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

NCT04041050

Description:

There are 3 parts to this study for which the primary objectives are to evaluate safety and tolerability, including dose-limiting toxicities (DLTs), and pharmacokinetics 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.

Related Conditions:
  • Essential Thrombocythemia
  • Myelofibrosis
  • Polycythemia Vera
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating Safety and Tolerability, and Pharmacokinetics of Navitoclax Alone and in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasm
  • Official Title: A Phase 1 Open-Label Study Evaluating Safety and Tolerability, and Pharmacokinetics of Navitoclax Alone and in Combination With Ruxolitinib in Myeloproliferative Neoplasm Subjects

Clinical Trial IDs

  • ORG STUDY ID: M19-753
  • NCT ID: NCT04041050

Conditions

  • Myeloproliferative Neoplasm

Interventions

DrugSynonymsArms
NavitoclaxABT-263Experimental: Part 3: Navitoclax Monotherapy
RuxolitinibPart 2: Navitoclax + Ruxolitinib Combination Therapy

Purpose

There are 3 parts to this study for which the primary objectives are to evaluate safety and tolerability, including dose-limiting toxicities (DLTs), and pharmacokinetics 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.

Trial Arms

NameTypeDescriptionInterventions
Part 1: Navitoclax MonotherapyExperimentalVarious doses of navitoclax administered at a starting dose of 50 mg orally once daily (QD).
  • Navitoclax
Part 2: Navitoclax + Ruxolitinib Combination TherapyExperimentalParticipants will receive various doses of navitoclax , starting at a dose of 50 mg orally once daily (QD). In addition, each participant will continue to administer ruxolitinib ≥ 10 mg orally twice daily (BID).
  • Navitoclax
  • Ruxolitinib
Experimental: Part 3: Navitoclax MonotherapyExperimentalParticipants will receive Dose A orally once daily (QD).
  • Navitoclax

Eligibility Criteria

        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.

               -  Must have received ruxolitinib therapy for at least 12 weeks and be currently on
                  a stable dose (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:

          -  At screening or baseline (pre-dose on Day 1), participant has QT interval corrected
             for heart rate (QTc) interval by Fridericia's correction (QTcF) ≤ 470 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.

        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:

          -  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.

          -  Must not show leukemic transformation (> 10% blasts in peripheral blood or bone marrow
             biopsy).

          -  Must not be currently on medications that interfere with coagulation (including
             warfarin) or platelet function except for low-dose aspirin (up to 100 mg) and LMWH.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants with Dose Limiting Toxicities (DLT)
Time Frame:Up to 28 days after the navitoclax initiation
Safety Issue:
Description:Dose limiting toxicities for dose escalation purposes will be determined on events that occur during the first 28-day cycle of navitoclax.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Up to approximately 96 weeks
Safety Issue:
Description:ORR is defined as the sum of rates of complete remission (CR) + partial remission (PR) associated with the addition of navitoclax to ruxolitinib according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment/European Leukemia Net (IWG-MRT/ELN) criteria.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AbbVie

Trial Keywords

  • Myeloproliferative Neoplasm (MPN)
  • Polycythemia Vera (PV)
  • Essential Thrombocythemia (ET)
  • Myelofibrosis (MF)
  • cancer
  • navitoclax
  • ruxolitinib

Last Updated

August 10, 2020