A Phase 1/2 Study of Pacritinib in Combination With Azacitidine for the Treatment of IPSS-M Moderate Low to Very High Risk Myelodysplastic Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 入组人数
- 25
- 主要终点
- Optimal Dose of Pacritinib in Combination with Azacitidine - Phase 1
研究概览
简要总结
This study will be conducted as a phase 1/2 study of safety and preliminary efficacy of pacritinib in combination with azacitidine for IPSS-M moderate low to very high risk MDS. Phase one will be a 3 + 3 design to assess the dose for the phase two portion. The phase two portion will employ a simon min-max two-stage design whereby fifteen patients will be enrolled in the first stage then ten more if at least two patients in stage one have a response. The dosing of pacritinib for the phase two study will be based on the phase one findings. Standard dosing of azacitidine will be used. A correlative study will be conducted in conjunction with the trial where the investigators will measure whole blood collected pre-treatment and at four days post-treatment to measure intracellular flow and phosflow to detect JAK/STAT, NF-κβ, and AKT/mTOR signaling in patient samples and how treatment affects these pathways.
详细描述
Phase I Design:
Phase one will be a 3 + 3 design to assess the dose for the phase two portion. The investigators will use a two-stage accrual design at each dose considered. The investigators will initially enter three subjects at 300mg total. If none of the three experiences a dose-limiting toxicity (DLT) the investigators will proceed to 400mg total as our second dose. If one of the three experiences DLT, the investigators will enter three additional patients at 300mg total. If at most one experience DLT in the cohort of six at 300mg total, the investigators will proceed with 400mg total as our second dose. If two or more experience DLT in the cohort of six at 300mg total, the investigators will proceed to 200mg total as our second dose. If two or more experiences DLT in the original cohort of three at 300mg total, the investigators will proceed to 200mg total as our second dose.
For the second dose (400mg or 200mg) three subjects will be initially treated. If none or one of the three experience a DLT, then the investigators will accrue three more subjects at that dose. If at most one of six experience a DLT, then the second dose will be given for phase two, called the highest tested dose if 400mg and highest tolerated dose if 200mg. If two or more of six experience a DLT on 400mg total, then the previous dose (300mg total) will be declared the highest tolerated dose. If two or more of six experience a DLT on 200mg total, then the investigators will terminate the trial.
If there are two or more dose-limiting toxicities in the cohort of three on 400mg total, then the previous dose (300mg total) will be declared highest tolerated dose. If there are two or more dose-limiting toxicities in the cohort of three on 200mg total, then the investigators will terminate the trial.
No patient will be treated at a higher dose until the three or six patients have completed their toxicity evaluation period at the current dose. With this plan, a dose with a 50% or greater probability of causing a dose-limiting toxicity has at most a 12.5% chance of satisfying the conditions for dose escalation after the first three subjects and at least a 50% chance of stopping at three. With the two-stages (3-6) together, there is at most a 17.2% chance of escalation.
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
- •Individuals must meet all of the following inclusion criteria to be eligible to participate in the study:
- •Patients must have histologic evidence of intermediate to high-risk myelodysplastic syndrome defined as having an IPSS-M score of moderate low, moderate high, high or very high risk. This will be assessed based on evaluations performed prior to screening for trial. Of note, the most recent evaluation pre-trial may be used which does not have to necessarily be at diagnosis.
- •Subjects must have recovered from the toxic effects of any prior chemotherapy to ≤ Grade 1 (except alopecia).
- •Required screening visit laboratory values: CrCL ≥45; total bilirubin <2xULN except for patients with known Gilbert's disease; SGPT (ALT) ≤2xULN, PTT ≤1.5xULN.
- •Negative pregnancy test for women with child-bearing potential at screening visit.
- •Initial screening baseline QTc ≤480ms.
- •Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing.
- •Patients must have an absolute neutrophil count of ≥750 to enroll in study, this must be achieved without the addition of growth factor medication.
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Any prior exposure to a hypomethylating agent (azacitidine or decitabine)
- •Any prior exposure to JAK2 inhibitor therapy (ie ruxolitinib or prior pacritinib therapy)
- •Any exposure within the past seven days of initiation of study treatment to a strong CYP3A inhibitor/inducer.
