A Study Evaluating the Safety and Pharmacokinetics of ABBV-744 in Participants With Relapsed/Refractory Acute Myeloid Leukemia (AML) Cancer

Study Overview
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Brief Summary
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This is an open-label, Phase 1, dose-escalation (Segment 1) and expansion (Segment 2) study to determine the maximum tolerated dose (MTD) and/or the recommended phase two dose (RPTD), and to assess the safety, preliminary efficacy, and pharmacokinetic (PK) profile of ABBV-744 in participants with relapsed/refractory Acute Myeloid Leukemia (AML).

Official Title
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A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABBV-744 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: ABBV-744


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have AML not amenable to curative therapy, refractory to standard of care therapy or for which standard of care therapy does not exist. Participants who are candidates for stem cell transplantation must have been offered this therapeutic option. Must consent to provide biomarker analyses as described in the protocol. Must have an Eastern Cooperative Oncology Group (ECOG) Performance status of: Dose Escalation (Segment 1): 0 - 1 Dose Expansion (Segment 2): 0 - 2 Dose Escalation: Must have a serum albumin during Screening of >= 3.0 g/dL. Participant has adequate bone marrow, renal and hepatic function. Exclusion Criteria: Participant with known active Central Nervous System (CNS) disease. Participant has received anti-cancer traditional medicine or anti-cancer herbal remedies within 14 days prior to ABBV-744 dosing. Saw palmetto is considered anti-cancer herbal remedy. Participant has received anti-cancer therapy within a period of 14 days or 5 half-lives (whichever is longer; except for immunotherapy where a period of 21 days will be acceptable) prior to Study Day 1. Except for hydroxyurea which will be allowed during screening and treatment for controlling leukocytosis. Participant has been previously treated with a Bromodomain and Extra-Terminal (BET) inhibitor Participant has unresolved clinically significant toxicities from most recent prior anti-cancer therapy, defined as any Common Terminology Criteria for Adverse Events (CTCAE v 4.03) grade 2 or higher clinically significant toxicity (excluding alopecia). Participant has received the following within 7 days prior to the first dose of study drug: corticosteroid therapy, CYP3A inhibitors, CYP3A inducers. Participant consumed grapefruit or grapefruit products within 3 days prior to the first dose of study drug. Participant had major surgery within 28 days prior to Study Day 1. Participant is unable to swallow or absorb oral tablets. Participant has known infection with hepatitis B or hepatitis C. Participant has active peptic ulcer disease or other hemorrhagic esophagitis/gastritis, enteritis, colitis. Participant has symptoms of gross hematuria or gross hemoptysis Has electrocardiogram with a QT interval corrected for heart rate using Fridericia's formula (QTcF) > 470 msec or ECG with second degree type 2 or third degree atrioventricular block.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABBV-744 Dose Escalation<br>ABBV-744 will be administered at escalating dose levels until the maximum tolerated dose is reached and a recommended Phase 2 dose is determined. | Drug: ABBV-744<br>* Tablet, oral<br>|
| Experimental: ABBV-744 Dose Expansion<br>ABBV-744 will be administered at the recommended Phase 2 dose determined during the Dose Escalation phase. | Drug: ABBV-744<br>* Tablet, oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) of ABBV-744 | Cmax of ABBV-744. | Through Cycle 2 ( each cycle is 28 days) | 
| Time to Cmax (Tmax) of ABBV-744 | Tmax of ABBV-744. | Through Cycle 2 ( each cycle is 28 days) | 
| Area under the plasma concentration-time curve (AUC) from time 0 to the time of the last measurable concentration (AUCt) of ABBV-744 | Area under the plasma concentration-time curve (AUC) from time 0 to the time of the last measurable concentration (AUCt) of ABBV-744. | Through Cycle 2 ( each cycle is 28 days) | 
| Terminal Phase Elimination Rate Constant (β) of ABBV-744 | Terminal Phase Elimination Rate Constant (β) of ABBV-744. | Through Cycle 2 ( each cycle is 28 days) | 
| Area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUCinf) of ABBV-744 | Area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUCinf) of ABBV-744. | Through Cycle 2 ( each cycle is 28 days) | 
| Dose-limiting toxicity (DLT) of ABBV-744 | DLT events are defined as clinically significant adverse events or abnormal laboratory values assessed as unrelated to disease progression, underlying disease, intercurrent illness, or concomitant medications and occurring during the first 4 weeks after administration of the first dose and that meets additional criteria as described in the protocol. | Up to 28 days after first dose of study drug | 
| Maximum Tolerated Dose (MTD) for ABBV-744 | The MTD is defined as the highest dose for which the estimated posterior mean DLT rate is <= 33% and excessive toxicity probability is limited to maximum of 25% during the first 28 days. | Up to 28 days after first dose of study drug | 
| Recommended Phase 2 Dose (RPTD) for ABBV-744 | RPTD will be determined from a review available safety, pharmacokinetic, and efficacy data during the dose escalation phase (Segment 1) of the study. | Up to 28 days after first dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite complete remission (CRc) | Percentage of participants who achieve composite complete remission (CRc), comprised of complete remission (CR) + CR with incomplete blood count recovery (CRi) is based on the International Working Group (IWG) criteria and European Leukemia Net criteria. | Up to 2 years | 
| Complete Remission (CR) + CR with partial hematologic recovery (CRh) | Percentage of participants who achieve CR + CR with partial hematologic recovery (CRh) is based on the International Working Group (IWG) criteria and European Leukemia Net criteria. | Up to 2 years | 
| Objective Response Rate (ORR) | Percentage of participants who achieve ORR [composite complete remission (CRc) + Partial remission (PR)] is based on the International Working Group (IWG) criteria (CRc, PR) and European Leukemia Net criteria. | Up to 2 years | 
| Duration of Response (DOR) | DOR is defined as the number of days from the date of first response to the first occurrence of progression or death from any cause, whichever occurs first. | Up to 2 years | 
| Event-free survival (EFS) | Percentage of participants who achieve EFS, where EFS is defined as the date of first dose of study drug to the date of primary refractory disease, relapse from CR or CRi, or death from any cause. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia (AML), Relapsed/refractory acute myeloid leukemia, Dose-limiting toxicity, Recommended phase two dose, Pharmacokinetics