Acalabrutinib (ACP-196) in Combination With ACP-319, for Treatment of B-Cell Malignancies

Study Overview
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Brief Summary
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This study is evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy acalabrutinib and ACP 319 in B-cell malignancies.

Detailed Description
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Part 1, Dose Escalation, is comprised of 3 dosing cohorts of 6 subjects each. Acalabrutinib dosing is fixed in all cohorts at 100 mg PO twice daily (BID). In addition to acalabrutinib, subjects in Cohort 1 will receive ACP-319, 25 mg BID; Cohort 2 will receive ACP-319, 50 mg BID: and Cohort 3 will receive ACP-319 100 mg BID. The maximum tolerated dose (MTD) of the study treatment combination will be determined by assessing dose-related toxicities (DLTs) for each cohort at the end of Cycle 1 prior to dose escalation. If there are greater than or equal to 2 DLTs in a cohort, dose escalation will not occur and the MTD will be the highest daily dose for which less than 33% of the subjects in that cohort experienced DLTs in Cycle 1. Part 2, Dose Expansion, includes 12 subjects per histology, dosing at the MTD for the combination of acalabrutinib and ACP-319 established in Part 1. Subjects will continue dosing until disease progression or unacceptable drug-related toxicity.

Official Title
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A Phase 1/2 Proof-of-Concept Study of the Combination of ACP-196 and ACP-319 in Subjects With B-cell Malignancies

Conditions
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Non-Hodgkins Lymphoma, Multiple Myeloma, B-All

Intervention / Treatment
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* Drug: Acalabrutinib
* Drug: ACP-319


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Diagnosis of a b-cell malignancy as documented by medical records and with histology based on criteria established by the World Health Organization (WHO). Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Agreement to use contraception during the study and for 90 days after the last dose of study drugs if sexually active and able to bear or beget children. Exclusion Criteria A life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of study drugs, or put the study outcomes at undue risk. Central nervous system (CNS) involvement by lymphoma/leukemia Any therapeutic antibody within 4 weeks of first dose of study drugs. The time from the last dose of the most recent chemotherapy or experimental therapy to the first dose of study drugs is < 5 times the half-life of the previously administered agent(s). ANC < 0.5 x 10^9/L or platelet count < 50 x 10^9/L unless due to disease involvement in the bone marrow. Creatinine > 1.5 x institutional upper limit of normal (ULN); total bilirubin > 1.5 x ULN (unless due to Gilbert's disease); and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3.0 x ULN.

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: Dose Escalation and Expansion<br>The acalabrutinib dose will be fixed and the ACP-319 dose will be escalated in each of three cohorts, and each cohort will take both study drugs by mouth, twice per day (BID) at approximately 12 hour intervals. Expansion groups of up to 12 subjects for Germinal center B-cell (GCB) DLBCL and Non-GCB DLBCL to take a fixed dose of acalabrutinib and ACP-319. Each disease group will take both study drugs by mouth, twice per day (BID) at approximately 12 hour intervals. | Drug: Acalabrutinib<br>* Oral<br>* Other names: ACP-196;Drug: ACP-319<br>* Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Response and Overall Response Rate | Best response and overall response rate per the criteria investigator uses for each disease histology. Standardized response and progression criteria is based on established criteria for B-cell malignancies, including WM (Cheson 2014; Owen 2013; Hallek 2008; Bladé 1998; and Durie 2006). | from the start of the treatment to the last evaluable disease assessment, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bruton tyrosine kinase inhibitor, Btk, B-Cell Malignancies, Mantle Cell, Multiple Myeloma, CLL, SLL, DLBCL, Follicular, Waldenstrom, B-All