- •Subjects must not be receiving any chemotherapy agents (except hydroxyurea) within the past thirty days.
- •Subjects must not be receiving growth factors (erythropoietin mimetics, granulocyte stimulating factor mimetics, thrombopoietin mimetics) for two weeks prior to enrollment bone marrow. Subjects may not receive growth factors for the duration of this study.
- •Subjects with a "currently active" second malignancy, other than curatively treated non-melanoma skin cancer, carcinoma in situ of the cervix, resected incidental prostate cancer (staged pT2 with Gleason Score ≤ 6 and postoperative PSA <0.5 ng/mL), or other adequately treated carcinoma-in-situ are eligible. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for ≥ 1 year.
- •Subjects with uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure (NYHA class 2), myocardial infarction within the past 6 months or serious uncontrolled cardiac arrhythmia are not eligible.
- •Bleeding event grade >=2 (CTCAE 5.0) within prior three months unless provoked (e.g., by surgery or trauma)
- •Use of anticoagulant or antiplatelet agents within fourteen days prior to day one with the exception of low dose aspirin (81mg daily).
- •Subjects with other severe concurrent disease which in the judgment of the investigator would make the patient inappropriate for entry into this study are ineligible.
- •Active or uncontrolled diarrhea or constipation.
- •Subjects must not have evidence of active disease in the CNS.
- •Subjects must not have received any investigational agents within fourteen days or five half-lives (whichever is longer) of study entry.
- •Subjects must not be pregnant or breastfeeding. Pregnancy tests must be obtained for all females of child-bearing potential. Pregnant or lactating patients are ineligible for this study due to the unknown human fetal or teratogenic toxicities of pacritinib. Males or women of childbearing potential may not participate unless they have agreed to use a highly effective contraceptive method (defined in section 10.4.4).
- •Subjects who have uncontrolled infection are not eligible. Patients must have any active infections under control. Fungal disease must be stable for at least two weeks before study entry.
- •Subjects with bacteremia must have documented negative blood cultures prior to study entry.
- •Subjects who are currently candidates for allogeneic transplantation, have a suitable donor, and are willing to undergo transplantation prior to study start.
- •Subjects who cannot hold a medication, over the counter, or supplemental product that in the investigator's opinion may put the patient at increased harm.
研究组 & 干预措施
Pacritinib 100 mg twice daily (200 mg total) - Dose level X-1 + azacitidine
Participants will receive oral Pacritinib 100mg administered twice daily (200 mg total) in combination with Azacitidine 75mg/m² administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D)
干预措施: Laboratory Testing (Diagnostic Test)
Pacritinib 100 mg twice daily (200 mg total) - Dose level X-1 + azacitidine
Participants will receive oral Pacritinib 100mg administered twice daily (200 mg total) in combination with Azacitidine 75mg/m² administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D)
干预措施: Quality of Life in Myelodysplasia Scale (Other)
Pacritinib 100 mg AM / 200 mg PM (300 mg total) - Dose level X (starting dose) + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Quality of Life in Myelodysplasia Scale (Other)
Pacritinib 200 mg twice daily (400 mg total) - Dose level X+1 + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Bone Marrow Biopsy and Aspirate (Procedure)
Pacritinib 200 mg twice daily (400 mg total) - Dose level X+1 + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Laboratory Testing (Diagnostic Test)
Pacritinib 200 mg twice daily (400 mg total) - Dose level X+1 + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Electrocardiogram (Diagnostic Test)
Pacritinib 200 mg twice daily (400 mg total) - Dose level X+1 + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Quality of Life in Myelodysplasia Scale (Other)
Pacritinib RP2D + azacitidine - Phase 2 Expansion
Participants receive Pacritinib at the recommended Phase 2 dose (RP2D) as determined during the Phase 1 dose-escalation portion of the study, in combination with Azacitidine 75 mg/m2 intravenously or subcutaneously on Days 1-7 of each 28-day cycle.
