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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

Phase 1
Active, not recruiting
Conditions
Myelofibrosis (MF)
Interventions
Drug: ABBV-744
Drug: Ruxolitinib
Drug: Navitoclax
Registration Number
NCT04454658
Lead Sponsor
AbbVie
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.

Detailed Description

Not available

Recruitment & Eligibility

Status
ACTIVE_NOT_RECRUITING
Sex
All
Target Recruitment
21
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.
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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.
Read More

Study & Design

Study Type
INTERVENTIONAL
Study Design
SEQUENTIAL
Arm && Interventions
GroupInterventionDescription
Segment A: ABBV-744 Dose Identification and OptimizationABBV-744Participants who have been previously treated with Janus Kinase inhibitor(s) (JAKi) and stopped such therapy, will receive different dosing regimens and schedules of ABBV-744 to identify the safe dosing regimen and schedule.
Segment A: ABBV-744 MonotherapyABBV-744Participants will receive the identified safe dosing regimen of ABBV-744 as monotherapy.
Segment B: Ruxolitinib + ABBV-744 "Add on" TherapyABBV-744Participants whose disease (myelofibrosis) is inadequately controlled by ongoing ruxolitinib therapy will receive ruxolitinib and ABBV-744 as "add-on" therapy.
Segment B: Ruxolitinib + ABBV-744 "Add on" TherapyRuxolitinibParticipants whose disease (myelofibrosis) is inadequately controlled by ongoing ruxolitinib therapy will receive ruxolitinib and ABBV-744 as "add-on" therapy.
Segment C: ABBV-744 + NavitoclaxABBV-744Participants who have previously been exposed to JAKi, and stopped such therapy, will receive ABBV-744 and navitoclax.
Segment D: ABBV-744 + RuxolitinibABBV-744Participants who have never received JAKi will receive ABBV-744 and ruxolitinib.
Segment D: ABBV-744 + RuxolitinibRuxolitinibParticipants who have never received JAKi will receive ABBV-744 and ruxolitinib.
Segment C: ABBV-744 + NavitoclaxNavitoclaxParticipants who have previously been exposed to JAKi, and stopped such therapy, will receive ABBV-744 and navitoclax.
Primary Outcome Measures
NameTimeMethod
Percentage of Participants With Adverse EventsUp to Approximately 1 year from start of study

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.

Secondary Outcome Measures
NameTimeMethod
Half-Life (t1/2) Of ABBV-744Up To Week 12

Half-life of ABBV-744 will be calculated.

Percentage Of Participants Who Achieve Spleen Volume Reduction Of 35% Or Greater (SVR35)Up To Week 24

Reduction in spleen volume is measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan.

Maximum Observed Plasma Concentration (Cmax) of ABBV-744Up To Week 12

Maximum observed plasma concentration (Cmax) of ABBV-744.

Time To Cmax (Tmax) Of ABBV-744Up To Week 12

The amount of time taken to reach Cmax.

Area Under The Concentration Versus Time Curve (AUC) Of ABBV-744Up To Week 12

AUC of ABBV-744 will be calculated.

Accumulation Ratio Of ABBV-744Up To Week 12

Pharmacokinetic parameters will include accumulation ratio of ABBV-744.

Apparent Clearance (CL/F) Of ABBV-744Up To Week 12

CL/F of ABBV-744 will be calculated.

Apparent Volume Of Distribution (Vd/F) Of ABBV-744Up To Week 12

Vd/F of ABBV-744 will be calculated.

Percentage Of Participants With >= 50% Reduction In Total Symptom Score (TSS)Up to Week 24

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).

Objective Response Rate (ORR)Week 24

ORR is defined as the sum of rates of partial remission (PR) or better.

Maximum Observed Plasma Concentration (Cmax) Of NavitoclaxUp To Week 12

Maximum Observed Plasma Concentration (Cmax) Of Navitoclax.

Time To Cmax (Tmax) Of NavitoclaxUp To Week 12

The amount of time taken to reach Cmax.

Area Under The Concentration Versus Time Curve (AUC) Of NavitoclaxUp To Week 12

AUC of Navitoclax will be calculated.

Maximum Observed Plasma Concentration (Cmax) Of RuxolitinibUp To Week 12

Maximum Observed Plasma Concentration (Cmax) Of Ruxolitinib.

Time To Cmax (Tmax) Of RuxolitinibUp To Week 12

The amount of time taken to reach Cmax.

Area Under The Concentration Versus Time Curve (AUC) Of RuxolitinibUp To Week 12

AUC of Ruxolitinib will be calculated.

