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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

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ClinicalTrials.gov Identifier: NCT04041050
Recruitment Status : Recruiting
First Posted : August 1, 2019
Last Update Posted : November 5, 2021
Sponsor:
Information provided by (Responsible Party):
AbbVie

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).

Condition or disease Intervention/treatment Phase
Myeloproliferative Neoplasm Drug: Navitoclax Drug: Ruxolitinib Drug: Celecoxib Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 62 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Open-Label Study Evaluating the Safety and Tolerability, and Pharmacokinetics of Navitoclax Monotherapy and in Combination With Ruxolitinib in Myeloproliferative Neoplasm Subjects
Actual Study Start Date : November 8, 2019
Estimated Primary Completion Date : January 12, 2025
Estimated Study Completion Date : January 12, 2025


Arm Intervention/treatment
Experimental: Part 1: Navitoclax Monotherapy
Participants will receive various doses of navitoclax once daily (QD).
Drug: Navitoclax
Tablet; Oral
Other Name: ABT-263

Experimental: Part 2: Navitoclax + Ruxolitinib Combination Therapy
Participants will receive various doses of navitoclax once daily (QD) in combination with ruxolitinib twice daily (BID).
Drug: Navitoclax
Tablet; Oral
Other Name: ABT-263

Drug: Ruxolitinib
Tablet; Oral

Experimental: Part 3: Navitoclax Monotherapy
Participants will receive navitoclax once daily (QD).
Drug: Navitoclax
Tablet; Oral
Other Name: ABT-263

Experimental: Part 4: Navitoclax + Celecoxib
Participants will receive navitoclax once daily (QD) starting on Day 3. Participants will also receive celecoxib single dose on Day 1 and Day 7.
Drug: Navitoclax
Tablet; Oral
Other Name: ABT-263

Drug: Celecoxib
Capsule; Oral
Other Name: Celebrex




Primary Outcome Measures :
  1. Number of Participants with Dose Limiting Toxicities (DLT) (Part 1 and Part 2) [ Time Frame: Up to 28 days after the navitoclax initiation ]
    Dose limiting toxicities for dose escalation purposes will be determined on events that occur during the first 28-day cycle of navitoclax.

  2. Maximum Observed Plasma Concentration (Cmax) of Navitoclax [ Time Frame: Up to approximately 1 day ]
    Maximum Observed Plasma Concentration (Cmax) of Navitoclax.

  3. Maximum Observed Plasma Concentration (Cmax) of Celecoxib (Part 4) [ Time Frame: Up to approximately 1 day ]
    Maximum Observed Plasma Concentration (Cmax) of Celecoxib.

  4. Time to Cmax (peak time, Tmax) of Navitoclax [ Time Frame: Up to approximately 1 day ]
    Tmax defined as time to maximum observed plasma concentration of Navitoclax.

  5. Time to Cmax (peak time, Tmax) of Celecoxib (Part 4) [ Time Frame: Up to approximately 1 day ]
    Tmax defined as time to maximum observed plasma concentration of Celecoxib.

  6. Area Under the Plasma Concentration-time Curve from time 0 to the time of the last measurable concentration (AUCt) of Navitoclax [ Time Frame: Up to approximately 2 days ]
    Area under the plasma concentration-time curve from time zero to the last measurable concentration of Navitoclax.

  7. Area Under the Plasma Concentration-time Curve from time 0 to the time of the last measurable concentration (AUCt) of Celecoxib (Part 4) [ Time Frame: Up to approximately 2 days ]
    Area under the plasma concentration-time curve from time zero to the last measurable concentration of Celecoxib.

  8. Number of Participants with Adverse Events [ Time Frame: From first dose of study drug until 30 days following last dose of study drug (up to approximately 5 years). ]
    An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

  9. Change in QT interval corrected for heart rate interval by Fridericia's correction formula (QTcF) (Part 3) [ Time Frame: From first dose of study drug until 30 days following last dose of study drug. ]
    Change in QTCF (Part 3).


Secondary Outcome Measures :
  1. Overall Response Rate [ Time Frame: Up to approximately 96 weeks ]
    ORR according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment/European Leukemia Net (IWG-MRT/ELN) criteria for participants with myelofibrosis, essential thrombocythemia, and polycythemia vera, and according to IWG criteria for subjects with CMML.



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 or spleen volume >= 50 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) <= 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.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04041050


Contacts
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Contact: ABBVIE CALL CENTER 844-663-3742 abbvieclinicaltrials@abbvie.com

Locations
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Sponsors and Collaborators
AbbVie
Investigators
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Study Director: ABBVIE INC. AbbVie
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Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT04041050    
Other Study ID Numbers: M19-753
2020-002597-27 ( EudraCT Number )
First Posted: August 1, 2019    Key Record Dates
Last Update Posted: November 5, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by AbbVie:
Myeloproliferative Neoplasm (MPN)
Chronic myelomonocytic leukemia (CMML)
Polycythemia Vera (PV)
Essential Thrombocythemia (ET)
Myelofibrosis (MF)
cancer
navitoclax
ruxolitinib
Additional relevant MeSH terms:
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Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Celecoxib
Navitoclax
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents