Neoplasms

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Waldenstrom Macroglobulinemia

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

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Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

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All Drugs and Chemicals

Amino Acids

Acalabrutinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Subjects previously treated with Waldenström Macroglobulinemia N=92

Subjects with treatment-naïve Waldenström Macroglobulinemia. N=14

Acalabrutinib (ACP-196)

AstraZeneca Clinical study Information Center

The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics, and activity of acalabrutinib in treating subjects with WM.

Clinical studies have shown that targeting the B-cell receptor (BCR) signaling pathway by inhibiting Bruton tyrosine kinase (BTK) produces significant clinical benefit in patients with non-Hodgkin lymphoma, including Waldenström macroglobulinemia (WM). Ibrutinib (IMBRUVICA®), an oral, small-molecule BTK inhibitor has been approved for the treatment for chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and WM.

Acerta Pharma BV (AcertaPharma) has developed a novel BTK inhibitor, acalabrutinib, that achieves significant oral bioavailability and potency in preclinical models.

The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics, and activity of acalabrutinib in treating subjects with WM.

An Open-label, Phase 2 Study of ACP-196 in Subjects With Waldenström Macroglobulinemia

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

ORR defined as the rate of subjects achieving a Miner Response (MR) or better including complete response (CR), very good partial response (VGPR), partial response (PR) and MR; The definition of responses are evaluated by investigators using both Modified 6th criteria (refer to protocol table 4-2 , 4-3) and Modified 3rd International Workshop of Waldenström Macroglobulinemia (IWWM) criteria (refer to protocol table 4-4 and table 4-5 for definition). For Modified 6th criteria, MR is defined as (1) monoclonal IgM protein is detectable, (2) no new signs or symptoms of active disease, (3) and patient has \>=25% but \< 50% reduction in serum monoclonal IgM level from baseline. PR and VGPR both require (1) and (2) as MR, but PR also requires the \>=50% and \<90% reduction in serum monoclonal IgM level as well as reduction in extramedullary disease. VGPR requires \>= 90% reduction in serum IgM and complete resolution of extramedullary disease.

Kaplan-Meier (K-M) estimates of the PFS assessments and its 95% confidence interval are provided using both modified 3rd and 6th IWWM criteria by investigator. K-M estimates at a certain time (ex. all subjects complete Cycle 27) provides the estimated percentage of the subjects who are still alive or have not progressed by the given time over all patients at risk. Per 6th IWWM criteria, the progressive disease is defined as \>= 25% increase in serum IgM level with an absolute increase of at least 500 mg/dL from lowest nadir (requires confirmation on at least 2 consecutive measurements at least 4 weeks apart) and/or progression of clinical features attributable to the disease. Per modified 3rd IWWM criteria, besides IgM requirement as 6th criteria, it could also includes progression of clinically significant disease related symptoms and/or death from any cause or initiation of a new anti-neoplastic therapy.

Outcome Measure was pre-specified to summarize data per investigator assessment with respect to subject's vital/survival status is presented in the RRF and irrespective of iWWM 3rd or 6th criteria. Kaplan-Meier (K-M) estimates at a certain time (ex. all subjects complete Cycle 27) provides the estimated percentage of the subjects who are still alive by the given time over all patients at risk.

DOR is defined as the interval from the first documentation of Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR) or Minor Response (MR) to the earlier of the first documentation of definitive PD or death from any cause. The summary statistics are provided for DOR.

Acerta Pharma BV

In original protocol, subjects were planned to be randomized 1:1 into 2 cohorts: Acala 100 mg BIDx28 days and 200 mg QDx28 days respectively. After enrollment started, 6 pts received Acala 200 mg QD (5 pts previously treated,1 pt treatment naïve).Per safety and occupancy data in CLL pts, a protocol amendment was made on 13MAR2015, and the 6 pts on 200 mg QD were switched to 100 BID for the remainder of the study. Median 200 mg QD exposure prior to switch was 6.9 \[range: 2.4-13.8\] months.

Previously Treated (PT) Cohort 1

Previously Treated (PT) Cohort 2

Previously Treated (PT) Total

Treatment Naive (TN) Cohort 1

Treatment Naive (TN) Cohort 2

Treatment Naive (TN) Total

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United Kingdom

Netherlands

Italy

Greece

France

Region of Enrollment

Global Clinical Lead

ORR 6th IWWM criteria (CR+VGPR+PR+MR)

CR (6th IWWM criteria)

VGPR (6th IWWM criteria)

PR (6th IWWM criteria)

MR (6th)

Previously Treated (N=92)

Treatment Naive (N=14)

In the original protocol, previously treated subjects were planned to be randomized 1:1 into 2 cohorts: Cohort 1 to receive Acala 100 mg BID for 28 days and Cohort 2 to receive Acala 200 mg once daily (QD) for 28 days. After enrollment started, the dose regimen was amended. The 200 mg QD dose was eliminated, and subjects who were enrolled under the original protocol and received treatment with 200 mg QD were switched to 100 mg BID. Results are combined.

Overall Response Rate (ORR) of Acalabrutinib in Subjects as Assessed by Investigator Per IWWM 6th Criteria

K-M Point Est. for PFS by 6th IWWM criteria

K-M Point Est. for PFS by 3rd IWWM criteria

Progression-free Survival (PFS) of Acalabrutinib by Investigator

Overall Survival (OS) of Acalabrutinib by Investigator

DOR by Modified 3rd IWWM criteria

DOR by 6th IWWM Criteria

Summary of Duration of Response (DOR)

ORR 3rd IWWM criteria (CR+VGPR+PR+MR)

CR (IWWM 3rd criteria)

VGPR (IWWM 3rd criteria)

PR (IWWM 3rd criteria)

MR (IWWM 3rd criteria)

Overall Response Rate (ORR) of Acalabrutinib in Subjects as Assessed by Investigator Per IWWM 3rd Criteria

Overall Study

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