A Study Evaluating Safety and Tolerability, and Pharmacokinetics of Navitoclax Monotherapy and in Combination With Ruxolitinib in Participants With Myeloproliferative Neoplasm
- Conditions
- Myeloproliferative Neoplasm
- Interventions
- Registration Number
- NCT04041050
- Lead Sponsor
- AbbVie
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 85
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.
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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 2: Navitoclax + Ruxolitinib Combination Therapy Ruxolitinib Participants will receive various doses of navitoclax once daily (QD) in combination with ruxolitinib twice daily (BID). Part 5: Navitoclax + Ruxolitinib Combination Therapy Ruxolitinib Participants will receive ruxolitinib BID and navitoclax QD for drug-drug interaction (DDI) assessment, followed by continued administration of navitoclax in combination with ruxolitinib. Part 4: Navitoclax + Celecoxib 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. Part 1: Navitoclax Monotherapy Navitoclax Participants will receive various doses of navitoclax once daily (QD). Part 2: Navitoclax + Ruxolitinib Combination Therapy Navitoclax Participants will receive various doses of navitoclax once daily (QD) in combination with ruxolitinib twice daily (BID). Part 3: Navitoclax Monotherapy Navitoclax Participants will receive navitoclax once daily (QD). Part 4: Navitoclax + Celecoxib Navitoclax Participants will receive navitoclax once daily (QD) starting on Day 3. Participants will also receive celecoxib single dose on Day 1 and Day 7. Part 5: Navitoclax + Ruxolitinib Combination Therapy Navitoclax Participants will receive ruxolitinib BID and navitoclax QD for drug-drug interaction (DDI) assessment, followed by continued administration of navitoclax in combination with ruxolitinib.
- Primary Outcome Measures
Name Time Method Area Under the Plasma Concentration-time Curve from time 0 to the time of the last measurable concentration (AUCt) of Navitoclax Up to approximately 2 days Area under the plasma concentration-time curve from time zero to the last measurable concentration of Navitoclax.
Number of Participants with Adverse Events 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 participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
Number of Participants with Dose Limiting Toxicities (DLT) (Part 1 and Part 2) 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.
Time to Cmax (peak time, Tmax) of Celecoxib (Part 4) Up to approximately 1 day Tmax defined as time to maximum observed plasma concentration of Celecoxib.
Maximum Observed Plasma Concentration (Cmax) of Navitoclax (Part 2 and 5) Up to approximately 1 day Maximum Observed Plasma Concentration (Cmax) of Navitoclax.
Maximum Observed Plasma Concentration (Cmax) of Celecoxib (Part 4) Up to approximately 1 day Maximum Observed Plasma Concentration (Cmax) of Celecoxib.
Time to Cmax (peak time, Tmax) of Navitoclax (Part 2 and 5) Up to approximately 1 day Tmax defined as time to maximum observed plasma 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) Up to approximately 2 days Area under the plasma concentration-time curve from time zero to the last measurable concentration of Celecoxib.
Change in QT interval corrected for heart rate interval by Fridericia's correction formula (QTcF) (Part 3) From first dose of study drug until 30 days following last dose of study drug. Change in QTcF (Part 3).
- Secondary Outcome Measures
Name Time Method Overall Response Rate 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 participants with CMML.
Trial Locations
- Locations (42)
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
City of Hope /ID# 239769
🇺🇸Duarte, California, United States
UCLA /Id# 222784
🇺🇸Los Angeles, California, United States
Norton Cancer Institute - St. Matthews /ID# 239300
🇺🇸Louisville, Kentucky, 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
Pennsylvania Cancer Specialists Research Institute - Gettysburg /ID# 242550
🇺🇸Gettysburg, Pennsylvania, United States
Gabrail Cancer Center Research /ID# 228924
🇺🇸Canton, Ohio, 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, Bruxelles-Capitale, Belgium
UMHAT Sveti Georgi /ID# 240022
🇧🇬Plovdiv, Bulgaria
AP-HP - Hopital Saint-Louis /ID# 240685
🇫🇷Paris, France
IUCT Oncopole /ID# 242353
🇫🇷Toulouse Cedex 9, France
Universitaetsklinikum Freiburg /ID# 222791
🇩🇪Freiburg, Baden-Wuerttemberg, Germany
Klinikum Kassel /ID# 225440
🇩🇪Kassel, Hessen, Germany
Universitaetsmedizin Rostock /ID# 225436
🇩🇪Rostock, Mecklenburg-Vorpommern, Germany
Charite Universitaetsklinikum Berlin - Campus Virchow /ID# 224835
🇩🇪Berlin, Germany
ASST Spedali civili di Brescia /ID# 224962
🇮🇹Brescia, Italy
Shonan Kamakura General Hospital /ID# 224315
🇯🇵Kamakura-shi, Kanagawa, Japan
Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRCCS /ID# 224071
🇮🇹Meldola, Italy
Osaka University Hospital /ID# 213235
🇯🇵Suita-shi, Osaka, Japan
Hospital Duran i Reynals /ID# 224007
🇪🇸Hospitalet de Llobregat, Barcelona, Spain
University of Yamanashi Hospital /ID# 229279
🇯🇵Chuo-shi, Yamanashi, Japan
University Clinical Center Serbia /ID# 240674
🇷🇸Belgrade, Beograd, Serbia
Clinica Universidad de Navarra - Pamplona /ID# 224839
🇪🇸Pamplona, Navarra, Spain
Kaohsiung Medical University Chung-Ho Memorial Hospital /ID# 215631
🇨🇳Kaohsiung, Taiwan
CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 226041
🇪🇸Madrid, Spain
China Medical University Hospital /ID# 215634
🇨🇳Taichung, Taiwan
Dokuz Eylul University Medical Faculty /ID# 239952
🇹🇷Izmir, Turkey
Centre Antoine Lacassagne - Nice /ID# 242293
🇫🇷Nice, Alpes-Maritimes, France
Fondazione Policlinico Universitario Agostino Gemelli IRCCS-Universita Cattolica /ID# 221408
🇮🇹Rome, Lazio, Italy
Klinicki bolnicki centar Zagreb /ID# 240140
ðŸ‡ðŸ‡·Zagreb, Grad Zagreb, Croatia
UMHAT Sveti Ivan Rilski /ID# 240077
🇧🇬Sofia, Bulgaria
CHU Amiens-Picardie Site Sud /ID# 240792
🇫🇷Amiens CEDEX 1, Somme, France
Kindai University Hospital /ID# 213241
🇯🇵Osakasayama-shi, Osaka, Japan
Juntendo University Hospital /ID# 213255
🇯🇵Bunkyo-ku, Tokyo, Japan
Gloucestershire Hospitals NHS Foundation Trust /ID# 241189
🇬🇧Cheltenham, Gloucestershire, United Kingdom
Duplicate_Brigitte Harris Cancer Pavilion /ID# 238686
🇺🇸Detroit, Michigan, United States
Northwestern University Feinberg School of Medicine /ID# 224203
🇺🇸Chicago, Illinois, United States
Duplicate_Karolinska University Hospital /ID# 239992
🇸🇪Stockholm, Stockholms Lan, Sweden
Linkoping University Hospital /ID# 239995
🇸🇪Linkoping, Sweden