This study will be conducted as a phase 1/2 study of safety and preliminary efficacy ofpacritinib 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 phasetwo portion will employ a simon min-max two-stage design whereby fifteen patients will beenrolled in the first stage then ten more if at least two patients in stage one have aresponse. The dosing of pacritinib for the phase two study will be based on the phase onefindings. Standard dosing of azacitidine will be used. A correlative study will beconducted in conjunction with the trial where the investigators will measure whole bloodcollected pre-treatment and at four days post-treatment to measure intracellular flow andphosflow to detect JAK/STAT, NF-κβ, and AKT/mTOR signaling in patient samples and howtreatment affects these pathways.
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.
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
Other Name: Vonjo
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.
Other Name: Vidaza,5-Azacytidine
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.
Other Name: BMA/BMB,Bone Marrow Examination,Bone Marrow Test
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.
Other Name: CMP,Magnesium Phosphorous,LDH,Uric Acid
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 Name: ECG
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).
Other Name: QUALMS
Inclusion Criteria:
- Individuals must meet all of the following inclusion criteria to be eligible to
participate in the study:
1. 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.
2. Subjects must have recovered from the toxic effects of any prior chemotherapy
to ≤ Grade 1 (except alopecia).
3. Required screening visit laboratory values: CrCL ≥45; total bilirubin <2xULN
except for patients with known Gilbert's disease; SGPT (ALT) ≤2xULN, PTT
≤1.5xULN.
4. Negative pregnancy test for women with child-bearing potential at screening
visit.
5. Initial screening baseline QTc ≤480ms.
6. Patients must be able to sign consent and be willing and able to comply with
scheduled visits, treatment plan and laboratory testing.
7. 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:
1. Any prior exposure to a hypomethylating agent (azacitidine or decitabine)
2. Any prior exposure to JAK2 inhibitor therapy (ie ruxolitinib or prior
pacritinib therapy)
3. Any exposure within the past seven days of initiation of study treatment to a
strong CYP3A inhibitor/inducer.
4. Subjects must not be receiving any chemotherapy agents (except hydroxyurea)
within the past thirty days.
5. 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.
6. 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.
7. 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.
8. Bleeding event grade >=2 (CTCAE 5.0) within prior three months unless provoked
(e.g., by surgery or trauma)
9. Use of anticoagulant or antiplatelet agents within fourteen days prior to day
one with the exception of low dose aspirin (81mg daily).
10. 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.
11. Active or uncontrolled diarrhea or constipation.
12. Subjects must not have evidence of active disease in the CNS.
13. Subjects must not have received any investigational agents within fourteen days
or five half-lives (whichever is longer) of study entry.
14. 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).
15. 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.
16. Subjects with bacteremia must have documented negative blood cultures prior to
study entry.
17. Subjects who are currently candidates for allogeneic transplantation, have a
suitable donor, and are willing to undergo transplantation prior to study
start.
18. 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.
Not Provided
Chetan S Jeurkar, DO
215-955-8874
Chetan.Jeurkar@jefferson.edu
Chetan Jeurkar, DO, Principal Investigator
Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University