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

• ClinicalTrials.gov Identifier: NCT04041050
• Recruitment Status: Recruiting
• First Posted: August 1, 2019
• Last Update Posted: August 9, 2022
• Sponsor: AbbVie
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: July 30, 2019
• First Posted Date: August 1, 2019
• Last Update Posted Date: August 9, 2022
• Actual Study Start Date: November 8, 2019
• Estimated Primary Completion Date: September 8, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 19, 2022)

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

Original Primary Outcome Measures (submitted: July 30, 2019)

• Number of Participants with Dose Limiting Toxicities (DLT) [ 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.
• Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Up to approximately 2 days ]
  Maximum Observed Plasma Concentration (Cmax)
• Time to Cmax (peak time, Tmax) [ Time Frame: Up to approximately 2 days ]
  Tmax defined as time to maximum observed plasma concentration.
• Area Under the Plasma Concentration-time Curve from time 0 to the time of the last measurable concentration (AUCt) [ Time Frame: Up to approximately 2 days ]
  Area under the plasma concentration-time curve from time zero to the last measurable concentration.
• 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 3 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.

Current Secondary Outcome Measures (submitted: August 17, 2021)

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.

Original Secondary Outcome Measures (submitted: July 30, 2019)

Overall Response Rate (ORR) [ Time Frame: Up to approximately 96 weeks ]

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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Evaluating Safety and Tolerability, and Pharmacokinetics of Navitoclax Monotherapy and in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasm
• 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
• 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Myeloproliferative Neoplasm

Intervention

• Drug: Navitoclax
  Tablet; Oral
  Other Name: ABT-263
• Drug: Ruxolitinib
  Tablet; Oral
• Drug: Celecoxib
  Capsule; Oral
  Other Name: Celebrex

Study Arms

• Experimental: Part 1: Navitoclax Monotherapy
  Participants will receive various doses of navitoclax once daily (QD).
  Intervention: Drug: Navitoclax
• Experimental: Part 2: Navitoclax + Ruxolitinib Combination Therapy
  Participants will receive various doses of navitoclax once daily (QD) in combination with ruxolitinib twice daily (BID).
  Interventions:

  • Drug: Navitoclax
  • Drug: Ruxolitinib
• Experimental: Part 3: Navitoclax Monotherapy
  Participants will receive navitoclax once daily (QD).
  Intervention: Drug: Navitoclax
• 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.
  Interventions:

  • Drug: Navitoclax
  • Drug: Celecoxib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 17, 2021): 62
• Original Estimated Enrollment (submitted: July 30, 2019): 12
• Estimated Study Completion Date: September 8, 2024
• Estimated Primary Completion Date: September 8, 2024 (Final data collection date for primary outcome measure)

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 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Belgium, Bulgaria, Croatia, France, Germany, Italy, Japan, Russian Federation, Serbia, Spain, Sweden, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04041050
• Other Study ID Numbers: M19-753; 2020-002597-27 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: AbbVie
• Original Responsible Party: Same as current
• Current Study Sponsor: AbbVie
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: ABBVIE INC.; AbbVie

• PRS Account: AbbVie
• Verification Date: August 2022