Pacritinib With Aza for Upfront Myelodysplastic Syndrome
brief summary
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.
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