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

Sponsor

AbbVie (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04041050

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

1.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

There are 4 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 participants with myeloproliferative neoplasm (MPN) or chronic myelomonocytic leukemia (CMML).

Condition or Disease	Intervention/Treatment	Phase
Myeloproliferative Neoplasm	Drug: Navitoclax Drug: Ruxolitinib Drug: Celecoxib	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

62 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 8, 2019

Anticipated Primary Completion Date :

Sep 8, 2024

Anticipated Study Completion Date :

Sep 8, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: Navitoclax Monotherapy Participants will receive various doses of navitoclax once daily (QD).	Drug: Navitoclax Tablet; Oral Other Names: ABT-263
Experimental: Part 2: Navitoclax + Ruxolitinib Combination Therapy Participants will receive various doses of navitoclax once daily (QD) in combination with ruxolitinib twice daily (BID).	Drug: Navitoclax Tablet; Oral Other Names: ABT-263 Drug: Ruxolitinib Tablet; Oral
Experimental: Part 3: Navitoclax Monotherapy Participants will receive navitoclax once daily (QD).	Drug: Navitoclax Tablet; Oral Other Names: ABT-263
Experimental: 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.	Drug: Navitoclax Tablet; Oral Other Names: ABT-263 Drug: Celecoxib Capsule; Oral Other Names: Celebrex

Outcome Measures

Primary Outcome Measures

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.
Maximum Observed Plasma Concentration (Cmax) of Navitoclax [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 [Up to approximately 1 day]
Tmax defined as time to maximum observed plasma concentration 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.
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.
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.
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 subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
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

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 subjects with CMML.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope /ID# 239769	Duarte	California	United States	91010
2	Providence Medical Foundation /ID# 242558	Fullerton	California	United States	92835
3	Moores Cancer Center at UC San Diego /ID# 229584	La Jolla	California	United States	92093
4	UCLA /Id# 222784	Los Angeles	California	United States	90095-1678
5	Northwestern University Feinberg School of Medicine /ID# 224203	Chicago	Illinois	United States	60611-2927
6	Investigative Clinical Research of Indiana - Indianapolis /ID# 244717	Indianapolis	Indiana	United States	46260
7	Norton Cancer Institute - St Matthews /ID# 239300	Louisville	Kentucky	United States	40207
8	Brigitte Harris Cancer Pavilion /ID# 238686	Detroit	Michigan	United States	48202-2610
9	Onc/Hematology West PC dba Nebraska Cancer Specialists /ID# 242554	Omaha	Nebraska	United States	68130
10	East Carolina University Brody School of Medicine /ID# 238560	Greenville	North Carolina	United States	27834
11	Gabrail Cancer Center Research /ID# 228924	Canton	Ohio	United States	44718
12	Pennsylvania Cancer Specialists Research Institute - Gettysburg /ID# 242550	Gettysburg	Pennsylvania	United States	17325
13	Virginia Commonwealth University Medical Center Main Hospital /ID# 228169	Richmond	Virginia	United States	23219
14	UCL Saint-Luc /ID# 225314	Woluwe-Saint-Lambert	Bruxelles-Capitale	Belgium	1200
15	UMHAT Sveti Georgi /ID# 240022	Plovdiv		Bulgaria	4002
16	UMHAT Sveti Ivan Rilski /ID# 240077	Sofia		Bulgaria	1431
17	Klinicki bolnicki centar Zagreb /ID# 240140	Zagreb	Grad Zagreb	Croatia	10000
18	Centre Antoine Lacassagne - Nice /ID# 242293	Nice	Alpes-Maritimes	France	06189
19	CHU Amiens-Picardie Site Sud /ID# 240792	Amiens CEDEX 1	Somme	France	80054
20	AP-HP - Hopital Saint-Louis /ID# 240685	Paris		France	75010
21	IUCT Oncopole /ID# 242353	Toulouse Cedex 9		France	31059
22	Universitaetsklinikum Freiburg /ID# 222791	Freiburg	Baden-Wuerttemberg	Germany	79106
23	Charite Universitaetsklinikum Berlin - Campus Virchow /ID# 224835	Berlin		Germany	13353
24	Klinikum Kassel /ID# 225440	Kassel		Germany	34125
25	Universitaetsmedizin Rostock /ID# 225436	Rostock		Germany	18057
26	Fondazione Policlinico Universitario Agostino Gemelli IRCCS-Università Cattolica /ID# 221408	Rome	Lazio	Italy	00168
27	ASST Spedali civili di Brescia /ID# 224962	Brescia		Italy	25123
28	Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRCCS /ID# 224071	Meldola		Italy	47014
29	Shonan Kamakura General Hospital /ID# 224315	Kamakura-shi	Kanagawa	Japan	247-8533
30	Kindai University Hospital /ID# 213241	Osakasayama-shi	Osaka	Japan	589-8511
31	Osaka University Hospital /ID# 213235	Suita-shi	Osaka	Japan	565-0871
32	Juntendo University Hospital /ID# 213255	Bunkyo-ku	Tokyo	Japan	113-8431
33	University of Yamanashi Hospital /ID# 229279	Chuo-shi	Yamanashi	Japan	409-3821
34	Moscow State budget healthcare /ID# 240859	Moscow	Moskva	Russian Federation	125284
35	Almazov National Medical Research Centre /ID# 240858	Sankt-Peterburg		Russian Federation	197341
36	University Clinical Center Serbia /ID# 240674	Belgrade	Beograd	Serbia	11000
37	Hospital Duran i Reynals /ID# 224007	Hospitalet de Llobregat	Barcelona	Spain	08907
38	CLINICA UNIVERSIDAD DE NAVARRA-Pamplona /ID# 224839	Pamplona	Navarra	Spain	31008
39	CLINICA UNIVERSIDAD DE NAVARRA-Madrid /ID# 226041	Madrid		Spain	28027
40	Linkoping University Hospital /ID# 239995	Linkoping		Sweden	581 85
41	Karolinska University Hospital /ID# 239992	Stockholm		Sweden	141 86
42	Kaohsiung Medical University Chung-Ho Memorial Hospital /ID# 215631	Kaohsiung		Taiwan	807
43	China Medical University Hospital /ID# 215634	Taichung City		Taiwan	40447
44	Dokuz Eylul University Medical Faculty /ID# 239952	Izmir		Turkey	35340
45	Gloucestershire Hospitals NHS Foundation Trust /ID# 241189	Cheltenham	Gloucestershire	United Kingdom	GL53 7AN
46	Guys and St Thomas NHS Foundation Trust /ID# 223963	London	London, City Of	United Kingdom	SE1 9RT