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

Myeloproliferative Neoplasm Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04041050
• Other study ID #: M19-753
• Secondary ID: 2020-002597-27
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: November 8, 2019
• Est. completion date: September 8, 2024

Study information

• Verified date: May 2023
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 85
• Est. completion date: September 8, 2024
• Est. primary completion date: September 8, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Myeloproliferative Disorders
• Myeloproliferative Neoplasm
• Neoplasms

Intervention

Drug:
• Navitoclax
Tablet; Oral
• Ruxolitinib
Tablet; Oral
• Celecoxib
Capsule; Oral

Locations

Country	Name	City	State
Belgium	UCL Saint-Luc /ID# 225314	Woluwe-Saint-Lambert	Bruxelles-Capitale
Bulgaria	UMHAT Sveti Georgi /ID# 240022	Plovdiv
Bulgaria	UMHAT Sveti Ivan Rilski /ID# 240077	Sofia
Croatia	Klinicki bolnicki centar Zagreb /ID# 240140	Zagreb	Grad Zagreb
France	CHU Amiens-Picardie Site Sud /ID# 240792	Amiens CEDEX 1	Somme
France	Centre Antoine Lacassagne - Nice /ID# 242293	Nice	Alpes-Maritimes
France	AP-HP - Hopital Saint-Louis /ID# 240685	Paris
France	IUCT Oncopole /ID# 242353	Toulouse Cedex 9
Germany	Charite Universitaetsklinikum Berlin - Campus Virchow /ID# 224835	Berlin
Germany	Universitaetsklinikum Freiburg /ID# 222791	Freiburg	Baden-Wuerttemberg
Germany	Klinikum Kassel /ID# 225440	Kassel
Germany	Universitaetsmedizin Rostock /ID# 225436	Rostock
Italy	ASST Spedali civili di Brescia /ID# 224962	Brescia
Italy	Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRCCS /ID# 224071	Meldola
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS-Università Cattolica /ID# 221408	Rome	Lazio
Japan	Juntendo University Hospital /ID# 213255	Bunkyo-ku	Tokyo
Japan	University of Yamanashi Hospital /ID# 229279	Chuo-shi	Yamanashi
Japan	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
Serbia	University Clinical Center Serbia /ID# 240674	Belgrade	Beograd
Spain	Hospital Duran i Reynals /ID# 224007	Hospitalet de Llobregat	Barcelona
Spain	CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 226041	Madrid
Spain	CLINICA UNIVERSIDAD DE NAVARRA-Pamplona /ID# 224839	Pamplona	Navarra
Sweden	Linkoping University Hospital /ID# 239995	Linkoping
Sweden	Karolinska University Hospital /ID# 239992	Stockholm
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital /ID# 215631	Kaohsiung
Taiwan	China Medical University Hospital /ID# 215634	Taichung City
Turkey	Dokuz Eylul University Medical Faculty /ID# 239952	Izmir
United Kingdom	Gloucestershire Hospitals NHS Foundation Trust /ID# 241189	Cheltenham	Gloucestershire
United States	Gabrail Cancer Center Research /ID# 228924	Canton	Ohio
United States	Northwestern University Feinberg School of Medicine /ID# 224203	Chicago	Illinois
United States	Brigitte Harris Cancer Pavilion /ID# 238686	Detroit	Michigan
United States	City of Hope /ID# 239769	Duarte	California
United States	Providence Medical Foundation /ID# 242558	Fullerton	California
United States	Pennsylvania Cancer Specialists Research Institute - Gettysburg /ID# 242550	Gettysburg	Pennsylvania
United States	East Carolina University Brody School of Medicine /ID# 238560	Greenville	North Carolina
United States	Moores Cancer Center at UC San Diego /ID# 229584	La Jolla	California
United States	UCLA /Id# 222784	Los Angeles	California
United States	Norton Cancer Institute - St Matthews /ID# 239300	Louisville	Kentucky
United States	Onc/Hematology West PC dba Nebraska Cancer Specialists /ID# 242554	Omaha	Nebraska
United States	Virginia Commonwealth University Medical Center Main Hospital /ID# 228169	Richmond	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie

Countries where clinical trial is conducted

United States,  Belgium,  Bulgaria,  Croatia,  France,  Germany,  Italy,  Japan,  Serbia,  Spain,  Sweden,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Maximum Observed Plasma Concentration (Cmax) of Navitoclax (Part 2 and 5)	Maximum Observed Plasma Concentration (Cmax) of Navitoclax.	Up to approximately 1 day
Primary	Maximum Observed Plasma Concentration (Cmax) of Celecoxib (Part 4)	Maximum Observed Plasma Concentration (Cmax) of Celecoxib.	Up to approximately 1 day
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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).
Primary	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	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