A Phase 1, Open-Label Study of LY5830966, a Type II JAK2 Inhibitor, in Patients With Myelofibrosis Previously Treated With a Type I JAK2 Inhibitor, JAK2 Inhibitor-Naïve Myelofibrosis, or High-risk Relapsed/Refractory Polycythemia Vera
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 256
- 试验地点
- 33
- 主要终点
- Number of patients with Dose Limiting Toxicities (DLTs)
研究概览
简要总结
J8G-MC-JDIA (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 Janus Kinase 2 (JAK2) inhibitor, LY5830966, in participants with primary or secondary myelofibrosis previously treated with at least one type I JAK2 inhibitor.
详细描述
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 LY5830966 and establish a Maximally Tolerated Dose (MTD) and/or inform the establishment of a candidate Recommended Phase 3 dose (RP3D). The RP3D may be the maximally tolerated dose (MTD) or may be a dose below the MTD. The candidate RP3D will be based on adverse event (AE) pattern, pharmacokinetics (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 RP3D 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of PMF, post-PV MF, or post-ET MF.
- •Dynamic International Prognostic Scoring System (DIPSS) Intermediate-1, Intermediate-2 or High-risk MF with less than or equal to (≤)10% blasts, regardless of JAK2 mutation status.
- •Estimated spleen volume greater than or equal to (≥)450 cubic centimeter (cm ³)
- •Myelofibrosis Symptom Assessment Form, version 4.0 (MFSAF v.4.0) TSS ≥10, or at least 2 of 7 MFSAF-assessed symptoms with scores ≥
- •Eastern Cooperative Oncology Group performance score (ECOG PS) of 0, 1, 2, or
- •Prior therapy with at least 1 type I JAK2 inhibitor, and either failed to achieve a response or relapsed after achieving a response.
- •Absolute neutrophil count greater than or equal to 1,000 per microliter of blood (ANC ≥1.0×10^9/L).
- •Platelet count ≥75×10^9/L.
- •Estimated glomerular filtration rate greater than or equal to 45 milliliters per minute per 1.73 square meters (eGFR ≥45 mL/min/1.73m²).
- •Serum total bilirubin ≤2.0 × upper limit of normal (ULN).
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 × upper limit normal (ULN).
- •QTcF ≤470 msec.
- •Polycythemia vera (PV) Only
- •Confirmed diagnosis of PV
- •Participants must have high-risk disease as defined by 60 years of age or older and/or have prior history of thrombotic event
- •R/R or intolerant to at least one line of prior therapy including but not limited to interferon-based therapies, ruxolitinib, or hydroxyurea (HU) as defined by European LeukemiaNet (ELN) criteria
排除标准
- •Prior splenectomy or splenic irradiation within 3 months.
- •Ongoing use of systemic corticosteroids at dose equivalent to greater than (>) 20 milligrams per day (mg/day) of prednisone.
- •Active, uncontrolled systemic infection or active Hepatitis B or C
- •Chemotherapy in the previous 4 weeks or prior JAK2 inhibitor not discontinued per required washout prior to first dose
- •Peripheral neuropathy ≥ Grade 2 (NCI CTCAE v 5.0).
- •Pregnant or breastfeeding: males planning to father a child during treatment and for 3 months after last dose.
- •Requirement for therapy with a medication that is a strong Cytochrome P450 3A4 CYP3A4 inhibitor as a concomitant medication.
- •Currently on an interventional therapeutic trial in the treatment phase.
- •Significant cardiovascular disease
- •Active second primary malignancy (or diagnosed within 2 years) at high risk of progression, with standard exceptions (treated skin cancer, in situ cervical cancer, curatively treated localized breast/prostate cancer)
- •Prolongation of the corrected QTcF ≥470 millisecond during screening
- •Individual with a history of (noninfectious) pneumonitis/interstitial lung disease.
- •First line (1L) MF only:
- •Prior treatment with JAK2 inhibitors
- •High-risk R/R PV only:
- •Prior PV-directed therapy without required washout
- •Active or chronic bleeding within 2 months prior to enrollment
- •Clinically significant thrombosis (e.g., pulmonary embolism, deep vein thrombosis, or splenic vein thrombosis) within 2 months prior to enrollment
- •Requires phlebotomy at hematocrit levels <45%.
研究组 & 干预措施
Cohort 1
Dose A of LY5830966 taken orally by participants.
干预措施: LY5830966 (Drug)
Cohort 2
Dose B of LY5830966 taken orally by participants.
干预措施: LY5830966 (Drug)
Cohort 3
Dose C of LY5830966 taken orally by participants.
干预措施: LY5830966 (Drug)
Cohort 4
Dose D of LY5830966 taken orally by participants.
干预措施: LY5830966 (Drug)
Cohort 5
Dose E of LY5830966 taken orally by participants.
干预措施: LY5830966 (Drug)
Dose Expansion Cohort 1
Candidate RP3D of LY5830966 taken orally by participants.
干预措施: LY5830966 (Drug)
Dose Expansion Cohort 2
Alternative candidate RP3D of LY5830966 taken orally by participants.
干预措施: LY5830966 (Drug)
Dose Exploration Cohort 1
Dose F of LY5830966 taken orally by participants
干预措施: LY5830966 (Drug)
Dose Exploration Cohort 2
Dose G of LY5830966 taken orally by participants
干预措施: LY5830966 (Drug)
Dose Exploration Cohort 3
Dose H of LY5830966 taken orally by participants[
干预措施: LY5830966 (Drug)
结局指标
主要结局
Number of patients with Dose Limiting Toxicities (DLTs)
时间窗: Baseline through study completion, an average of 1 year
Protocol-defined potential DLTs will be assessed by the Safety Review Committee at routine intervals.
Number of patients with treatment-emergent adverse events as assessed by CTCAE v 5.0.
时间窗: Baseline through study completion, an average of 1 year
Treatment Emergent AEs will be assessed during routine study visits and compared to Baseline to continuously evaluate safety and tolerability of AJ1-11095.
To establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of AJ1-11095
时间窗: Baseline through study completion, an average of 1 year
Safety evaluations will occur consistently for each patient and across patients to assess MTD or RP2D. See description of safety evaluations described in outcomes 1 and 2 mentioned above.
Number of patients with treatment-emergent adverse events (TEAEs) as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v 5.0).
时间窗: Baseline through study completion, an average of 1 year
Treatment Emergent AEs will be assessed during routine study visits and compared to Baseline to continuously evaluate safety and tolerability of LY5830966.
To establish the maximum tolerated dose (MTD) and/or recommended phase 3 dose (RP3D) of LY5830966
时间窗: Baseline through study completion, an average of 1 year
Safety evaluations will occur consistently for each patient and across patients to assess MTD or RP3D. See description of safety evaluations described in outcomes 1 and 2 mentioned above.
次要结局
- To assess clinical response to AJ1-11095 evaluated by spleen volume assessments.(Baseline through Week 24)
- To assess clinical response to AJ1-11095 evaluated by spleen length assessments.(Baseline through Week 24)
- To evaluate the Tmax of AJ1-11095(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 assess clinical response to AJ1-11095 evaluated by the Total Symptom Score (TSS).(Baseline through Week 24)
- To assess clinical response to AJ1-11095 evaluated through spleen size improvement.(Baseline through Week 24)
- To evaluate the Area Under the Curve (AUC) of AJ1-11095(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(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(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 assess clinical response to LY5830966 evaluated by the Total Symptom Score (TSS).(Baseline through Week 24)
- To assess clinical response to LY5830966 evaluated by spleen volume assessments.(Baseline through Week 24)
- To assess clinical response to LY5830966 evaluated by spleen length assessments.(Baseline through Week 24)
- To assess clinical response to LY5830966 evaluated through spleen size improvement.(Baseline through Week 24)
- To evaluate the Area Under the Curve (AUC) of LY5830966(Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), and Cycle 2 (Day 1 and 24 hrs post).)
- To evaluate the Cmax of LY5830966(Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), and Cycle 2 (Day 1 and 24 hrs post).)
- To evaluate the Tmax of LY5830966(Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), and Cycle 2 (Day 1 and 24 hrs post).)
- To evaluate the half-life of LY5830966(Pre dose and post dose Cycle 1 (Day 1, and Day 2 (24hrs post), and Cycle 2 (Day 1 and 24 hrs post).)