Clinical trial NCT04041050: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Myeloproliferative Neoplasm
Keywords: Myeloproliferative Neoplasm (MPN)
Chronic myelomonocytic leukemia (CMML)
Polycythemia Vera (PV)
Essential Thrombocythemia (ET)
Myelofibrosis (MF)
cancer
navitoclax
ruxolitinib
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2019-08-01
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Number of Participants with Dose Limiting Toxicities (DLT) (Part 1 and Part 2)
timeFrame: Up to 28 days after the navitoclax initiation
measure: Maximum Observed Plasma Concentration (Cmax) of Navitoclax (Part 2 and 5)
timeFrame: Up to approximately 1 day
measure: Maximum Observed Plasma Concentration (Cmax) of Celecoxib (Part 4)
timeFrame: Up to approximately 1 day
measure: Time to Cmax (peak time, Tmax) of Navitoclax (Part 2 and 5)
timeFrame: Up to approximately 1 day
measure: Time to Cmax (peak time, Tmax) of Celecoxib (Part 4)
timeFrame: Up to approximately 1 day
measure: Area Under the Plasma Concentration-time Curve from time 0 to the time of the last measurable concentration (AUCt) of Navitoclax
timeFrame: Up to approximately 2 days
measure: Area Under the Plasma Concentration-time Curve from time 0 to the time of the last measurable concentration (AUCt) of Celecoxib (Part 4)
timeFrame: Up to approximately 2 days
measure: Number of Participants with Adverse Events
timeFrame: From first dose of study drug until 30 days following last dose of study drug (up to approximately 5 years).
measure: Change in QT interval corrected for heart rate interval by Fridericia's correction formula (QTcF) (Part 3)
timeFrame: From first dose of study drug until 30 days following last dose of study drug.
Secondary outcomes:
measure: Overall Response Rate
timeFrame: Up to approximately 96 weeks
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope /ID# 239769
state: California
city: Fullerton
country: United States
facility: Providence - St. Jude Medical Center /ID# 242558
state: California
city: La Jolla
country: United States
facility: Moores Cancer Center at UC San Diego /ID# 229584
state: California
city: Los Angeles
country: United States
facility: UCLA /Id# 222784
state: California
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine /ID# 224203
state: Illinois
city: Louisville
country: United States
facility: Norton Cancer Institute - St. Matthews /ID# 239300
state: Kentucky
city: Detroit
country: United States
facility: Duplicate_Brigitte Harris Cancer Pavilion /ID# 238686
state: Michigan
city: Omaha
country: United States
facility: Nebraska Cancer Specialists - Omaha - Wright Street /ID# 242554
state: Nebraska
city: Greenville
country: United States
facility: Duplicate_East Carolina University Brody School of Medicine /ID# 238560
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center Research /ID# 228924
state: Ohio
city: Gettysburg
country: United States
facility: Pennsylvania Cancer Specialists Research Institute - Gettysburg /ID# 242550
state: Pennsylvania
city: Richmond
country: United States
facility: Virginia Commonwealth University Medical Center Main Hospital /ID# 228169
state: Virginia
city: Woluwe-Saint-Lambert
country: Belgium
facility: Cliniques Universitaires UCL Saint-Luc /ID# 225314
state: Bruxelles-Capitale
city: Plovdiv
country: Bulgaria
facility: UMHAT Sveti Georgi /ID# 240022
city: Sofia
country: Bulgaria
facility: UMHAT Sveti Ivan Rilski /ID# 240077
city: Zagreb
country: Croatia
facility: Klinicki bolnicki centar Zagreb /ID# 240140
state: Grad Zagreb
city: Nice
country: France
facility: Centre Antoine Lacassagne - Nice /ID# 242293
state: Alpes-Maritimes
city: Amiens CEDEX 1
country: France
facility: CHU Amiens-Picardie Site Sud /ID# 240792
state: Somme
city: Paris
country: France
facility: AP-HP - Hopital Saint-Louis /ID# 240685
city: Toulouse Cedex 9
country: France
facility: IUCT Oncopole /ID# 242353
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg /ID# 222791
state: Baden-Wuerttemberg
city: Kassel
country: Germany
facility: Klinikum Kassel /ID# 225440
state: Hessen
city: Rostock
country: Germany
facility: Universitaetsmedizin Rostock /ID# 225436
state: Mecklenburg-Vorpommern
city: Berlin
country: Germany
facility: Charite Universitaetsklinikum Berlin - Campus Virchow /ID# 224835
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS-Universita Cattolica /ID# 221408
state: Lazio
city: Brescia
country: Italy
facility: ASST Spedali civili di Brescia /ID# 224962
city: Meldola
country: Italy
facility: Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRCCS /ID# 224071
city: Kamakura-shi
country: Japan
facility: Shonan Kamakura General Hospital /ID# 224315
state: Kanagawa
city: Osakasayama-shi
country: Japan
facility: Kindai University Hospital /ID# 213241
state: Osaka
city: Suita-shi
country: Japan
facility: Osaka University Hospital /ID# 213235
state: Osaka
city: Bunkyo-ku
country: Japan
facility: Juntendo University Hospital /ID# 213255
state: Tokyo
city: Chuo-shi
country: Japan
facility: University of Yamanashi Hospital /ID# 229279
state: Yamanashi
city: Belgrade
country: Serbia
facility: University Clinical Center Serbia /ID# 240674
state: Beograd
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Duran i Reynals /ID# 224007
state: Barcelona
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra - Pamplona /ID# 224839
state: Navarra
city: Madrid
country: Spain
facility: CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 226041
city: Stockholm
country: Sweden
facility: Duplicate_Karolinska University Hospital /ID# 239992
state: Stockholms Lan
city: Linkoping
country: Sweden
facility: Linkoping University Hospital /ID# 239995
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital /ID# 215631
city: Taichung
country: Taiwan
facility: China Medical University Hospital /ID# 215634
city: Izmir
country: Turkey
facility: Dokuz Eylul University Medical Faculty /ID# 239952
city: Cheltenham
country: United Kingdom
facility: Gloucestershire Hospitals NHS Foundation Trust /ID# 241189
state: Gloucestershire
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References: