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

NCT04041050 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: M19-7532020-002597-27
• Study Type: interventional
• Target: 85
• Locations: 13 countries
• Sites: 40

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

Keywords

Myeloproliferative Neoplasm (MPN); Chronic myelomonocytic leukemia (CMML); Polycythemia Vera (PV); Essential Thrombocythemia (ET); Myelofibrosis (MF); cancer; navitoclax; ruxolitinib

Outcome Measures

Primary Outcomes (9)

• 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 Outcomes (1)

• Overall Response Rate

  Up to approximately 96 weeks

Study Arms (5)

Part 1: Navitoclax Monotherapy

EXPERIMENTAL

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

Drug: Navitoclax

Part 2: Navitoclax + Ruxolitinib Combination Therapy

EXPERIMENTAL

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

Drug: Navitoclax; Drug: Ruxolitinib

Part 3: Navitoclax Monotherapy

EXPERIMENTAL

Participants will receive navitoclax once daily (QD).

Drug: Navitoclax

Part 4: Navitoclax + Celecoxib

EXPERIMENTAL

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; Drug: Celecoxib

Part 5: Navitoclax + Ruxolitinib Combination Therapy

EXPERIMENTAL

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: Navitoclax; Drug: Ruxolitinib

Interventions

Navitoclax DRUG

Tablet; Oral

Also known as: ABT-263

Part 1: Navitoclax Monotherapy; Part 2: Navitoclax + Ruxolitinib Combination Therapy; Part 3: Navitoclax Monotherapy; Part 4: Navitoclax + Celecoxib; Part 5: Navitoclax + Ruxolitinib Combination Therapy

Ruxolitinib DRUG

Tablet; Oral

Part 2: Navitoclax + Ruxolitinib Combination Therapy; Part 5: Navitoclax + Ruxolitinib Combination Therapy

Celecoxib DRUG

Capsule; Oral

Also known as: Celebrex

Part 4: Navitoclax + Celecoxib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• AbbVie: lead

Study Sites (42)

City of Hope /ID# 239769

Duarte, California, 91010, United States

Location

Providence - St. Jude Medical Center /ID# 242558

Fullerton, California, 92835, United States

Location

Moores Cancer Center at UC San Diego /ID# 229584

La Jolla, California, 92093, United States

Location

UCLA /Id# 222784

Los Angeles, California, 90095-1678, United States

Location

Northwestern University Feinberg School of Medicine /ID# 224203

Chicago, Illinois, 60611-2927, United States

Location

Norton Cancer Institute - St. Matthews /ID# 239300

Louisville, Kentucky, 40207, United States

Location

Duplicate_Brigitte Harris Cancer Pavilion /ID# 238686

Detroit, Michigan, 48202-2610, United States

Location

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

Omaha, Nebraska, 68130, United States

Location

Duplicate_East Carolina University Brody School of Medicine /ID# 238560

Greenville, North Carolina, 27834, United States

Location

Gabrail Cancer Center Research /ID# 228924

Canton, Ohio, 44718, United States

Location

Pennsylvania Cancer Specialists Research Institute - Gettysburg /ID# 242550

Gettysburg, Pennsylvania, 17325, United States

Location

Virginia Commonwealth University Medical Center Main Hospital /ID# 228169

Richmond, Virginia, 23219, United States

Location

Cliniques Universitaires UCL Saint-Luc /ID# 225314

Woluwe-Saint-Lambert, Brussels Capital, 1200, Belgium

Location

UMHAT Sveti Georgi /ID# 240022

Plovdiv, 4002, Bulgaria

Location

UMHAT Sveti Ivan Rilski /ID# 240077

Sofia, 1431, Bulgaria

Location

Klinicki bolnicki centar Zagreb /ID# 240140

Zagreb, City of Zagreb, 10000, Croatia

Location

Centre Antoine Lacassagne - Nice /ID# 242293

Nice, Alpes-Maritimes, 06189, France

Location

CHU Amiens-Picardie Site Sud /ID# 240792

Amiens, Somme, 80054, France

Location

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

Paris, 75010, France

Location

IUCT Oncopole /ID# 242353

Toulouse, 31059, France

Location

Universitaetsklinikum Freiburg /ID# 222791

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

Klinikum Kassel /ID# 225440

Kassel, Hesse, 34125, Germany

Location

Universitaetsmedizin Rostock /ID# 225436

Rostock, Mecklenburg-Vorpommern, 18057, Germany

Location

Charite Universitaetsklinikum Berlin - Campus Virchow /ID# 224835

Berlin, 13353, Germany

Location

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

Rome, Lazio, 00168, Italy

Location

ASST Spedali civili di Brescia /ID# 224962

Brescia, 25123, Italy

Location

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

Meldola, 47014, Italy

Location

Shonan Kamakura General Hospital /ID# 224315

Kamakura-shi, Kanagawa, 247-8533, Japan

Location

Kindai University Hospital /ID# 213241

Osakasayama-shi, Osaka, 589-8511, Japan

Location

Osaka University Hospital /ID# 213235

Suita-shi, Osaka, 565-0871, Japan

Location

Juntendo University Hospital /ID# 213255

Bunkyo-ku, Tokyo, 113-8431, Japan

Location

University of Yamanashi Hospital /ID# 229279

Chuo-shi, Yamanashi, 409-3821, Japan

Location

University Clinical Center Serbia /ID# 240674

Belgrade, Beograd, 11000, Serbia

Location

Hospital Duran i Reynals /ID# 224007

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Clinica Universidad de Navarra - Pamplona /ID# 224839

Pamplona, Navarre, 31008, Spain

Location

CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 226041

Madrid, 28027, Spain

Location

Duplicate_Karolinska University Hospital /ID# 239992

Stockholm, Stockholm County, 141 86, Sweden

Location

Linkoping University Hospital /ID# 239995

Linköping, 581 85, Sweden

Location

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

Kaohsiung City, 807, Taiwan

Location

China Medical University Hospital /ID# 215634

Taichung, 40447, Taiwan

Location

Dokuz Eylul University Medical Faculty /ID# 239952

Izmir, 35340, Turkey (Türkiye)

Location

Gloucestershire Hospitals NHS Foundation Trust /ID# 241189

Cheltenham, Gloucestershire, GL53 7AN, United Kingdom

Location

MeSH Terms

Conditions

Myeloproliferative Disorders; Leukemia, Myelomonocytic, Chronic; Polycythemia Vera; Thrombocythemia, Essential; Primary Myelofibrosis; Neoplasms

Interventions

navitoclax; ruxolitinib; Celecoxib

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Blood Coagulation Disorders; Thrombocytosis; Blood Platelet Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• ABBVIE INC.

  AbbVie

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 30, 2019
• First Posted: August 1, 2019
• Study Start: November 8, 2019
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: February 14, 2025

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

TU (1); ES (3); DE (4); SE (1); CR (1); FR (4); US (12); BE (1); BU (2); TW (2); JP (5); GB (1); IT (3)