Pacritinib in Combination With Low Dose Decitabine in Intermediate-High Risk Myelofibrosis or Myeloproliferative Neoplasm (MPN)/Myelodysplastic Syndrome (MDS)

NCT02564536 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: 201510166
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

For the first 28 day cycle, all patients will be treated with single agent pacritinib at 200 mg twice daily. The investigators chose this starting dose based on the previous three phase I studies of pacritinib as a single agent which showed that the maximum tolerated dose (MTD) to be 500 mg, and subsequently, the dose of 400 mg daily was recommended for the phase II studies. Recently, the results of the phase III PERSIST-1 trial comparing pacritinib to best available therapy (BAT) in patients with MF was reported at the 2015 American Society of Clinical Oncology (ASCO) annual meeting. Pacritinib was found to be significantly more effective than BAT at reducing spleen volume at 24 weeks of therapy and improving constitutional symptoms. Low dose decitabine has demonstrated depletion of DNMT1 in normal hematopoietic stem cells (HSC) without cytotoxicity and subcutaneous (SC) instead of intravenous (IV) administration may avoid high peak levels that can cause apoptosis. Furthermore, the low toxicity associated with low dose decitabine would allow for more frequent (1 to 3 times weekly) administration of the drug which would catch more cells in S-phase via greater exposure time. Based on these findings, a starting dose of decitabine 5 mg/m2 SC twice weekly should be well tolerated and effective in patients with MF and MPN/MDS syndromes when combined with pacritinib 400 mg daily.

Conditions

Chronic Myelomonocytic Leukemia; Juvenile Myelomonocytic Leukemia; Atypical Chronic Myeloid Leukemia; Myeloproliferative Neoplasm; Myelodysplastic Syndromes; Myelofibrosis

Outcome Measures

Primary Outcomes (1)

• Safety of regimen as measured by adverse events

  The descriptions and grading for adverse events are found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

  30 days after completion of treatment (up to 1 year)

Secondary Outcomes (4)

• Rate of objective response as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) consensus

  End of treatment (up to 48 weeks)

• Rate of hematologic response

  End of treatment (up to 48 weeks)

• Rate of symptom response as measured by the total symptom score (TSS)

  End of treatment (up to 48 weeks)

• Rate of spleen response

  End of treatment (up to 48 weeks)

Study Arms (1)

Arm 1: Pacritinib and Decitabine

EXPERIMENTAL

* Patients will receive one cycle of single agent pacritinib. * Patients who tolerate single agent pacritinib will then receive up to 11 cycles of pacritinib and decitabine combination therapy. * Patients who do not tolerate single agent pacritinib (require dose interruption for more than 7 days before Cycle 2 Day 1) will be considered non-evaluable and replaced. * Pacritinib will be administered orally at a dose of 200 mg twice daily continuously for Days 1 through 28 of a 28-day cycle. * Decitabine will be administered as a subcutaneous injection in clinic on Days 1, 5, 8, 12, 15, 19, 22, and 26 of a 28-day cycle. * Patients may continue treatment for up to 12 cycles.

Drug: Pacritinib; Drug: Decitabine

Interventions

Pacritinib DRUG

-Patients should take pacritinib at approximately the same times every day with a glass of water, with or without food.

Arm 1: Pacritinib and Decitabine

Decitabine DRUG

-From commercial stock

Arm 1: Pacritinib and Decitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Confirmed diagnosis of:
• Primary MF or post-PV/ET MF classified as high risk, intermediate-2 risk, or intermediate-1 risk who are unresponsive or unable to receive current therapy which may or may not include ruxolitinib OR
• MPN/MDS Syndrome (chronic myelomonocytic leukemia \[CMML\], juvenile myelomonocytic leukemia \[JMML\], atypical chronic myeloid leukemia \[aCML\], or MDS/MPN unclassifiable)
• ECOG 0-3
• Required laboratory values:
• Neutrophil count of ≥ 0.5 x 109/L
• Bone marrow blood blast count \< 20%
• AST and ALT ≤ 3 x ULN (≤ 5 x ULN if liver is involved by extramedullary hematopoiesis as judged by the investigator or if related to iron chelator therapy that was started within the prior 60 days)
• Total creatinine \< 2.5mg/dL
• Total bilirubin ≤ 2.0 x ULN
• Age ≥ 18 years old at enrollment.
• If female, must be:
• postmenopausal for at least 1 year before the screening visit OR
• surgically sterile OR
• agreeable to practicing 2 effective methods of contraception prior to study entry, for the duration of study participation, and for 30 days after the last dose of study treatment.

You may not qualify if:

• Prior treatment with more than two JAK2 inhibitors or with pacritinib
• Known positive status for human immunodeficiency virus (HIV)
• Chronic, active, or acute viral hepatitis A, B, or C infection, or a hepatitis B or C carrier
• Use of chemotherapy, biologic therapy, radiation therapy, erythropoietin or related erythropoiesis stimulating agents, or investigational therapy within 2 weeks of the first dose of study drug
• History of allogeneic stem cell transplant or transplant eligible
• Currently receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to pacritinib or other agents used in the study
• Ongoing gastrointestinal medical condition such as Crohn's disease, inflammatory bowel disease, chronic diarrhea, or chronic constipation that could interfere with absorption of oral medication
• Active bleeding that requires hospitalization during the screening period
• Other malignancy requiring active treatment at time of study entry
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, or serious medical or psychiatric illness/social situations that would limit compliance with study requirements.
• Life expectancy \< 6 months
• Pregnant and/or breastfeeding. Patient must have a negative pregnancy test within 14 days of study entry.
• Receiving treatment with any potent CYP3A4 inhibitors within 7 days of the first dose of study drug
• Patients with MF who are eligible for enrollment in the pacritinib "PERSIST-2" study at WUSM (NCT02055781) HRPO 201406075.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• CTI BioPharma: collaborator

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Myeloproliferative Disorders; Myelodysplastic Syndromes; Primary Myelofibrosis

Interventions

11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene; Decitabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Camille Abboud, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2015
• First Posted: September 30, 2015
• Study Start: June 1, 2017
• Primary Completion: June 30, 2020
• Study Completion: June 30, 2020
• Last Updated: May 8, 2017

Record last verified: 2017-05

Data Sharing

• IPD Sharing: Will not share