Myelofibrosis Treated With Pacritinib Before aSCT. (HOVON134MF) (HOVON134MF)

A Phase II Trial in Patients With Myelofibrosis (Primary, Post-ET or Post PV-MF) Treated With the Selective JAK2 Inhibitor Pacritinib Before Reduced-intensity Conditioning Allogeneic Stem Cell Transplantation

The only curative treatment for patients with myelofibrosis (MF) is allogeneic stem cell transplantation (SCT). Treatment with JAK2 inhibitors like pacritinib improves condition of MF patients, decreases spleen size and might diminish graft-versus-host disease (GvHD), thereby improving the outcome of SCT.

Study Overview

• Status: Active, not recruiting
• Conditions: Myelofibrosis
• Intervention / Treatment: Drug: Pacritinib

Detailed Description

Despite recent new therapeutic options, allogeneic Stem Cell Transplantation remains the only curative option in patients with Myelofibrosis. Therefore, optimalization of this therapy remains a major challenge. Improvement of the clinical condition of these patients, decreasing spleen size can be accomplished by JAK2 inhibitor treatment and might improve SCT outcome. In addition, selective JAK2 inhibitors might modulate GvHD which can also add to improved SCT outcome. Also, decreasing the burden/activity of the disease before allo-SCT might also improve final disease response. The first, limited, clinical data of ruxolitinib treatment before allo-SCT show controversial effects on the outcome of SCT. Therefore, additional prospective clinical trials have to be done to establish the role of JAK2 inhibition before allogeneic SCT. Since ruxolitinib has considerable myelosuppressive effects which might limit the clinical use in some MF patients, other selective JAK2 inhibitors might be useful in this setting. Pacritinib, as a JAK2/FLT3 inhibitor, has a very potent JAK2 inhibitory activity without myelosuppressive effects and might therefore be more suitable than ruxolitinib. The major possible side effects are gastro-intestinal and can be managed with medication. In several studies, pacritinib has shown to be effective in decreasing spleen size and has shown to improve clinical condition of patients. Therefore, this compound seems promising in improving the outcome of allo-SCT. Although pacritinib causes no inhibition of JAK1 activity and therefore might have limited effects in decreasing inflammatory response, this might also be of benefit since a "withdrawal syndrome" as has been described after cessation of ruxolitinib is not to be expected.

With this trial, using pacritinib treatment before allo-SCT, the issue of improvement of SCT outcome will be investigated.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium
    • BE-Antwerpen-ZNASTUIVENBERG
  • Gent, Belgium
    • BE-Gent-UZGENT
  • Leuven, Belgium
    • BE-Leuven-UZLEUVEN
  • Roeselare, Belgium
    • BE-Roeselare-AZDELTA
• Netherlands
  • Amsterdam, Netherlands
    • NL-Amsterdam-AMC
  • Amsterdam, Netherlands
    • NL-Amsterdam-VUMC
  • Groningen, Netherlands
    • NL-Groningen-UMCG
  • Maastricht, Netherlands
    • NL-Maastricht-MUMC
  • Nijmegen, Netherlands
    • NL-Nijmegen-RADBOUDUMC
  • Rotterdam, Netherlands
    • NL-Rotterdam-ERASMUSMC
  • Rotterdam, Netherlands
    • NL-Rotterdam-EMCDANIEL
  • Utrecht, Netherlands
    • NL-Utrecht-UMCUTRECHT

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with a confirmed diagnosis of post-ET, post-PV or primary myelofibrosis
• Intermediate-2 or high-risk according to DIPSS plus (Appendix E)
• Age 18-70 years inclusive
• WHO performance status 0-2 (Appendix C)
• All men and women of childbearing potential must agree to use adequate contraception during the study
• Written informed consent
• Patient is capable of giving informed consent

Exclusion Criteria:

