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

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

There are 5 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 Part 5, all eligible participants will receive ruxolitinib twice daily and navitoclax once daily for drug-drug interaction (DDI) assessment, followed by continued administration of navitoclax in combination with ruxolitinib.

Study Overview

• Status: Active, not recruiting
• Conditions: Myeloproliferative Neoplasm
• Intervention / Treatment: Drug: Ruxolitinib; Drug: Navitoclax; Drug: Celecoxib

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: ABBVIE CALL CENTER; Phone Number: 844-663-3742; Email: abbvieclinicaltrials@abbvie.com

Study Locations

• Belgium
  • Bruxelles-Capitale
    • Woluwe-Saint-Lambert, Bruxelles-Capitale, Belgium, 1200
      • UCL Saint-Luc /ID# 225314
• Bulgaria
  • Plovdiv, Bulgaria, 4002
    • UMHAT Sveti Georgi /ID# 240022
  • Sofia, Bulgaria, 1431
    • UMHAT Sveti Ivan Rilski /ID# 240077
• Croatia
  • Grad Zagreb
    • Zagreb, Grad Zagreb, Croatia, 10000
      • Klinicki bolnicki centar Zagreb /ID# 240140
• France
  • Paris, France, 75010
    • AP-HP - Hopital Saint-Louis /ID# 240685
  • Toulouse Cedex 9, France, 31059
    • IUCT Oncopole /ID# 242353
  • Alpes-Maritimes
    • Nice, Alpes-Maritimes, France, 06189
      • Centre Antoine Lacassagne - Nice /ID# 242293
  • Somme
    • Amiens CEDEX 1, Somme, France, 80054
      • CHU Amiens-Picardie Site Sud /ID# 240792
• Germany
  • Berlin, Germany, 13353
    • Charite Universitaetsklinikum Berlin - Campus Virchow /ID# 224835
  • Kassel, Germany, 34125
    • Klinikum Kassel /ID# 225440
  • Rostock, Germany, 18057
    • Universitaetsmedizin Rostock /ID# 225436
  • Baden-Wuerttemberg
    • Freiburg, Baden-Wuerttemberg, Germany, 79106
      • Universitaetsklinikum Freiburg /ID# 222791
• Italy
  • Brescia, Italy, 25123
    • ASST Spedali civili di Brescia /ID# 224962
  • Meldola, Italy, 47014
    • Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRCCS /ID# 224071
  • Lazio
    • Rome, Lazio, Italy, 00168
      • Fondazione Policlinico Universitario Agostino Gemelli IRCCS-Università Cattolica /ID# 221408
• Japan
  • Kanagawa
    • Kamakura-shi, Kanagawa, Japan, 247-8533
      • Shonan Kamakura General Hospital /ID# 224315
  • Osaka
    • Osakasayama-shi, Osaka, Japan, 589-8511
      • Kindai University Hospital /ID# 213241
    • Suita-shi, Osaka, Japan, 565-0871
      • Osaka University Hospital /ID# 213235
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8431
      • Juntendo University Hospital /ID# 213255
  • Yamanashi
    • Chuo-shi, Yamanashi, Japan, 409-3821
      • University of Yamanashi Hospital /ID# 229279
• Serbia
  • Beograd
    • Belgrade, Beograd, Serbia, 11000
      • University Clinical Center Serbia /ID# 240674
• Spain
  • Madrid, Spain, 28027
    • CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 226041
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Hospital Duran i Reynals /ID# 224007
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • CLINICA UNIVERSIDAD DE NAVARRA-Pamplona /ID# 224839
• Sweden
  • Linkoping, Sweden, 581 85
    • Linkoping University Hospital /ID# 239995
  • Stockholm, Sweden, 141 86
    • Karolinska University Hospital /ID# 239992
• Taiwan
  • Kaohsiung, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital /ID# 215631
  • Taichung City, Taiwan, 40447
    • China Medical University Hospital /ID# 215634
• Turkey
  • Izmir, Turkey, 35340
    • Dokuz Eylul University Medical Faculty /ID# 239952
• United Kingdom
  • Gloucestershire
    • Cheltenham, Gloucestershire, United Kingdom, GL53 7AN
      • Gloucestershire Hospitals NHS Foundation Trust /ID# 241189
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope /ID# 239769
    • Fullerton, California, United States, 92835
      • Providence Medical Foundation /ID# 242558
    • La Jolla, California, United States, 92093
      • Moores Cancer Center at UC San Diego /ID# 229584
    • Los Angeles, California, United States, 90095-1678
      • UCLA /Id# 222784
  • Illinois
    • Chicago, Illinois, United States, 60611-2927
      • Northwestern University Feinberg School of Medicine /ID# 224203
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Norton Cancer Institute - St Matthews /ID# 239300
  • Michigan
    • Detroit, Michigan, United States, 48202-2610
      • Brigitte Harris Cancer Pavilion /ID# 238686
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • Onc/Hematology West PC dba Nebraska Cancer Specialists /ID# 242554
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • East Carolina University Brody School of Medicine /ID# 238560
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research /ID# 228924
  • Pennsylvania
    • Gettysburg, Pennsylvania, United States, 17325
      • Pennsylvania Cancer Specialists Research Institute - Gettysburg /ID# 242550
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Virginia Commonwealth University Medical Center Main Hospital /ID# 228169

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Part 5 (Participants in US and Europe):

• Has a documented diagnosis of primary MF as defined by the WHO classification, post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF.
• Classified as intermediate-2 or high-risk MF, as defined by the Dynamic International Prognostic Scoring System (DIPSS).
• Requiring treatment for MF and must either have no prior treatment with a JAK2 inhibitor or have received treatment with ruxolitinib as noted in the protocol.
• Have an ECOG performance status <=2.
• Have adequate bone marrow, kidney, liver and hematology blood values as detailed in the 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.