Trial Locations

Locations (43)

Royal Perth Hospital /ID# 241678

🇦🇺

Perth, Western Australia, Australia

The Mount Sinai Hospital /ID# 221549

🇺🇸

New York, New York, United States

University of Oklahoma, Stephenson Cancer Center /ID# 224095

🇺🇸

Oklahoma City, Oklahoma, United States

Instituto Nacional de Cancer (INCA) /ID# 226637

🇧🇷

Rio de Janeiro, Brazil

Real e Benemérita Associação Portuguesa de Beneficência /ID# 226641

🇧🇷

Sao Paulo, Brazil

SHAT Hematologic Diseases /ID# 226007

🇧🇬

Sofia, Bulgaria

University of California, Davis Comprehensive Cancer Center /ID# 221790

🇺🇸

Sacramento, California, United States

Dartmouth-Hitchcock Medical Center /ID# 224623

🇺🇸

Lebanon, New Hampshire, United States

Weill Cornell Medical College /ID# 227069

🇺🇸

New York, New York, United States

Roswell Park Cancer Institute /ID# 222557

🇺🇸

Buffalo, New York, United States

Texas Oncology- Baylor Charles A. Sammons Cancer Center /ID# 240004

🇺🇸

Dallas, Texas, United States

Oregon Health and Science University /ID# 221801

🇺🇸

Portland, Oregon, United States

Hospital Italiano de Buenos Aires /ID# 226945

🇦🇷

Ciudad Autonoma Buenos Aires, Ciudad Autonoma De Buenos Aires, Argentina

VA Puget Sound Health Care System /ID# 224208

🇺🇸

Seattle, Washington, United States

Townsville University Hospital /ID# 225859

🇦🇺

Douglas, Queensland, Australia

Royal Hobart Hospital /ID# 241677

🇦🇺

Hobart, Tasmania, Australia

Hospital de Clinicas de Porto Alegre /ID# 226635

🇧🇷

Porto Alegre, Rio Grande Do Sul, Brazil

Hospital das Clinicas da Universidade Federal de Goiás /ID# 226636

🇧🇷

Goiania, Goias, Brazil

Sociedade Beneficente Israelita Brasileira Hospital Albert Einstein /ID# 226640

🇧🇷

São Paulo, Sao Paulo, Brazil

Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao /ID# 226639

🇧🇷

Sao Paulo, Brazil

Icegclinic /Id# 231086

🇨🇱

La Florida, Region Metropolitana De Santiago, Chile

Clinexpert Kft. Fazis I Vizsgalohely /ID# 242249

🇭🇺

Gyongyos, Heves, Hungary

Fundacion Arturo Lopez Perez /ID# 225037

🇨🇱

Providencia, Region Metropolitana De Santiago, Chile

Semmelweis Egyetem /ID# 224085

🇭🇺

Budapest, Hungary

The Chaim Sheba Medical Center /ID# 222151

🇮🇱

Ramat Gan, Tel-Aviv, Israel

Tel Aviv Sourasky Medical Center /ID# 223548

🇮🇱

Tel Aviv, Tel-Aviv, Israel

Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico /ID# 244397

🇮🇹

Milan, Italy

Hadassah Medical Center-Hebrew University /ID# 243852

🇮🇱

Jerusalem, Yerushalayim, Israel

Hokkaido University Hospital /ID# 228038

🇯🇵

Sapporo-shi, Hokkaido, Japan

Osaka Metropolitan University Hospital /ID# 225502

🇯🇵

Osaka-shi, Osaka, Japan

University of Yamanashi Hospital /ID# 225503

🇯🇵

Chuo-shi, Yamanashi, Japan

Hospital Santa Creu i Sant Pau /ID# 238501

🇪🇸

Barcelona, Spain

Duplicate_Inje University Busan Paik Hospital /ID# 233707

🇰🇷

Busan, Busan Gwang Yeogsi, Korea, Republic of

Hospital General Universitario Gregorio Maranon /ID# 233279

🇪🇸

Madrid, Spain

Orebro Universitetssjukhuset /ID# 228514

🇸🇪

Orebro, Orebro Lan, Sweden

Akademiska Sjukhuset /ID# 228515

🇸🇪

Uppsala, Uppsala Lan, Sweden

Koc Universitesi Hastanesi Translasyonel Tıp Arastırma Merkezi /ID# 234214

🇹🇷

Istanbul, Turkey

Dr. Abdurrahman Yurtaslan Ankara Onkoloji Egitim ve Arastirma Hastanesi /ID# 234215

🇹🇷

Ankara, Turkey

Kyushu University Hospital /ID# 228035

🇯🇵

Fukuoka-shi, Fukuoka, Japan

Hospital Universitario Austral /ID# 228909

🇦🇷

Pilar, Buenos Aires, Argentina

Sociedad de Investigaciones Médicas Limitada /ID# 224175

🇨🇱

Temuco, Chile

UMHAT Sveta Marina /ID# 226681

🇧🇬

Varna, Bulgaria

Gabrail Cancer Center Research /ID# 222802

🇺🇸

Canton, Ohio, United States

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