• Previous treatment with JAK2 inhibitors within 2 weeks of study inclusion. Patients who have been treated with pacritinib as their previous JAK2 inhibitor treatment cannot participate in this study
• Any GI or metabolic condition (e.g. inflammatory or chronic functional bowel disorder such as Crohn's Disease, Inflammatory Bowel Disease, chronic diarrhea or constipation) that could interfere with absorption of oral medication
• Left ventricular cardiac ejection fraction of ≤ 45% by echocardiogram or multigated acquisition (MUGA) scan
• Impaired liver and renal function, defined by liver transaminases (aspartate aminotransferase [AST]/serum glutamic oxaloacetic transaminase [SGOT] and alanine aminotransferase [ALT]/serum glutamic pyruvic transaminase [SGPT]), >3 × the upper limit of normal (ULN) (AST/ALT >5 × ULN if transaminase elevation is related to MF), direct bilirubin >4× ULN, and creatinine clearance ˂ 40 ml/min.
• Impaired coagulation function, defined by prothrombin time (PT)/international normalized ratio (INR), partial thromboplastin time (APTT)>1.5 x ULN.
• Experimental treatment within four weeks before inclusion for PMF, Post-PV, or Post-ET MF
• Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix D)
• Treatment with a potent strong CYP3A4 inhibitor or a strong cytochrome P450 (CYP450) inducer within the last 2 weeks
• Treatment with anticoagulation or antiplatelet agents, except for aspirin dosages of ≤100 mg per day, within the last 2 weeks
• New York Heart Association Class II, III, or IV congestive heart failure
• QTc prolongation >450 ms as assessed by ECG and corrected by Federicia method or other factors that increase the risk for QT interval prolongation (e.g., heart failure, hypokalemia [defined as serum potassium <3.0 mEq/L that is persistent and refractory to correction], family history of long QT interval syndrome, or concomitant use of medications that may prolong QT interval)
• Significant recent bleeding history defined as NCI CTCAE grade ≥2 within the last 3 months, unless precipitated by an inciting event (e.g., surgery, trauma, injury)
• Any history of CTCAE grade ≥2 non-dysrhythmia cardiac conditions within the last 6 months. Patients with asymptomatic grade 2 non-dysrhythmia cardiac conditions may be considered for inclusion, with the approval of the principal investigator, if stable and unlikely to affect patient safety.
• Any history of CTCAE grade ≥2 cardiac dysrhythmias within the last 6 months. Patients with non-QTc CTCAE grade 2 cardiac dysrhythmias may be considered for inclusion, with the approval of the principal investigator, if the dysrhythmias are stable, asymptomatic, and unlikely to affect patient safety.
• Patients with active, uncontrolled infections
• Patients known to be HIV (human immunodeficiency virus)-positive
• Active hepatitis A, B or C
• History of active malignancy during the past 3 years, except basal carcinoma of the skin or stage 0 cervical carcinoma
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, cancer, etc.)
• Pregnant or breastfeeding women
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pacritinib treatment befor allo-SCT; The effect of pacritinib treatment during 3 to 4 cycles before allo-SCT on engraftment 6 months (day +180) post allo-SCT in MF patients.	Drug: Pacritinib; Patients receive up to 4 cycles of pacritinib before allo-SCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients receiving allo-SCT, with failure within or at day 180 post-transplant.	Failure can be defined by one of the following parameters: Primary graft failure; Acute graft versus host disease grade 3-4; Secondary graft failure; Death, from any cause	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Adverse events will be monitored.	5 years
Progression free survival	Progression free survival as time between registration or SCT until progression/relapse or death from any cause	5 years
Overall survival	Over all survival, calculated from either registration or SCT.	5 years
Relapse mortality	Death due to the disease or after progression	5 years
Non-relapse mortality	Death not due to disease or relapse	5 years
Quality of life during and after treatment	Quality of life during and after treatment will be recorded by use of the MPN-SAF questionnaire. From a total of 27 questions, the scores (from 0 to 10) from the following 10 questions are added and subsequently averaged to come to a total quality of life score.; fatigue; satisfction after a meal; stomach complaints; not able to perform activities; concentration problems; night sweat; itch; bone pain; fever; sudden weight loss	5 years

Collaborators and Investigators

• Sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Collaborators: CTI BioPharma; Dutch Cancer Society
• Investigators: Principal Investigator: Peter AW te Boekhorst, M.D. PhD, Erasmus Medical Center

Publications and helpful links

Helpful Links

• HOVON Foundation (STICHTING HEMATO-ONCOLOGIE VOOR VOLWASSENEN NEDERLAND)

Study record dates

Study Major Dates

• Study Start (Actual): June 4, 2018
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): February 1, 2027

Study Registration Dates

• First Submitted: March 26, 2018
• First Submitted That Met QC Criteria: August 23, 2018
• First Posted (Actual): August 24, 2018

Study Record Updates

• Last Update Posted (Actual): August 22, 2022
• Last Update Submitted That Met QC Criteria: August 19, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Myelofibrosis; Allogeneic Stem Cell Transplantation; Pacritinib; Hemato-Oncology; JAK2 inhibitor
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Primary Myelofibrosis
• Other Study ID Numbers: HO134; 2015-000195-98 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No