Pacritinib w/ Talazoparib in Pts w/ Myeloproliferative Neoplasms Unresponsive to JAK2 Inhibition

May 2, 2024 updated by: Fox Chase Cancer Center

Phase I Study Accessing the Safety of Pacritinib in Combination With Talazoparib in Patients With Myeloproliferative Neoplasms Unresponsive to Frontline JAK2 (Janus Kinase 2) Inhibition

This is a prospective phase I dose-escalation study, with the primary objective to access the MTD and find the RP2D of talazoparib, given in combination with standard of care dosing of pacritinib.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a prospective phase I dose-escalation study, with the primary objective to access the MTD and find the RP2D of talazoparib, given in combination with standard of care dosing of pacritinib. Subjects must have a diagnosis of a myeloproliferative neoplasm and progressed or become intolerant to any JAK2 directed therapy. To be eligible for the therapy, patients are required to consent to a bone marrow biopsy at the beginning of study treatment. The treatment protocol involves initiating pacritinib on day -7 (lead-in phase, starting day -7 for cycle 1) with a standard of care dose of 200mg twice daily (BID). Subsequently, talazoparib will be given on day 1 of the treatment cycle. Cohort 1 will enroll patients at the starting dose of 0.25mg talazoparib for 14 days (dose level 1) and DLT (dose-limiting toxicity) rate will inform the subsequent dose levels (DLs).

Investigators plan to use a Bayesian Optimal Interval Design (BOIN) to determine the maximum tolerated dose (MTD) in patients with Ph-MPNs (Philadelphia chromosome negative myeloproliferative neoplasms) who have either not responded to or cannot tolerate ruxolitinib monotherapy. Subjects who are currently receiving JAK2-directed therapy will undergo a one-day washout period before starting the study treatment, as abrupt discontinuation of JAK2 inhibition can lead to side effects. This brief interval allows for the resolution of any lingering effects before initiating the new treatment. A bone marrow aspirate and or biopsy will be obtained to assess response to therapy at the end of each cycle of treatment (28 days), prior to beginning the next cycle as per physician discretion. Peripheral blood and bone marrow mononuclear cells will be checked for γ-H2AX (histone H2A family X) at set time points as a biomarker assay to assess for DNA damage in the same manner as the pre-clinical models published in our previous studies. Patients may remain on study drug unless they experience an unacceptable toxicity, fail to show a benefit, or they attain remission and it is felt by the investigator that they can proceed to an allogenic stem cell transplant.

Study Type

Interventional

Enrollment (Estimated)

24

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19111-2497
        • Recruiting
        • Fox Chase Cancer Center - Philadelphia
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF), post-essential thrombocythemia-myelofibrosis (PET-MF), chronic myelomonocytic leukemia, polycythemia vera, or essential thrombocytosis according to the 2008 World Health Organization criteria
  • Subject has at least 2 symptoms with a score ≥ 3 or a total score of ≥ 12, as measured by the MFSAF(Myelofibrosis Symptom Assessment Form) v4.0
  • Subject classified as intermediate-2 or high-risk MF, as defined by the Dynamic International Prognostic Scoring System Plus (DIPSS+70).
  • Age > 18 years.
  • ECOG (Eastern Cooperative Oncology Group) performance status 0-2
  • Subject must have received prior treatment with a single JAK2 inhibitor 4.1.6 for at least 12 weeks with documented disease progression OR subject must have appearance of new splenomegaly that is palpable to at least 5 cm below the left costal margin (LCM) in subjects with no evidence of splenomegaly prior to the initiation of any first line JAK2 inhibitor
  • Baseline QTc (corrected QT interval) <0.47 seconds (Bazett formula)
  • Patients must have normal organ function as defined in protocol.
  • Ability to understand and willingness to sign a written informed consent and HIPAA consent document

Exclusion Criteria:

  • Patients may not be receiving any other investigational agents
  • Subjects must not be experiencing toxicity due to prior therapy that has not resolved to ≤Grade 1 by study registration, with the exception of sensory neuropathy related to previous systemic therapy exposure, alopecia and fatigue.
  • Patients that have transformed to Acute Myeloid Leukemia defined by >20% blasts count on peripheral blood smear or bone marrow biopsy evaluation
  • Uncontrolled inter-current illness including, but not limited to, any other malignancy (with the exception of hormonal therapy for breast cancer/prostate cancer in remission >1 year and for non-hormonal therapies for other cancers in remission for >3 years), other ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients with history of hemorrhagic stroke and evidence of uncontrolled bleeding as well as bleeding disorder
  • Known HIV positive patients on combination antiretroviral therapy are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
  • Pregnant or breast-feeding.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Dose Level -1
0.25 mg (PO, QD) Talazoparib (Days 1-7) 200 mg (PO, BID) Pacritinib (Day 1-28, Lead in dosing of Pacritinib day -7 for the first cycle of treatment)
Drug: Talazoparib
pacritinib in combination with talazoparib
Other Names:
  • talzenna
Drug: pacritinib
pacritinib in combination with talazoparib
Other Names:
  • vonjo
Experimental: Dose Level 1
0.25 mg (PO, QD) Talazoparib (Days 1-14) 200 mg (PO, BID) Pacritinib (Day 1-28, Lead in dosing of Pacritinib day -7 for the first cycle of treatment)
Drug: Talazoparib
pacritinib in combination with talazoparib
Other Names:
  • talzenna
Drug: pacritinib
pacritinib in combination with talazoparib
Other Names:
  • vonjo
Experimental: Dose Level 2
0.5 mg (PO, QD) Talazoparib (Days 1-14) 200 mg (PO, BID) Pacritinib (Day 1-28, Lead in dosing of Pacritinib day -7 for the first cycle of treatment)
Drug: Talazoparib
pacritinib in combination with talazoparib
Other Names:
  • talzenna
Drug: pacritinib
pacritinib in combination with talazoparib
Other Names:
  • vonjo
Experimental: Dose Level 3
0.75 mg (PO, QD) Talazoparib (Days 1-14) 200 mg (PO, BID) Pacritinib (Day 1-28, Lead in dosing of Pacritinib day -7 for the first cycle of treatment)
Drug: Talazoparib
pacritinib in combination with talazoparib
Other Names:
  • talzenna
Drug: pacritinib
pacritinib in combination with talazoparib
Other Names:
  • vonjo
Experimental: Dose Level 4
1 mg (PO, QD) Talazoparib (Days 1-14) 200 mg (PO, BID) Pacritinib (Day 1-28, Lead in dosing of Pacritinib day -7 for the first cycle of treatment)
Drug: Talazoparib
pacritinib in combination with talazoparib
Other Names:
  • talzenna
Drug: pacritinib
pacritinib in combination with talazoparib
Other Names:
  • vonjo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose (MTD)
Time Frame: 6 years
To define the maximum tolerated dose (MTD) of talazoparib in combination with standard of care dosing of pacritinib in order to establish a recommended phase II dose (RP2D).
6 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of grade 3 or higher toxicity
Time Frame: 6 years
Rate of grade 3 or higher toxicities occurring with the combination of talazoparib and pacritinib in patients with MPNs that have failed to respond to one line of JAK2 directed therapy.
6 years
Response rate
Time Frame: 6 years
Response rate defined by a 35% or greater spleen volume reduction (SVR) or a >25% reduction in total symptom score (TSS) at week 24 (per IWG-MTR (International Working Group for Myelofibrosis Research and Treatment) criteria).
6 years
Disease control rate
Time Frame: 6 years
Disease control rate, defined by improvement in quality of life measures, spleen size, and hematological recovery
6 years
Progression free survival
Time Frame: 6 years
Progression free survival, defined as the time of enrollment to disease progression
6 years
Overall survival
Time Frame: 6 years
Overall survival, defined by time from enrollment to death from any cause
6 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fox Chase Cancer Center

Investigators

  • Principal Investigator: Peter Abdelmessieh, DO, MSc, Fox Chase Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 5, 2024

Primary Completion (Estimated)

August 22, 2029

Study Completion (Estimated)

August 27, 2030

Study Registration Dates

First Submitted

January 12, 2024

First Submitted That Met QC Criteria

January 12, 2024

First Posted (Actual)

January 23, 2024

Study Record Updates

Last Update Posted (Actual)

May 3, 2024

Last Update Submitted That Met QC Criteria

May 2, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 23-1048
  • HM-224 (Other Identifier: Fox Chase Cancer Center)

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

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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