Therapeutic RSK1 Targeting in Myelofibrosis
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Number of participants with adverse events
研究概览
简要总结
This is a phase Ib study evaluating PMD-026, an oral inhibitor of ribosomal protein S6 kinase A1 (RSK1), in participants with myelofibrosis (MF).The dose escalation portion utilizes a standard 3+3 design to evaluate two dose levels with an additional dose de-escalation portion to identify the recommended phase II dose (RP2D); subsequently, an additional 6 patients will be enrolled in the dose expansion portion evaluating the efficacy of PMD-026.
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
- •Histologically confirmed diagnosis of primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis in chronic phase, according to the 2016 WHO criteria
- •Patients must have had at least 1 prior JAK inhibitor treatment for a minimum of 12 weeks and their disease was determined resistant or refractory, and/or their response was lost or intolerant to treatment.
- •Intermediate-2 or High-risk MF, as defined by the Dynamic International Prognostic Scoring System (DIPSS).
- •Presence of measurable disease as defined by:
- •Splenomegaly defined as estimated spleen volume of ≥450 cm3 by imaging with either MRI, CT or ultrasound, or a palpable spleen >=5 cm from the costal margin.
- •Baseline MFSAF v4.0 Total Symptom Score ≥ 10
- •At least 18 years of age.
- •ECOG performance status ≤
- •Adequate organ function as defined below:
- •Total bilirubin ≤ 1.5 x IULN (unless the participant has a history of Gilbert's syndrome)
- •AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
- •Creatinine clearance ≥ 30 mL/min by Cockcroft-Gault
- •Adequate laboratory parameters:
- •Absolute Neutrophil Count (ANC) ≥ 100/mm^3
- •Platelets ≥50,000/mm^3
- •Blasts ≤ 10% on manual differential
- •The effects of PMD-026 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 30 days after completion of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.
- •Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
排除标准
- •Prior allogeneic or autologous stem cell transplantation within the previous 12 months
- •Prior splenectomy
- •Prior splenic irradiation if < 3 months between last radiation and screening visit.
- •Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
- •Currently receiving any other investigational agents or planning to receive any investigational agents within 28 days before the planned first dose of PMD-
- •Currently receiving a JAK inhibitor or planning to receive a JAK inhibitor within 7 days before the planned first dose of PMD-
- •In patients with ongoing JAK inhibitor therapy (i.e. ruxolitinib) at screening, it must be tapered over a period of at least 7 days. Patients on a low dose of ruxolitinib (e.g. 5 mg QD) may have a reduced taper period or no taper.
- •Known active disease involving the CNS.
- •QTcF >450 msec for males, >470 msec for females (calculated using Fridericia's formula).
- •A history of hypersensitivity or allergic reactions attributed to compounds of similar chemical or biologic composition to PMD-026 or other agents used in the study.
- •Any major surgery within 28 days prior to the first dose of PMD-
- •Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, autoimmune disease, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
- •Unable to swallow or retain oral medications.
- •Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 35 days of study entry (repeated on C1D1).
研究组 & 干预措施
Dose Expansion - Recommended Phase II Dose (RP2D): PMD-026
PMD-026 will be taken by mouth twice daily at the recommended phase II dose every day of each 28-day cycle.
Dose Escalation Dose Level 1 (Starting Dose): PMD-026
PMD-026 will be taken by mouth twice daily at the assigned dose every day of each 28-day cycle.
Dose Escalation Dose Level -1: PMD-026
PMD-026 will be taken by mouth twice daily at the assigned dose every day of each 28-day cycle.
干预措施: PMD-026 (Drug)
Dose Escalation Dose Level 2: PMD-026
PMD-026 will be taken by mouth twice daily at the assigned dose every day of each 28-day cycle.
干预措施: PMD-026 (Drug)
结局指标
主要结局
Number of participants with adverse events
时间窗: From cycle 1 day 1 through 28 days after last dose (estimated to be 1 year and 28 days)
Graded per CTCAE v5.0.
Number of participants with dose limiting toxicities (DLTs) based on occurrence of serious treatment-emergent adverse events (Dose Escalation only)
时间窗: During cycle 1 of treatment (each cycle is 28 days)
Dose limiting toxicities are defined in the protocol.
Recommended phase II dose (RP2D) (Dose Escalation only)
时间窗: Completion of cycle 1 (each cycle is 28 days) of all dose-escalation patients (estimated to be 1 year and 28 days)
The RP2D will be determined based on review of safety and tolerability endpoints in dose escalation.
Changes in spleen size (Dose Expansion and RP2D Cohort in Dose Escalation)
时间窗: Baseline and after 24 weeks of treatment (estimated to be 24 weeks)
Measured by ultrasound or other abdominal imaging.
Changes in Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 Total Symptom Score (Dose Expansion and PR2D Cohort in Dose Escalation)
时间窗: Baseline and after 24 weeks of treatment (estimated to be 24 weeks)
The MFSAF assesses patient's symptom burden with 7-items that are scored from 0 (Absent) to 10 (Worst Imaginable). The total score can range from 0-70 with the higher score meaning more severe symptoms.
Bone marrow histopathologic response (Dose Expansion and RP2D Cohort in Dose Escalation)
时间窗: Baseline and after 24 weeks of treatment (estimated to be 24 weeks)
Bone marrow histopathologic response will be evaluated by the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria.
Overall response rate (ORR) (Dose Expansion and RP2D Cohort in Dose Escalation)
时间窗: Baseline and after 24 weeks of treatment (estimated to be 24 weeks)
Defined as CR (complete remission/response) + PR (partial remission/response) + CI (clinical improvement). Responses are defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) consensus.
次要结局
- Percentage of patients with 35% or greater reduction in spleen volume as determined by ultrasound or other imaging modalities(At 24 weeks and at the end of treatment (estimated to be 1 year))
- Percentage of participants with 25% or greater reduction in spleen volume as determined by ultrasound or other imaging modalities(At 24 weeks and at the end of treatment (estimated to be 1 year))
- Percentage of patients with a 50% or greater improvement in Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) Total Symptom Score(At 24 weeks and at the end of treatment (estimated to be 1 year))
- Percentage of patients with a reduction in National Institutes of Health Patient Reported Outcomes Measurement Information System (NIH PROMIS) Short Form v2.0 - Physical Function 8c 7-day scores(At 24 weeks and at the end of treatment (estimated to be 1 year))
- Overall response rate (ORR)(At 24 weeks and at the end of treatment (estimated to be 1 year))
- Change in bone marrow fibrosis grading by WHO grading(At 24 weeks and at the end of treatment (estimated to be 1 year))
- Change in blast percentage in the bone marrow(At 24 weeks and at the end of treatment (estimated to be 1 year))