Part 5 Only:

• Have accelerated MF, defined as > 10% blasts in peripheral blood or bone marrow aspirate and biopsy.
• Eligible for stem cell transplantation at time of study entry.
• Had prior therapy with a BH3 mimetic compound or BET inhibitor.
• Currently on medications that interfere with coagulation (including warfarin) or platelet function except for low-dose aspirin (up to 100 mg) and LMWH.
• Have received strong CYP3A inhibitors or CYP2C9 inhibitors within 28 days of 5 half-lives of the drug (whichever is shorter) prior to the first dose of study drugs.
• Have received strong CYP3A inducers or CYP2C9 inducers within 10 days prior to the first dose of study drugs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Navitoclax Monotherapy; Participants will receive various doses of navitoclax once daily (QD).	Drug: Navitoclax; Tablet; Oral; Other Names: 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: Ruxolitinib; Tablet; Oral; Drug: Navitoclax; Tablet; Oral; Other Names: ABT-263
Experimental: Part 3: Navitoclax Monotherapy; Participants will receive navitoclax once daily (QD).	Drug: Navitoclax; Tablet; Oral; Other Names: 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 Names: ABT-263; Drug: Celecoxib; Capsule; Oral; Other Names: Celebrex
Experimental: Part 5: Navitoclax + Ruxolitinib Combination Therapy; Participants will receive ruxolitinib BID and navitoclax QD for drug-drug interaction (DDI) assessment, followed by continued administration of navitoclax in combination with ruxolitinib.	Drug: Ruxolitinib; Tablet; Oral; Drug: Navitoclax; Tablet; Oral; Other Names: ABT-263

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Dose Limiting Toxicities (DLT) (Part 1 and Part 2)	Dose limiting toxicities for dose escalation purposes will be determined on events that occur during the first 28-day cycle of navitoclax.	Up to 28 days after the navitoclax initiation
Maximum Observed Plasma Concentration (Cmax) of Navitoclax (Part 2 and 5)	Maximum Observed Plasma Concentration (Cmax) of Navitoclax.	Up to approximately 1 day
Maximum Observed Plasma Concentration (Cmax) of Celecoxib (Part 4)	Maximum Observed Plasma Concentration (Cmax) of Celecoxib.	Up to approximately 1 day
Time to Cmax (peak time, Tmax) of Navitoclax (Part 2 and 5)	Tmax defined as time to maximum observed plasma concentration of Navitoclax.	Up to approximately 1 day
Time to Cmax (peak time, Tmax) of Celecoxib (Part 4)	Tmax defined as time to maximum observed plasma concentration of Celecoxib.	Up to approximately 1 day
Area Under the Plasma Concentration-time Curve from time 0 to the time of the last measurable concentration (AUCt) of Navitoclax	Area under the plasma concentration-time curve from time zero to the last measurable concentration of Navitoclax.	Up to approximately 2 days
Area Under the Plasma Concentration-time Curve from time 0 to the time of the last measurable concentration (AUCt) of Celecoxib (Part 4)	Area under the plasma concentration-time curve from time zero to the last measurable concentration of Celecoxib.	Up to approximately 2 days
Number of Participants with Adverse Events	An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.	From first dose of study drug until 30 days following last dose of study drug (up to approximately 5 years).
Change in QT interval corrected for heart rate interval by Fridericia's correction formula (QTcF) (Part 3)	Change in QTcF (Part 3).	From first dose of study drug until 30 days following last dose of study drug.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	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 participants with CMML.	Up to approximately 96 weeks

Collaborators and Investigators

• Sponsor: AbbVie
• Investigators: Study Director: ABBVIE INC., AbbVie

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2019
• Primary Completion (Anticipated): September 8, 2024
• Study Completion (Anticipated): September 8, 2024

Study Registration Dates

• First Submitted: July 30, 2019
• First Submitted That Met QC Criteria: July 30, 2019
• First Posted (Actual): August 1, 2019

Study Record Updates

• Last Update Posted (Actual): May 16, 2023
• Last Update Submitted That Met QC Criteria: May 15, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: cancer; Chronic myelomonocytic leukemia (CMML); ruxolitinib; navitoclax; Polycythemia Vera (PV); Essential Thrombocythemia (ET); Myelofibrosis (MF); Myeloproliferative Neoplasm (MPN)
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Neoplasms; Myeloproliferative Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Cyclooxygenase 2 Inhibitors; Celecoxib; Navitoclax
• Other Study ID Numbers: M19-753; 2020-002597-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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