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
Keywords
Abstract
Dates
Last Verified: | 05/31/2020 |
First Submitted: | 06/29/2020 |
Estimated Enrollment Submitted: | 06/29/2020 |
First Posted: | 06/30/2020 |
Last Update Submitted: | 06/29/2020 |
Last Update Posted: | 06/30/2020 |
Actual Study Start Date: | 07/13/2020 |
Estimated Primary Completion Date: | 11/21/2022 |
Estimated Study Completion Date: | 11/21/2022 |
Condition or disease
Intervention/treatment
Drug: ABBV-744
Drug: Segment C: ABBV-744 + Navitoclax
Drug: Ruxolitinib
Phase
Arm Groups
Arm | Intervention/treatment |
---|---|
Experimental: Segment A: ABBV-744 Dose Identification and Optimization Participants 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. | |
Experimental: Segment A: ABBV-744 Monotherapy Participants will receive the identified safe dosing regimen of ABBV-744 as monotherapy. | |
Experimental: Segment B: Ruxolitinib + ABBV-744 "Add on" Therapy Participants whose disease (myelofibrosis) is inadequately controlled by ongoing ruxolitinib therapy will receive ruxolitinib and ABBV-744 as "add-on" therapy. | |
Experimental: Segment C: ABBV-744 + Navitoclax Participants who have previously been exposed to JAKi, and stopped such therapy, will receive ABBV-744 and navitoclax. | Drug: Segment C: ABBV-744 + Navitoclax Tablet; Oral |
Experimental: Segment D: ABBV-744 + Ruxolitinib Participants who have never received JAKi will receive ABBV-744 and ruxolitinib. |
Eligibility Criteria
Ages Eligible for Study | 18 Years To 18 Years |
Sexes Eligible for Study | All |
Accepts Healthy Volunteers | Yes |
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 0 or 1. - 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 > 28 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 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 monotherapy; 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 > 28 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. |
Outcome
Primary Outcome Measures
1. Percentage of Participants With Adverse Events [Up to Approximately 1 year from start of study]
Secondary Outcome Measures
1. Percentage Of Participants Who Achieve Spleen Volume Reduction Of 35% Or Greater (SVR35) [Up To Week 24]
2. Maximum Observed Plasma Concentration (Cmax) of ABBV-744 [Up To Week 12]
3. Time To Cmax (Tmax) Of ABBV-744 [Up To Week 12]
4. Area Under The Concentration Versus Time Curve (AUC) Of ABBV-744 [Up To Week 12]
5. Half-Life (t1/2) Of ABBV-744 [Up To Week 12]
6. Accumulation Ratio Of ABBV-744 [Up To Week 12]
7. Apparent Clearance (CL/F) Of ABBV-744 [Up To Week 12]
8. Apparent Volume Of Distribution (Vd/F) Of ABBV-744 [Up To Week 12]
9. Percentage Of Participants With >= 50% Reduction In Total Symptom Score (TSS) [Week 24]
10. Objective Response Rate (ORR) [Week 24]
11. Maximum Observed Plasma Concentration (Cmax) Of Navitoclax [Up To Week 12]
12. Time To Cmax (Tmax) Of Navitoclax [Up To Week 12]
13. Area Under The Concentration Versus Time Curve (AUC) Of Navitoclax [Up To Week 12]
14. Maximum Observed Plasma Concentration (Cmax) Of Ruxolitinib [Up To Week 12]
15. Time To Cmax (Tmax) Of Ruxolitinib [Up To Week 12]
16. Area Under The Concentration Versus Time Curve (AUC) Of Ruxolitinib [Up To Week 12]