Clinical trial NCT04454658: 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
Official title: A Phase 1b Study Of ABBV-744 Alone Or In Combination With Ruxolitinib Or Navitoclax In Subjects With Myelofibrosis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Myelofibrosis (MF)
Keywords: ABBV-744
Navitoclax
Ruxolitinib
ABT-263
Cancer
Myelofibrosis
MF
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2020-07-01
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With Adverse Events
timeFrame: Up to Approximately 1 year from start of study
Secondary outcomes:
measure: Percentage Of Participants Who Achieve Spleen Volume Reduction Of 35% Or Greater (SVR35)
timeFrame: Up To Week 24
measure: Maximum Observed Plasma Concentration (Cmax) of ABBV-744
timeFrame: Up To Week 12
measure: Time To Cmax (Tmax) Of ABBV-744
timeFrame: Up To Week 12
measure: Area Under The Concentration Versus Time Curve (AUC) Of ABBV-744
timeFrame: Up To Week 12
measure: Half-Life (t1/2) Of ABBV-744
timeFrame: Up To Week 12
measure: Accumulation Ratio Of ABBV-744
timeFrame: Up To Week 12
measure: Apparent Clearance (CL/F) Of ABBV-744
timeFrame: Up To Week 12
measure: Apparent Volume Of Distribution (Vd/F) Of ABBV-744
timeFrame: Up To Week 12
measure: Percentage Of Participants With >= 50% Reduction In Total Symptom Score (TSS)
timeFrame: Up to Week 24
measure: Objective Response Rate (ORR)
timeFrame: Week 24
measure: Maximum Observed Plasma Concentration (Cmax) Of Navitoclax
timeFrame: Up To Week 12
measure: Time To Cmax (Tmax) Of Navitoclax
timeFrame: Up To Week 12
measure: Area Under The Concentration Versus Time Curve (AUC) Of Navitoclax
timeFrame: Up To Week 12
measure: Maximum Observed Plasma Concentration (Cmax) Of Ruxolitinib
timeFrame: Up To Week 12
measure: Time To Cmax (Tmax) Of Ruxolitinib
timeFrame: Up To Week 12
measure: Area Under The Concentration Versus Time Curve (AUC) Of Ruxolitinib
timeFrame: Up To Week 12
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California, Davis Comprehensive Cancer Center /ID# 221790
state: California
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center /ID# 224623
state: New Hampshire
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute /ID# 222557
state: New York
city: New York
country: United States
facility: The Mount Sinai Hospital /ID# 221549
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College /ID# 227069
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center Research /ID# 222802
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma, Stephenson Cancer Center /ID# 224095
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University /ID# 221801
state: Oregon
city: Dallas
country: United States
facility: Texas Oncology- Baylor Charles A. Sammons Cancer Center /ID# 240004
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System /ID# 224208
state: Washington
city: Pilar
country: Argentina
facility: Hospital Universitario Austral /ID# 228909
state: Buenos Aires
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires /ID# 226945
state: Ciudad Autonoma De Buenos Aires
city: Douglas
country: Australia
facility: Townsville University Hospital /ID# 225859
state: Queensland
city: Hobart
country: Australia
facility: Royal Hobart Hospital /ID# 241677
state: Tasmania
city: Perth
country: Australia
facility: Royal Perth Hospital /ID# 241678
state: Western Australia
city: Goiania
country: Brazil
facility: Hospital das Clinicas da Universidade Federal de Goiás /ID# 226636
state: Goias
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre /ID# 226635
state: Rio Grande Do Sul
city: São Paulo
country: Brazil
facility: Sociedade Beneficente Israelita Brasileira Hospital Albert Einstein /ID# 226640
state: Sao Paulo
city: Rio de Janeiro
country: Brazil
facility: Instituto Nacional de Cancer (INCA) /ID# 226637
city: Sao Paulo
country: Brazil
facility: Real e Benemérita Associação Portuguesa de Beneficência /ID# 226641
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao /ID# 226639
city: Sofia
country: Bulgaria
facility: SHAT Hematologic Diseases /ID# 226007
city: Varna
country: Bulgaria
facility: UMHAT Sveta Marina /ID# 226681
city: La Florida
country: Chile
facility: Icegclinic /Id# 231086
state: Region Metropolitana De Santiago
city: Providencia
country: Chile
facility: Fundacion Arturo Lopez Perez /ID# 225037
state: Region Metropolitana De Santiago
city: Temuco
country: Chile
facility: Sociedad de Investigaciones Médicas Limitada /ID# 224175
city: Gyongyos
country: Hungary
facility: Clinexpert Kft. Fazis I Vizsgalohely /ID# 242249
state: Heves
city: Budapest
country: Hungary
facility: Semmelweis Egyetem /ID# 224085
city: Ramat Gan
country: Israel
facility: The Chaim Sheba Medical Center /ID# 222151
state: Tel-Aviv
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center /ID# 223548
state: Tel-Aviv
city: Jerusalem
country: Israel
facility: Hadassah Medical Center-Hebrew University /ID# 243852
state: Yerushalayim
city: Milan
country: Italy
facility: Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico /ID# 244397
city: Fukuoka-shi
country: Japan
facility: Kyushu University Hospital /ID# 228035
state: Fukuoka
city: Sapporo-shi
country: Japan
facility: Hokkaido University Hospital /ID# 228038
state: Hokkaido
city: Osaka-shi
country: Japan
facility: Osaka Metropolitan University Hospital /ID# 225502
state: Osaka
city: Chuo-shi
country: Japan
facility: University of Yamanashi Hospital /ID# 225503
state: Yamanashi
city: Busan
country: Korea, Republic of
facility: Duplicate_Inje University Busan Paik Hospital /ID# 233707
state: Busan Gwang Yeogsi
city: Barcelona
country: Spain
facility: Hospital Santa Creu i Sant Pau /ID# 238501
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon /ID# 233279
city: Orebro
country: Sweden
facility: Orebro Universitetssjukhuset /ID# 228514
state: Orebro Lan
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset /ID# 228515
state: Uppsala Lan
city: Ankara
country: Turkey
facility: Dr. Abdurrahman Yurtaslan Ankara Onkoloji Egitim ve Arastirma Hastanesi /ID# 234215
city: Istanbul
country: Turkey
facility: Koc Universitesi Hastanesi Translasyonel Tıp Arastırma Merkezi /ID# 234214
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References: