Protocol: 23-1048 / IRB23-1048

Phase: I

Investigator: Peter Abdelmessieh, DO, MSC

Disease(s): Myeloid and Monocytic Leukemia

Full Title: HM-224: Phase I Study Assessing the Safety of Pacritinib in Combination with Talazoparib in Patients with Myeloproliferative Neoplasms Unresponsive to Frontline JAK2 Inhibition

 

Study Summary

Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) include:

Polycythemia Vera (PV)
Essential Thrombocythemia (ET)
Chronic Myleomonocytic Leukemia (CMML)
Primary Myelofibrosis (PMF)

These hyper-proliferative myeloid malignancies are associated with the mutations in JAK2, CALR, and MPL genes. Current treatment options for these diseases include cyto-reductive therapy with hydroxyurea and the JAK2 inhibitors. Although JAK2 inhibitors have greatly improved the quality of life in patients with MPNs by providing a prolonged reduction in spleen size and improvement in overall symptoms, it fails to alter the overall disease course. Response criteria exist for this disease and drug approvals to date have been based upon a composite of improved blood counts, reduction in spleen size and symptom improvement. MPNs often present in a chronic phase but will eventually accelerate and transform into secondary acute myeloid leukemia (sAML), which translates to very poor outcomes. This is due to their poor response to traditional cytotoxic chemotherapy. Currently, the only cure for these patients is an allogenic stem cell transplant, however this is often not an option for these patients due to the age at which this disease often presents and toxicity associated with stem cell transplant. Thus, it is imperative for new therapies to be developed considering how sparse drug development has been for this disease. Based upon preclinical studies, we believe the addition of a PARP inhibitor to standard of care therapy will improve outcomes for patients with MPN. The goal of this study is to evaluate the combination of the standard agent (Pacritinib) with a PARP inhibitor (Talazoparib) to determine tolerability and activity.

Eligibility

To be eligible for this study, patients must meet several criteria, including but not limited to the following:

Major Inclusion Criteria:

• Age of 18 years and older
• 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 greater than or equal to 3 or a total score of greater than or equal to 12, as measured by the MFSAF v4.0.
• Subject classified as intermediate-2 or high-risk MF, as defined by the Dynamic International Prognostic Scoring System Plus (DIPSS+70).
• ECOG performance status 0-2.
• Subject must have received prior treatment with a single JAK2 inhibitor:

1. For at least 12 weeks with documented disease progression using the IWG-MRT criteria OR
2. Subject must have appearance of new splenomegaly that is palpable to at least 5 cm below the left costal margin (LCM). This applies to subjects who did not have any evidence of splenomegaly prior to the initiation of any first line JAK2 inhibitor.

• Baseline QTc<0.47 seconds (Bazett formula).
• 1.8 Patients must have normal organ and marrow function as defined below:
• AST/ALT (SGOT/SGPT) < 3 times institutional normal limits
• ANC >1000/mm3
• Creatinine within normal institutional limits
• OR
• Creatinine clearance > 45 Ml/min/1.73 m2 for patients with creatinine levels above institutional normal
  
  

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 less than or equalt 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.
• 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.
• Pregnant or breast-feeding.

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