Pacritinib With Aza for Upfront Myelodysplastic Syndrome

Official title

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

Overview

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.

Detailed description

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.

Phase II Design:

Phase two of this trial is designed with the potential for early termination in the case of failure to prove efficacy. The design will be a Simon's two-stage admissible minimax design.40 Choice of design is guided by a desire to stop the trial early if the actual overall response rate (ORR) rate is 10% or less. If the ORR rate is 30% or greater, the investigators would like to have a low probability of failing to conclude effective.

With this design, the investigators have no more than a 10% chance of concluding ineffective (≤10% ORR) when the ORR is at least 30%. Similarly, the investigators have no more than a 5% chance of concluding effective (≥30% ORR) when it is ineffective. If the actual ORR is 10% or lower, the investigators have 55% probability that the trial will stop after the first fifteen subjects. The first stage of fifteen patients will include the patients in the phase one portion who were on the chosen phase two dose. If there are greater than five successes after the total twenty-five patient cohort, then the trial is considered a success.

Interventions

• Drug Pacritinib
  Pacritinib is an oral kinase inhibitor with activity against wild-type JAK2, mutant JAK2V617F, FLT3, IRAK1, and ACVR1. Administered twice daily at 200mg or 400mg total daily dose per Phase 1 dose escalatio
• Drug Azacitidine
  Lyophilized powder in 100mg single dose vials to be diluted in saline to generate 75 mg/m2 intravenous or subcutaneous solutions. Azacitidine to be given at 75mg/m2 infusion days 1-7 every four weeks.
• Procedure Bone Marrow Biopsy and Aspirate
  Bone marrow aspiration and biopsy as per standard of care obtained at baseline, infusion visit Days 2-7, and study completion Day 112.
• Diagnostic test Laboratory Testing
  Laboratory Tests to include CMP, Magnesium Phosphorous, LDH, Uric Acid, and CBC with Differential will be performed at baseline, Cycle 1, and at the start of each subsequent cycle.
• Diagnostic test Electrocardiogram
  ECG will be obtained on day 7 of each cycle to document QTc interval. ECGs will be performed at clinician's discretion in addition to ones required by study as outlined above.
• Other Quality of Life in Myelodysplasia Scale
  Quality of life will be assessed using QUALMS at baseline and after completion of 4 cycles (Day 112). QUALMS is a 38-item assessment tool for patients with myelodysplastic syndromes (MDS).

Primary outcome measures

• Optimal Dose of Pacritinib in Combination with Azacitidine - Phase 1 [Time frame: Baseline through Day 28 (Cycle 1)]
• Rate of Dose Limiting Toxicities (DLTs) - Phase 1 [Time frame: Baseline through Day 28 (Cycle 1)]
• Overall Response Rate (ORR) - Phase 2 [Time frame: Baseline through Week 16 (approximately 4 months)]

Secondary outcome measures (8)

• Duration of Overall Response Rate - Phase 2 [Time frame: Up to 2 years after last patient enrolled]
• Overall Surival - Phase 2 [Time frame: Up to 24 months]
• Number of Treatment Emergent Adverse Events (TEAEs) [Time frame: Baseline through Cycle 4, plus 30 days (Approximately 5 months)]
• Molecular Response Rate (Phase 2) [Time frame: Baseline through Week 16 (approximately 4 months)]
• Change in Intracellular Signaling Pathway Activation (JAK/STAT, NF-κB and AKT/mTOR [Time frame: Baseline]
• Change in Intracellular Signaling Pathway Activation (JAK/STAT, NF-κB and AKT/mTOR [Time frame: After four days of azacitidine and pacritinib therapy]
• Assessment of Quality of Life Using the quality of life in myelodysplasia scale (QUALMS) [Time frame: At Baseline]
• Assessment of Quality of Life Using the quality of life in myelodysplasia scale (QUALMS) [Time frame: After 4 cycles of treatment (approximately 112 days)]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07387354 · iRIS ID- 2024-2998 · JT 36125

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