Pacritinib in CMML

NCT06159491 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: GCO 23-1514
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase 1/2 trial of pacritinib in combination with azacitidine in patients with Chronic Myelomonocytic Leukemia (CMML). Patients will be newly diagnosed or previously treated but could not have received a prior JAK inhibitor. Patients who have previously been treated with a hypomethylating agent (HMA) must have received ≤ 1 cycle. Pacritinib will be initially tested at a dose of 200mg twice daily (dose level 0) in combination with azacitidine 75mg/m2, which can be administered subcutaneously or intravenously, for 7 days in a 28-day cycle. If there are 2 DLTs in the first 6 patients, there will be a dose escalation to pacritinib 100mg twice daily (dose level -1) and an additional 6 patients will be enrolled. Based on the phase 1, 3+3 dose de-escalation design, 6-12 patients will be enrolled in the phase 1 portion. After the completion of phase 1 and identification of the recommended phase 2 dose (RP2D), the trial will then proceed to phase 2 which will employ a Simon two stage design. This portion will include the 6 patients enrolled during the phase 1 portion at the MTD. An interim analysis for futility will occur. If 3 or fewer patients have had a clinical benefit (CB) or better, as defined by 2015 MDS/MPN IWG criteria, the PI and DSMC will meet to discuss the totality of the evidence and determine if the trial shall proceed. In the second stage, an additional 12 patients will be enrolled.

Conditions

Chronic Myelomonocytic Leukemia

Outcome Measures

Primary Outcomes (3)

• Dose-limiting toxicity of Pacritinib in combination with Azacitidine

  Phase 1: The recommended phase 2 dose (RP2D) for the combination of pacritinib with azacitidine will be determined based on the dose limiting toxicity (DLT) rate, defined as the proportion of participants in the DLT-evaluable population that experience a DLT within the first 4 weeks (1 cycle) of initiating treatment at the recommended phase 2 dose.

  at the end of one 28-day cycle

• Proportion of participants that achieve clinical benefit or better measured using 2015 MDS/MPN IWG Criteria

  Phase 2: The preliminary efficacy of pacritinib in combination with azacitidine will be defined as the proportion of participants that achieve clinical benefit or better within 24 weeks (6 cycles, each cyce) of initiating treatment. Clinical benefit as defined by 2015 MDS/MPN IWG criteria within erythroid response, platelet response, neutrophil response, spleen response or symptom response.

  24 weeks (6 cycles, each cycle is 28 days)

• Overall Response Rate (ORR) to measure clinical benefit

  Clinical benefit will be determined by evaluating overall response rate (ORR) which is defined by complete remission.

  24 weeks (6 cycles, each cycle is 28 days)

Secondary Outcomes (8)

• Number of Adverse events Grade 3 or higher measured using NCI CTCAE Version 5.0

  up to 30 days after last study dose (up to 6 cycles, each cycle 28 days)

• Duration of Response (DOR) to measure efficacy

  up to 24 months

• Overall Survival (OS) to measure efficacy

  up to 24 months

• Disease Free Survival (DFS) to measure efficacy

  up to 24 months

• Change in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SASF TSS)

  Baseline and after 3 and 6 cycles of therapy, each cycle is 28 days

Study Arms (1)

Pacritinib in combination with Azacitidine

EXPERIMENTAL

Participants will take pacritinib 200 mg BID for each 28 day cycle, azacitidine 75mg/m2 will be administered IV or SQ QD D1-7 of each 28 day cycle

Drug: Pacritinib; Drug: Azacitidine

Interventions

Pacritinib DRUG

Participants will take Pacritinib 100 mg - 200mg BID for each 28 day cycle

Pacritinib in combination with Azacitidine

Azacitidine DRUG

Azacitidine 75mg/m\^2 will be administered IV or SQ QD D1-7 of each 28 day cycle

Pacritinib in combination with Azacitidine

Eligibility Criteria

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

You may qualify if:

• Participants must be ≥18 years of age at time of signing the Informed Consent Form (ICF).
• Participants must voluntarily sign an ICF.
• Participants must have a pathologically confirmed diagnosis of chronic myelomonocytic leukemia per World Health Organization (WHO) or International Consensus Classification (ICC)
• Participants must be JAK inhibitor naïve.
• Participants may be hypomethylating agent (HMA) naïve or can be treated with up to one prior cycle.
• Participants must have either proliferative CMML (WBC ≥13 x 109/L) or have intermediate-2 or high risk CMML by the clinical/molecular CMML-specific prognostic scoring system (CPSS-Mol).
• Participants must have a life expectancy of at least 24 weeks per investigator.
• ECOG performance status ≤ 3.
• Females of reproductive potential should use effective contraception during treatment with azacitidine and for 6 months after the last dose and males with female partners of reproductive potential should use effective contraception during treatment with azacitidine and for 3 months after the last dose.
• Male participants should agree to use an adequate method of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy.
• Must have adequate organ function as demonstrated by the following:
• Serum total bilirubin ≤ 2.0 x upper limit of normal (ULN) unless considered due to leukemic organ involvement, Gilbert's syndrome, or hemolysis.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN.
• Creatinine clearance (CrCl) of ≥30 mL/min.
• PT or INR \<=1.5x ULN and PTT or aPTT \<=1.5x ULN.

You may not qualify if:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 2 weeks or within 5 half-lives of the prior investigational agent, whichever is shorter, of the first dose of treatment.
• Active Graft Versus Host Disease (GVHD), or any GVHD requiring treatment with immunosuppression, with the exception of topical steroids and systemic steroids at a dose equivalent to prednisone 10mg or less and at a stable or decreasing dose. Any GVHD treatment (including calcineurin inhibitors) must be discontinued at least 28 days prior to Day 1 of study treatment.
• Systemic treatment with a strong CYP3A4 inhibitor or a strong CYP450 inducer within 14 days prior to treatment Day 1 (see Appendix 13.7 and 13.8 for a list of CYP3A4 inhibitors and CYP450 inducers, respectively). Shorter washout periods may be permitted with approval of the Study Chair, provided that the washout period is at least five half-lives of the drug prior to treatment Day 1.
• Other invasive malignancies within the last 3 years, except curatively treated non-melanoma skin cancer, localized prostate, cervical cancer, and any curatively treated carcinoma in situ.
• Presence of active serious infection.
• If a patient is identified to have COVID-19 during the screening period, participants may be considered eligible if in the opinion of the investigator there are no COVID-19 sequlae that may place the patient at a higher risk of receiving investigational treatment.
• Any serious, unstable medical or psychiatric condition that would prevent, (as judged by the Investigator) the patient from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
• Known history of uncontrolled human immunodeficiency virus (HIV).
• Significant recent bleeding history defined as NCI CTCAE grade ≥2 within 3 months prior to treatment Day 1, unless precipitated by an inciting event (e.g., surgery, trauma, or injury).
• Systemic treatment with medications that increase the risk of bleeding, including anticoagulants, antiplatelet agents (except for aspirin dosages of ≤100 mg per day), anti-vascular endothelial growth factor (anti-VEGF) agents, and daily use of COX-1 inhibiting Non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to treatment Day 1.
• Heart failure other than NYHA class I (asymptomatic, without limitation).
• QT corrected by the Fridericia method (QTcF) prolongation \>480 ms or other factors that increase the risk for QT interval prolongation (e.g., hypokalemia \[defined as serum potassium \<3.0 mEq/L that is persistent and refractory to correction\], or history of long QT interval syndrome).
• Known active systemic hepatitis B, or C infection requiring therapy or known cirrhosis.
• Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or pharmaceutical sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific participant.
• Organ transplant recipients other than bone marrow transplant.

Sponsors & Collaborators

• Douglas Tremblay: lead
• Sobi, Inc.: collaborator

Study Sites (1)

The Mount Sinai Hospital

New York, New York, 10029, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myelomonocytic, Chronic

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; Azacitidine

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)

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

Study Officials

• Douglas Tremblay, MD

  Icahn School of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tina Czaplinska

CONTACT

917-841-2454; tina.czaplinska@mssm.edu

Katherine Vandris

CONTACT

katherine.vandris@mssm.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Model Details: Phase I will follow a 3+3 design in phase I with starting dose of 200mg with possibility of de-escalation if more than 1/3 or 1/6 experience DLT. Phase I will require 6-12 patients to select the MTD. Phase II, if MTD selected in Phase I, will follow a Simon's two stage design. The null hypothesis that the true response rate is 55% will be tested against a one-sided alternative that the response rate is 80%. In the first stage, 6 patients treated at the MTD from Phase I will be included. If there are 3 or fewer responses in these 6 patients, the study may be stopped. Otherwise, 12 additional patients will be accrued for a total of 18. The null hypothesis will be rejected if 13 or more responses are observed in 18 patients. This design yields a type I error rate of 9% and power of 82% when the true response rate is 80%.

Study Record Dates

• First Submitted: November 28, 2023
• First Posted: December 6, 2023
• Study Start: September 18, 2024
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027
• Last Updated: August 21, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR
• Time Frame: Immediately following publication. No end date.
• Access Criteria: Researchers who provide a methodologically sound proposal. To achieve aims in the approved proposal. Specify Other Mechanism Request submitted to Principal Investigator via e-mail: douglas.tremblay@mssm.edu.

Locations

US (1)