response to AJ1-11095 evaluated by spleen length assessments. [Срок оценки: Baseline through Week 24]
• To assess clinical response to AJ1-11095 evaluated through spleen size improvement. [Срок оценки: Baseline through Week 24]
• To evaluate the Area Under the Curve (AUC) of AJ1-11095 [Срок оценки: Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), Day 8, 15, 22, and Cycle 2 (Day 1 and 24 hrs post).]
• To evaluate the Cmax of AJ1-11095 [Срок оценки: Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), Day 8, 15, 22, and Cycle 2 (Day 1 and 24 hrs post).]
• To evaluate the Tmax of AJ1-11095 [Срок оценки: Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), Day 8, 15, 22, and Cycle 2 (Day 1 and 24 hrs post).]
• To evaluate the half-life of AJ1-11095 [Срок оценки: Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), Day 8, 15, 22, and Cycle 2 (Day 1 and 24 hrs post).]

Критерии участия

Критерии включения

• 18 years of age or older.
• Diagnosis of PMF, post-PV MF, or post-ET MF.
• DIPSS Intermediate-2 or High-risk MF with ≤10% blasts, regardless of JAK2 mutation status.
• Estimated spleen volume ≥450cm3.
• MFSAF v.4.0 TSS ≥10, or at least 2 of 7 MFSAF-assessed symptoms with scores ≥3.
• ECOG PS of 0, 1, 2, or 3.
• Prior therapy with at least 1 type I JAK2 inhibitor, and either failed to achieve a response or relapsed after achieving a response.
• ANC ≥1.0×10\^9/L.
• Platelet count ≥75×10\^9/L.
• eGFR ≥45 mL/min/1.73m2.
• Serum total bilirubin ≤2.0 × upper limit of normal (ULN).
• AST and ALT ≤3.0 × ULN.
• QTcF ≤480 msec.

Критерии исключения

• Prior splenectomy.
• Splenic irradiation within 3 months prior to first dose of study drug.
• Ongoing use of systemic corticosteroids at dose equivalent to >10mg/day of prednisone.
• Uncontrolled intercurrent illness such as an acute infection.
• Chronic active or acute hepatitis B or C infection.
• Chemotherapy in the previous 4 weeks prior to first dose of study drug (Hydrea is permitted until 5 days before starting protocol therapy).
• Use of a Type I JAK2 inhibitor must have been discontinued for at least 5 days or 5 half-lives prior to dosing (whichever is longer).
• Use of erythropoiesis stimulating agents (unless stable for >8 weeks).
• Peripheral neuropathy ≥ Grade 2 (NCI CTCAE v 5.0).
• Unable or unwilling to undergo CT or MRI for spleen size imaging.
• Pregnant or breastfeeding.
• Requirement for therapy with a medication that is a strong CYP3A4 inhibitor as a concomitant medication.

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 · 13 центров

• Stanford Cancer Institute — Palo Alto
• Moffitt Cancer Cancer Center — Tampa
• University of Kansas Medical Center — Kansas City
• Massachusetts General Hospital — Boston
• Dana Farber Cancer Institute — Boston
• University of Michigan — Ann Arbor
• Washington University School of Medicine — St Louis
• David H. Koch Center for Cancer Care at Memorial Sloan Kettering — New York
• … и ещё 5 центров

Испания · 3 центра

• Hospital General Universitario Gregorio Maranon — Madrid
• Hospital Clinic Barcelona — Barcelona
• Hospital Universitario Ramon y Cajal — Madrid

Италия · 2 центра

• IRCCS Azienda Ospedaliero-Universitaria di Bologna - Policlinico di Sant Orsola — Bologna
• Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico — Milan

Великобритания · 2 центра

• Guy's Hospital — London
• Genesis Cancer Care UK Limited - Oxford — Oxford

Франция · 1 центр

• AP-HP Hopital Saint-Louis — Paris

Идентификаторы

NCT: NCT06343805 · AJX-101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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