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A Study Evaluating Safety and Tolerability, and Pharmacokinetics of Navitoclax Monotherapy and in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasm

About

Brief Summary

There are 4 parts to this study for which the primary objectives are to evaluate safety, tolerability, and pharmacokinetics (PK) of navitoclax when administered alone (Part 1) or when administered in combination with ruxolitinib (Part 2). In Part 2, participants must have been receiving a stable dose of ruxolitinib therapy for at least 12 weeks prior to study enrollment. In Part 3, all eligible participants will receive navitoclax, with the primary objective being to evaluate potential navitoclax effect on QTc prolongation. In Part 4, effect of navitoclax is evaluated on the PK, safety, and tolerability of a single dose of celecoxib in participants with myeloproliferative neoplasm (MPN) or chronic myelomonocytic leukemia (CMML).

Primary Purpose
Treatment
Study Type
Interventional
Phase
Phase I

Eligibility

Gender
All
Healthy Volunteers
No
Minimum Age
18 Years
Maximum Age
N/A

Inclusion Criteria:

Parts 1 and 2:

  • Navitoclax Monotherapy (Part 1 Only - Japanese Participants):
    • Documented diagnosis of myelofibrosis (MF), polycythemia vera (PV) or essential thrombocythemia (ET) as defined by the World Health Organization (WHO) classification.
    • MF participants must have received and failed or are intolerant to ruxolitinib therapy.
    • ET or PV participants must be requiring cytoreduction who have failed or are intolerant to at least one prior therapy, or who refuse standard therapy.
  • Navitoclax + ruxolitinib Combination Therapy (Part 2 Only - Japanese and Taiwanese Participants):
    • Has documented diagnosis of primary MF, post-polycythemia vera MF (PPV-MF), or post-essential thrombocythemia (PET-MF) as defined by the World Health Organization (WHO) classification.
    • Is ineligible or unwilling to undergo stem cell transplantation at time of study entry.
    • Has splenomegaly as defined by a spleen palpable >= 5 cm below costal margin or spleen volume >= 450 cm^3 as assessed by magnetic resonance imaging (MRI) or computed topography (CT) scan.
    • Must have received ruxolitinib therapy for at least 12 weeks and be currently on a stable dose of ruxolitinib (as described in the protocol).
  • Must have adequate bone marrow, kidney, liver and hematology blood values as detailed in the study protocol.
  • Part 1 only: Cytoreduction for participants with ET and PV therapy within 14 days prior to the first dose of navitoclax will be allowed pending additional discussion with study doctor. Ruxolitinib for MF participants will not be allowed within 7 days prior to the first dose of study drug and during navitoclax administration.
  • Eastern Cooperative Oncology Group (ECOG) performance status <= 1. Part 3 and Part 4 (Participants in US and Europe):
  • Part 3 Only: At screening or baseline (pre-dose on Day 1), participant has QT interval corrected for heart rate (QTc) interval by Fridericia's correction (QTcF) <= 450 msec.
  • Participants with a documented diagnosis of primary or secondary MF, ET, PV or chronic myelomonocytic leukemia (CMML) as defined by the WHO classification.
  • Participants must be requiring treatment and have failed or are intolerant to at least one prior therapy or who refuse standard therapy.
  • ECOG performance status <= 2.
  • Must have adequate bone marrow, kidney, liver and hematology blood values as detailed in the study protocol.

Exclusion Criteria:

Part 1 and 2:

  • Shows leukemic transformation (> 10% blasts in peripheral blood or bone marrow biopsy).
  • Has a history of an active malignancy other than MPN within the past 2 years prior to study entry (exceptions detailed in the protocol).
  • Has a positive test result for HIV at screening.
  • Has chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment.
  • Has evidence of other clinically significant uncontrolled condition(s).
  • Has previously taken a BH3 mimetic compound.
  • Currently on medications that interfere with coagulation (including warfarin) or platelet function with the exception of low dose aspirin (up to 100 mg) and low-molecular-weight heparin (LMWH).
  • Has received strong or moderate CYP3A inhibitors (e.g., ketoconazole, clarithromycin) within 14 days prior to the administration of the first dose of navitoclax. Part 3 and Part 4:
  • Had prior therapy with a BH3 mimetic compound.
  • Have received strong or moderate CYP3A inhibitors within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of navitoclax.
  • Have received strong CYP3A inducers within 10 days prior to the first dose of navitoclax.
  • Show leukemic transformation (> 10% blasts in peripheral blood or bone marrow biopsy).
  • Currently on medications that interfere with coagulation (including warfarin) or platelet function except for low-dose aspirin (up to 100 mg) and LMWH. Part 4 Only:
  • Have received CYP2C9 inhibitors within 28 days or 5 half-lives of the drug (whichever is shorter) prior to the first dose of study drugs.
  • Have received CYP2C9 inducers within 10 days prior to the first dose of study drugs.

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Study Stats
Protocol No.
20-001654
Category
Hematology-Oncology
Oncology
Contact
Bruck Habtemariam
Location
  • UCLA Westwood
For Providers
NCT No.
NCT04041050
For detailed technical eligibility, visit ClinicalTrials.gov.