干预措施: Laboratory Testing (Diagnostic Test)
Pacritinib RP2D + azacitidine - Phase 2 Expansion
Participants receive Pacritinib at the recommended Phase 2 dose (RP2D) as determined during the Phase 1 dose-escalation portion of the study, in combination with Azacitidine 75 mg/m2 intravenously or subcutaneously on Days 1-7 of each 28-day cycle.
干预措施: Electrocardiogram (Diagnostic Test)
Pacritinib RP2D + azacitidine - Phase 2 Expansion
Participants receive Pacritinib at the recommended Phase 2 dose (RP2D) as determined during the Phase 1 dose-escalation portion of the study, in combination with Azacitidine 75 mg/m2 intravenously or subcutaneously on Days 1-7 of each 28-day cycle.
干预措施: Quality of Life in Myelodysplasia Scale (Other)
Pacritinib RP2D + azacitidine - Phase 2 Expansion
Participants receive Pacritinib at the recommended Phase 2 dose (RP2D) as determined during the Phase 1 dose-escalation portion of the study, in combination with Azacitidine 75 mg/m2 intravenously or subcutaneously on Days 1-7 of each 28-day cycle.
干预措施: Azacitidine (Drug)
Pacritinib 100 mg AM / 200 mg PM (300 mg total) - Dose level X (starting dose) + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Azacitidine (Drug)
Pacritinib 100 mg AM / 200 mg PM (300 mg total) - Dose level X (starting dose) + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Pacritinib (Drug)
Pacritinib 200 mg twice daily (400 mg total) - Dose level X+1 + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Pacritinib (Drug)
Pacritinib 100 mg AM / 200 mg PM (300 mg total) - Dose level X (starting dose) + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Electrocardiogram (Diagnostic Test)
Pacritinib RP2D + azacitidine - Phase 2 Expansion
Participants receive Pacritinib at the recommended Phase 2 dose (RP2D) as determined during the Phase 1 dose-escalation portion of the study, in combination with Azacitidine 75 mg/m2 intravenously or subcutaneously on Days 1-7 of each 28-day cycle.
干预措施: Bone Marrow Biopsy and Aspirate (Procedure)
Pacritinib 100 mg twice daily (200 mg total) - Dose level X-1 + azacitidine
Participants will receive oral Pacritinib 100mg administered twice daily (200 mg total) in combination with Azacitidine 75mg/m² administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D)
干预措施: Azacitidine (Drug)
Pacritinib 100 mg twice daily (200 mg total) - Dose level X-1 + azacitidine
Participants will receive oral Pacritinib 100mg administered twice daily (200 mg total) in combination with Azacitidine 75mg/m² administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D)
干预措施: Bone Marrow Biopsy and Aspirate (Procedure)
Pacritinib 100 mg twice daily (200 mg total) - Dose level X-1 + azacitidine
Participants will receive oral Pacritinib 100mg administered twice daily (200 mg total) in combination with Azacitidine 75mg/m² administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D)
干预措施: Electrocardiogram (Diagnostic Test)
Pacritinib 100 mg AM / 200 mg PM (300 mg total) - Dose level X (starting dose) + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Bone Marrow Biopsy and Aspirate (Procedure)
Pacritinib 100 mg AM / 200 mg PM (300 mg total) - Dose level X (starting dose) + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Laboratory Testing (Diagnostic Test)
Pacritinib 200 mg twice daily (400 mg total) - Dose level X+1 + azacitidine
Participants will receive oral Pacritinib administered twice daily in combination with Azacitidine administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D); the Phase 2 portion uses a Simon two-stage design to evaluate efficacy and safety at the RP2D.
干预措施: Azacitidine (Drug)
Pacritinib RP2D + azacitidine - Phase 2 Expansion
Participants receive Pacritinib at the recommended Phase 2 dose (RP2D) as determined during the Phase 1 dose-escalation portion of the study, in combination with Azacitidine 75 mg/m2 intravenously or subcutaneously on Days 1-7 of each 28-day cycle.
