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

NCT ID: NCT04041050

Last Updated: 2025-02-14

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 85 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-08
• Study Completion Date: 2026-12-31

Brief Summary

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.

Conditions

Myeloproliferative Neoplasm

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part 1: Navitoclax Monotherapy

Participants will receive various doses of navitoclax once daily (QD).

Group Type: EXPERIMENTAL

Navitoclax

Intervention Type: DRUG

Tablet; Oral

Part 2: Navitoclax + Ruxolitinib Combination Therapy

Participants will receive various doses of navitoclax once daily (QD) in combination with ruxolitinib twice daily (BID).

Group Type: EXPERIMENTAL

Navitoclax

Intervention Type: DRUG

Tablet; Oral

Ruxolitinib

Intervention Type: DRUG

Tablet; Oral

Part 3: Navitoclax Monotherapy

Participants will receive navitoclax once daily (QD).

Group Type: EXPERIMENTAL

Navitoclax

Intervention Type: DRUG

Tablet; Oral

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.

Group Type: EXPERIMENTAL

Navitoclax

Intervention Type: DRUG

Tablet; Oral

Celecoxib

Intervention Type: DRUG

Capsule; Oral

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.

Group Type: EXPERIMENTAL

Navitoclax

Intervention Type: DRUG

Tablet; Oral

Ruxolitinib

Intervention Type: DRUG

Tablet; Oral

Interventions

Navitoclax

Tablet; Oral

Intervention Type: DRUG

Ruxolitinib

Tablet; Oral

Intervention Type: DRUG

Celecoxib

Capsule; Oral

Intervention Type: DRUG

Other Intervention Names

ABT-263; Celebrex

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.

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AbbVie

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

ABBVIE INC.

Role: STUDY_DIRECTOR

AbbVie

Locations

City of Hope /ID# 239769

Duarte, California, United States

Providence - St. Jude Medical Center /ID# 242558

Fullerton, California, United States

Moores Cancer Center at UC San Diego /ID# 229584

La Jolla, California, United States

UCLA /Id# 222784

Los Angeles, California, United States

Northwestern University Feinberg School of Medicine /ID# 224203

Chicago, Illinois, United States

Norton Cancer Institute - St. Matthews /ID# 239300

Louisville, Kentucky, United States

Duplicate_Brigitte Harris Cancer Pavilion /ID# 238686

Detroit, Michigan, United States

Nebraska Cancer Specialists - Omaha - Wright Street /ID# 242554

Omaha, Nebraska, United States

Duplicate_East Carolina University Brody School of Medicine /ID# 238560

Greenville, North Carolina, United States

Gabrail Cancer Center Research /ID# 228924

Canton, Ohio, United States

Pennsylvania Cancer Specialists Research Institute - Gettysburg /ID# 242550

Gettysburg, Pennsylvania, United States

Virginia Commonwealth University Medical Center Main Hospital /ID# 228169

Richmond, Virginia, United States

Cliniques Universitaires UCL Saint-Luc /ID# 225314

Woluwe-Saint-Lambert, Brussels Capital, Belgium

UMHAT Sveti Georgi /ID# 240022

Plovdiv, , Bulgaria

UMHAT Sveti Ivan Rilski /ID# 240077

Sofia, , Bulgaria

Klinicki bolnicki centar Zagreb /ID# 240140

Zagreb, City of Zagreb, Croatia

Centre Antoine Lacassagne - Nice /ID# 242293

Nice, Alpes-Maritimes, France

CHU Amiens-Picardie Site Sud /ID# 240792

Amiens, Somme, France

AP-HP - Hopital Saint-Louis /ID# 240685

Paris, , France

IUCT Oncopole /ID# 242353

Toulouse, , France

Universitaetsklinikum Freiburg /ID# 222791

Freiburg im Breisgau, Baden-Wurttemberg, Germany

Klinikum Kassel /ID# 225440

Kassel, Hesse, Germany

Universitaetsmedizin Rostock /ID# 225436

Rostock, Mecklenburg-Vorpommern, Germany

Charite Universitaetsklinikum Berlin - Campus Virchow /ID# 224835

Berlin, , Germany

Fondazione Policlinico Universitario Agostino Gemelli IRCCS-Universita Cattolica /ID# 221408

Rome, Lazio, Italy

ASST Spedali civili di Brescia /ID# 224962

Brescia, , Italy

Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRCCS /ID# 224071

Meldola, , Italy

Shonan Kamakura General Hospital /ID# 224315

Kamakura-shi, Kanagawa, Japan

Kindai University Hospital /ID# 213241

Osakasayama-shi, Osaka, Japan

Osaka University Hospital /ID# 213235

Suita-shi, Osaka, Japan

Juntendo University Hospital /ID# 213255

Bunkyo-ku, Tokyo, Japan

University of Yamanashi Hospital /ID# 229279

Chuo-shi, Yamanashi, Japan

University Clinical Center Serbia /ID# 240674

Belgrade, Beograd, Serbia

Hospital Duran i Reynals /ID# 224007

L'Hospitalet de Llobregat, Barcelona, Spain

Clinica Universidad de Navarra - Pamplona /ID# 224839

Pamplona, Navarre, Spain

CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 226041

Madrid, , Spain

Duplicate_Karolinska University Hospital /ID# 239992

Stockholm, Stockholm County, Sweden

Linkoping University Hospital /ID# 239995

Linköping, , Sweden

Kaohsiung Medical University Chung-Ho Memorial Hospital /ID# 215631

Kaohsiung City, , Taiwan

China Medical University Hospital /ID# 215634

Taichung, , Taiwan

Dokuz Eylul University Medical Faculty /ID# 239952

Izmir, , Turkey (Türkiye)

Gloucestershire Hospitals NHS Foundation Trust /ID# 241189

Cheltenham, Gloucestershire, United Kingdom

Countries

United States; Belgium; Bulgaria; Croatia; France; Germany; Italy; Japan; Serbia; Spain; Sweden; Taiwan; Turkey (Türkiye); United Kingdom

Other Identifiers

2020-002597-27

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

M19-753

Identifier Type: -

Identifier Source: org_study_id