Safety and Tolerability Study of Oral ABBV-744 Tablet Alone or in Combination With Oral Ruxolitinib Tablet or Oral Navitoclax Tablet in Adult Participants With Myelofibrosis

Myelofibrosis (MF) Clinical Trial

Official title:

A Phase 1b Study Of ABBV-744 Alone Or In Combination With Ruxolitinib Or Navitoclax In Subjects With Myelofibrosis

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04454658
• Other study ID #: M20-247
• Secondary ID: 2020-001225-32
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: November 11, 2020
• Est. completion date: July 26, 2024

Study information

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

Clinical Trial Summary

Myelofibrosis (MF) is a bone marrow illness that affects blood-forming tissues in the body. MF disturbs the body's normal production of blood cells, causing extensive scarring in the bone marrow. This leads to severe anemia, weakness, fatigue, and an enlarged spleen. The purpose of this study is to see how safe and tolerable ABBV-744 is, when given alone, and in combination with ruxolitinib or navitoclax, for adult participants with MF. ABBV-744 is an investigational drug being developed for the treatment of MF. The study has 4 segments - A, B, C, and D. In Segment A, the safe dosing regimen of ABBV-744 is identified and then, given alone as monotherapy. In Segment B, C, and D, combination therapies of ABBV-744 with either ruxolitinib or navitoclax are given. Adult participants with a diagnosis of MF will be enrolled. Around 130 participants will be enrolled in 60 sites worldwide. In Segment A, participants will receive different doses and schedules of oral ABBV-744 tablet to identify safe dosing regimen. Additional participants will be enrolled at the identified monotherapy dosign regimen. In Segment B, participants will receive oral ruxolitinib and ABBV-744 will be given as "add-on" therapy. In Segment C, participants will receive ABBV-744 and oral navitoclax. In Segment D, participants will receive ABBV-744 and ruxolitinib. Participants will receive treatment until disease progression or the participants are not able to tolerate the study drugs. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of treatment will be checked by medical assessments, blood and bone marrow tests, checking for side effects, and completing questionnaires.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 21
• Est. completion date: July 26, 2024
• Est. primary completion date: July 26, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Laboratory values indicative of adequate bone marrow, renal, and hepatic function meeting protocol criteria.
• Completion of the Myelofibrosis System Assessment Form (MFSAF) on at least 4 out of the 7 days prior to Day 1 with at least 2 symptoms with a score >=3 or a total score of >=10.
• Documented diagnosis of intermediate or high-risk primary myelofibrosis (PMF), post-polycythemia vera MF (PPV-MF) or post-essential thrombocytopenia MF (PET-MF) as defined by the World Health Organization (WHO).
• Eastern Cooperative Oncology Group (ECOG) Performance Status of <= 2.
• Intermediate - 2, or High-Risk disease as defined by the Dynamic International Prognostic Scoring System (For Segment A only, Intermediate - 1 with palpable splenomegaly >=5 centimeters [cm] below costal margin are also eligible).
• Splenomegaly defined as spleen palpation measurement >= 5 cm below costal margin or spleen volume >= 450 cubic cms as assessed by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) scan (for Segments A and C, baseline spleen assessment must be obtained > 7 days after discontinuation of most recent Myelofibrosis (MF) therapy. If possible, this assessment should occur within 10 days of Cycle 1 Day 1).

Segment-Specific Prior Therapy Criteria:

• Segment A:
• Prior exposure to one or more Janus Kinase inhibitors (JAKi),[the most recent of which was discontinued > 14 days prior to Cycle 1 Day 1] and are intolerant, resistant, refractory or lost response to the JAKi.
• Segment B:
• Currently receiving ruxolitinib AND
• Willingness to reduce ruxolitinib dose (if on a higher dose); and on a stable dose for 14 days or longer prior to Cycle 1 Day 1; AND
• At least one of the following criteria (a, b, or c):

1. >= 24 weeks duration of current ruxolitinib course, with evidence of disease that is resistant, refractory, or has lost response to ruxolitinib therapy;

2. < 24 weeks duration of current ruxolitinib course with documented resistance, refractories, or loss of response, as defined by any of the

following:

• Appearance of new splenomegaly that is palpable to at least 5 cm below the left costal margin (LCM), in participants with no evidence of splenomegaly prior to the initiation of ruxolitinib.
• >=100% increase in the palpable distance below the LCM, in participants with measurable spleen distance 5 - 10 cm prior to the initiation of ruxolitinib.
• >=50% increase in the palpable distance below the LCM, in participants with measurable spleen > 10 cm prior to the initiation of ruxolitinib.
• A spleen volume increase >= 25% (as assessed by MRI or CT) in participants with a spleen volume assessment available prior to the initiation of ruxolitinib.

3. Prior treatment with ruxolitinib for >= 28 days complicated by any of the

following:

• Development of red blood cell transfusion requirement (at least 2 units/month for 2 months).
• Grade >= 3 adverse events of neutropenia and/or anemia while on ruxolitinib treatment, with improvement or resolution upon dose reduction.
• Segment C:
• Prior exposure to one or more JAKi (the most recent of which was discontinued > 14 days prior to Cycle 1 Day 1), and are intolerant, resistant, refractory or lost response to the JAKi. Exclusion Criteria:

Segment-Specific Prior Therapy Criteria:

• Segment A:
• Prior exposure to one or more Bromodomain and Extra-Terminal (BET) inhibitors.
• Segment B:
• Prior exposure to one or more BET inhibitors.
• Segment C:
• Prior exposure to one or more BET inhibitors and/or any B-Cell Lymphoma 2 (BCL)-2 and/or BCL- XL inhibitor, including navitoclax.
• Segment D:
• Prior exposure to JAKi and/or any BET inhibitor.

Related Conditions & MeSH terms

• Myelofibrosis (MF)
• Primary Myelofibrosis

Intervention

Drug:
• ABBV-744
Tablet; Oral
• Navitoclax
Tablet; Oral
• Ruxolitinib
Tablet; Oral

