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.
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.
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.
Sequential
Pacritinib
DrugPacritinib 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
Azacitidine
DrugLyophilized 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.
Bone Marrow Biopsy and Aspirate
Procedure/SurgeryBone marrow aspiration and biopsy as per standard of care obtained at baseline, infusion visit Days 2-7, and study completion Day 112.
Laboratory Testing
Diagnostic testLaboratory 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.
Electrocardiogram
Diagnostic testECG 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.
Quality of Life in Myelodysplasia Scale
Other interventionQuality 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).
Optimal Dose of Pacritinib in Combination with Azacitidine - Phase 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
"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
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.
Duration of Overall Response Rate - Phase 2
Time from first documented response (CR, PR, or HI per IWG criteria) until relapse, progression, or death from any cause.
Overall Surival - Phase 2
Time from study enrollment to death from any cause.
Number of Treatment Emergent Adverse Events (TEAEs)
Incidence, seriousness, severity, outcome, discontinuation or dose modifications related to TEAEs. This is separate from the primary endpoint of phase one which will be rate of DLTs.
Molecular Response Rate (Phase 2)
Assessment of molecular response will be done via rate of disappearance of relevant mutations via next-generation sequencing on pre and post treatment bone marrow samples.
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Thomas Jefferson University
Lead sponsor
CTI BioPharma
Collaborator
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