干预措施: Pacritinib (Drug)
Pacritinib 100 mg twice daily (200 mg total) - Dose level X-1 + azacitidine
Participants will receive oral Pacritinib 100mg administered twice daily (200 mg total) in combination with Azacitidine 75mg/m² administered intravenously or subcutaneously on Days 1-7 of each 28-day cycle. The Phase 1 portion uses a 3+3 dose-escalation design to identify the recommended Phase 2 dose (RP2D)
干预措施: Pacritinib (Drug)
结局指标
主要结局
Optimal Dose of Pacritinib in Combination with Azacitidine - Phase 1
时间窗: Baseline through Day 28 (Cycle 1)
"Phase 1 of the study is designed to determine the optimal dose of pacritinib in combination with azacitidine in subjects with moderate, high, and very high risk MDS. The optimal dose (recommended Phase 2 dose, RP2D) will be defined as the highest dose level associated with an acceptable rate of dose-limiting toxicities (DLTs) during Cycle 1, using a standard 3 + 3 dose-escalation design. DLTs are defined per NCI CTCAE v5.0 (Section 7.5 of protocol): * Any grade ≥ 3 non-hematologic toxicity (excluding grade 3 nausea, vomiting, or diarrhea that improves to ≤ grade 2 within 5 days); * Prolonged grade 4 hematologic toxicities not due to persistent disease; * Any grade 5 toxicity not attributable to disease progression. Safety, tolerability, and pharmacodynamic data will support RP2D selection. "
Rate of Dose Limiting Toxicities (DLTs) - Phase 1
时间窗: Baseline through Day 28 (Cycle 1)
"the proportion of participants experiencing dose limiting toxicities (DLTs) occurring within thirty days of first dose of study agent that meets the following qualifications and is potentially related to study medication or combination will be considered a dose limiting toxicity. DLTs are defined per NCI CTCAE v5.0 as: * Any grade ≥ 3 non-hematologic toxicity (excluding grade 3 nausea, vomiting, or diarrhea that improves to ≤ grade 2 within 5 days); * Prolonged grade 4 hematologic toxicities (e.g., neutropenia or thrombocytopenia not due to persistent disease); * Any grade 5 toxicity not attributable to disease progression."
Overall Response Rate (ORR) - Phase 2
时间窗: Baseline through Week 16 (approximately 4 months)
Overall response rate (ORR) = patients achieving CR (or CR equivalent), PR, CRL, CRh, or hematologic improvement (HI) ÷ total patients. ORR per IWG 2023 criteria; hematologic response per IWG 2018. Responses: CR, CR equivalent, PR, CRL, CRh, or HI (erythroid, platelet, neutrophil). IWG 2023: CR: BM \<5% blasts; Hb ≥10 g/dL; platelets ≥100×10⁹/L; ANC ≥1.0×10⁹/L; no blood blasts. CR equivalent: Baseline \<5% blasts + complete cytogenetic response. PR: CR criteria except ≥50% blast reduction (still ≥5%). CRL: \<5% blasts; no blood blasts; recovery of 1-2 lineages. CRh: \<5% blasts; no blood blasts; platelets \>50×10⁹/L; ANC \>0.5×10⁹/L. IWG 2018 HI: HI-E: Hb ↑ ≥1.5 g/dL or RBC TI ≥8 wks. HI-P: Platelets ↑ ≥30×10⁹/L or from \<20 to \>20×10⁹/L + ≥100% ↑. HI-N: ≥100% ↑ and absolute ↑ ≥0.5×10⁹/L.
次要结局
- Duration of Overall Response Rate - Phase 2(Up to 2 years after last patient enrolled)
- Overall Surival - Phase 2(Up to 24 months)
- Number of Treatment Emergent Adverse Events (TEAEs)(Baseline through Cycle 4, plus 30 days (Approximately 5 months))
- Molecular Response Rate (Phase 2)(Baseline through Week 16 (approximately 4 months))
- Change in Intracellular Signaling Pathway Activation (JAK/STAT, NF-κB and AKT/mTOR(Baseline)
- Change in Intracellular Signaling Pathway Activation (JAK/STAT, NF-κB and AKT/mTOR(After four days of azacitidine and pacritinib therapy)
- Assessment of Quality of Life Using the quality of life in myelodysplasia scale (QUALMS)(At Baseline)
- Assessment of Quality of Life Using the quality of life in myelodysplasia scale (QUALMS)(After 4 cycles of treatment (approximately 112 days))