Locations

Country	Name	City	State
Argentina	Hospital Italiano de Buenos Aires /ID# 226945	Ciudad Autonoma Buenos Aires	Ciudad Autonoma De Buenos Aires
Argentina	Hospital Universitario Austral /ID# 228909	Pilar	Buenos Aires
Australia	Townsville University Hospital /ID# 225859	Douglas	Queensland
Australia	Royal Hobart Hospital /ID# 241677	Hobart	Tasmania
Australia	Royal Perth Hospital /ID# 241678	Perth	Western Australia
Brazil	Hospital das Clinicas da Universidade Federal de Goiás /ID# 226636	Goiania	Goias
Brazil	Hospital de Clinicas de Porto Alegre /ID# 226635	Porto Alegre	Rio Grande Do Sul
Brazil	Instituto Nacional de Câncer José Alencar Gomes da Silva (INCA) /ID# 226637	Rio de Janeiro
Brazil	Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo /ID# 226639	Sao Paulo
Brazil	Real e Benemérita Associação Portuguesa de Beneficência /ID# 226641	Sao Paulo
Brazil	Sociedade Beneficente Israelita Brasileira Hospital Albert Einstein /ID# 226640	São Paulo	Sao Paulo
Bulgaria	SHAT Hematologic Diseases /ID# 226007	Sofia
Bulgaria	UMHAT Sveta Marina /ID# 226681	Varna
Chile	Icegclinic /Id# 231086	La Florida	Region Metropolitana De Santiago
Chile	Fundacion Arturo Lopez Perez /ID# 225037	Providencia	Region Metropolitana Santiago
Chile	Sociedad de Investigaciones Médicas Limitada /ID# 224175	Temuco
Hungary	Semmelweis Egyetem /ID# 224085	Budapest
Hungary	Clinexpert Kft. Fazis I Vizsgalohely /ID# 242249	Gyongyos	Heves
Israel	Hadassah Medical Center-Hebrew University /ID# 243852	Jerusalem	Yerushalayim
Israel	The Chaim Sheba Medical Center /ID# 222151	Ramat Gan	Tel-Aviv
Israel	Tel Aviv Sourasky Medical Center /ID# 223548	Tel Aviv-Yafo	Tel-Aviv
Italy	Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico /ID# 244397	Milan
Japan	University of Yamanashi Hospital /ID# 225503	Chuo-shi	Yamanashi
Japan	Kyushu University Hospital /ID# 228035	Fukuoka-shi	Fukuoka
Japan	Osaka Metropolitan University Hospital /ID# 225502	Osaka-shi	Osaka
Japan	Hokkaido University Hospital /ID# 228038	Sapporo-shi	Hokkaido
Korea, Republic of	Inje University Busan Paik Hospital /ID# 233707	Busan
Spain	Hospital Santa Creu i Sant Pau /ID# 238501	Barcelona
Spain	Hospital General Universitario Gregorio Maranon /ID# 233279	Madrid
Sweden	Orebro Universitetssjukhuset /ID# 228514	Orebro	Orebro Lan
Sweden	Akademiska Sjukhuset /ID# 228515	Uppsala	Uppsala Lan
Turkey	Dr. Abdurrahman Yurtaslan Ankara Onkoloji Egitim ve Arastirma Hastanesi /ID# 234215	Ankara
Turkey	Koc Universitesi Hastanesi Translasyonel Tip Arastirma Merkezi /ID# 234214	Istanbul
United States	Roswell Park Comprehensive Cancer Center /ID# 222557	Buffalo	New York
United States	Gabrail Cancer Center Research /ID# 222802	Canton	Ohio
United States	Texas Oncology- Baylor Charles A. Sammons Cancer Center /ID# 240004	Dallas	Texas
United States	Dartmouth-Hitchcock Medical Center /ID# 224623	Lebanon	New Hampshire
United States	The Mount Sinai Hospital /ID# 221549	New York	New York
United States	Weill Cornell Medical College /ID# 227069	New York	New York
United States	University of Oklahoma, Stephenson Cancer Center /ID# 224095	Oklahoma City	Oklahoma
United States	Oregon Health and Science Univ /ID# 221801	Portland	Oregon
United States	University of California, Davis Comprehensive Cancer Center /ID# 221790	Sacramento	California
United States	VA Puget Sound Health Care System /ID# 224208	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Bulgaria,  Chile,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Spain,  Sweden,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Adverse Events	An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with the treatment. The investigator assesses the relationship of each event to the use of study drug.	Up to Approximately 1 year from start of study
Secondary	Percentage Of Participants Who Achieve Spleen Volume Reduction Of 35% Or Greater (SVR35)	Reduction in spleen volume is measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan.	Up To Week 24
Secondary	Maximum Observed Plasma Concentration (Cmax) of ABBV-744	Maximum observed plasma concentration (Cmax) of ABBV-744.	Up To Week 12
Secondary	Time To Cmax (Tmax) Of ABBV-744	The amount of time taken to reach Cmax.	Up To Week 12
Secondary	Area Under The Concentration Versus Time Curve (AUC) Of ABBV-744	AUC of ABBV-744 will be calculated.	Up To Week 12
Secondary	Half-Life (t1/2) Of ABBV-744	Half-life of ABBV-744 will be calculated.	Up To Week 12
Secondary	Accumulation Ratio Of ABBV-744	Pharmacokinetic parameters will include accumulation ratio of ABBV-744.	Up To Week 12
Secondary	Apparent Clearance (CL/F) Of ABBV-744	CL/F of ABBV-744 will be calculated.	Up To Week 12
Secondary	Apparent Volume Of Distribution (Vd/F) Of ABBV-744	Vd/F of ABBV-744 will be calculated.	Up To Week 12
Secondary	Percentage Of Participants With >= 50% Reduction In Total Symptom Score (TSS)	TSS is assessed using the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. MFSAF v4.0 measures the burden of myelofibrosis-related symptoms. The symptoms are assessed on a 11-point numeric rating scale (NRS) anchored from 0 (absent) to 10 (worst imaginable).	Up to Week 24
Secondary	Objective Response Rate (ORR)	ORR is defined as the sum of rates of partial remission (PR) or better.	Week 24
Secondary	Maximum Observed Plasma Concentration (Cmax) Of Navitoclax	Maximum Observed Plasma Concentration (Cmax) Of Navitoclax.	Up To Week 12
Secondary	Time To Cmax (Tmax) Of Navitoclax	The amount of time taken to reach Cmax.	Up To Week 12
Secondary	Area Under The Concentration Versus Time Curve (AUC) Of Navitoclax	AUC of Navitoclax will be calculated.	Up To Week 12
Secondary	Maximum Observed Plasma Concentration (Cmax) Of Ruxolitinib	Maximum Observed Plasma Concentration (Cmax) Of Ruxolitinib.	Up To Week 12
Secondary	Time To Cmax (Tmax) Of Ruxolitinib	The amount of time taken to reach Cmax.	Up To Week 12
Secondary	Area Under The Concentration Versus Time Curve (AUC) Of Ruxolitinib	AUC of Ruxolitinib will be calculated.	Up To Week 12