Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Waldenstrom Macroglobulinemia

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Amino Acids

Acalabrutinib

Bendamustine Hydrochloride

Rituximab

Antineoplastic Agents, Immunological

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

100 mg Acalabrutinib (ACP-196) oral capsules twice daily for 1 year

Bendamustine and rituximab will be given for 6 x 28-day cycles. Bendamustine will be given intravenously at 90 mg/m2 on days 1 and 2 of each cycle. Rituximab will be given on day 1 of each cycle (375 mg/m2 intravenously for the first cycle and 1400 mg subcutaneously OR 375 mg/m2 intravenously for subsequent cycles (as per institutional procedures).

100 mg oral capsules twice daily for 1 year

Bendamustine

day 1 of each cycle (375 mg/m2 intravenously for the first cycle and 1400 mg subcutaneously OR 375 mg/m2 intravenously for subsequent cycles (as per institutional procedures).

Neil L Berinstein, MD

Neil Berinstein

This is a multi-centre, open label, single-arm, phase II clinical trial in untreated patients with Waldenstrom's Macroglobulinemia. Symptomatic, previously untreated patients will receive SOC bendamustine and rituximab for 6 28-day cycles. Bendamustine will be given intravenously at 90 mg/m2 on days 1 and 2 of each cycle. Rituximab will be given on day 1 of each cycle (375 mg/m2 intravenously for the first cycle and 1400 mg subcutaneously OR 375 mg/m2 intravenously for subsequent cycles (as per institutional procedures)). Concomitantly, participants will receive 100 mg of the investigational product, Acalabrutinib, orally for 1 year (365 days) at 100 mg BID.

This is a multi-centre, open label, single-arm, phase II clinical trial in untreated patients with WM. Patients will require a biopsy to confirm the pathology and molecular testing for MYD88, CXCR4 and P53 mutations. A bone marrow aspiration and biopsy will be performed to document WM and MRD. Participants will be classified into clinical risk categories based on the International Prognostic Scoring (IPS) System for WM. Symptomatic, previously untreated patients will receive SOC bendamustine and rituximab for 6 28-day cycles. Bendamustine will be given intravenously at 90 mg/m2 on days 1 and 2 of each cycle. Rituximab will be given on day 1 of each cycle (375 mg/m2 intravenously for the first cycle and 1400 mg subcutaneously OR 375 mg/m2 intravenously for subsequent cycles (as per institutional procedures)).

Concomitantly, participants will receive 100 mg of the investigational product, Acalabrutinib, orally for 1 year (365 days) at 100 mg BID. Patients will have pre-treatment computed tomography (CT) scans, and CT scans at 7, 12 and 18 months. Best objective response will be documented using the criteria from the Sixth International Workshop on Waldenstrom's Macroglobulinemia. Assessment of metabolic uptake by positron emission tomography (PET) scan is not considered appropriate for WM as WM usually do not take up fluorodeoxyglucose (FDG). Patients with WM will also have disease assessed using measurements of serum IgM, serum protein electrophoresis (SPE), immunofixation (IFA), and viscosity assessments measured serially. A bone marrow aspiration and biopsy will be done before treatment and at response assessment at cycle 6 and will be repeated if positive. Durability of response will also be assessed at 18 months.

Participants will be followed by extended follow-up by telephone for up to 6 years to obtain data on the secondary endpoints.

Bendamustine, Rituximab and Acalabrutinib

Bendamustine, Rituximab and Acalabrutinib in Waldenstrom's Macroglobulinemia

A Multi-Center, Open-Label, Single-Arm Phase II Trial of Bendamustine, Rituximab and the Second Generation BTK Inhibitor Acalabrutinib in Previously Untreated Waldenstrom's Macroglobulinemia

To document the best combined CR and VGPR rate of first-line treatment with bendamustine and rituximab plus acalabrutinib in patients with WM using response criteria from the Sixth International Workshop on Waldenstrom's Macroglobulinemia9. Response will be documented at cycle 7, 12 and 18 (durable CR).

using criteria from 6th international workshop on WM

MRD will be assessed at three on treatment timepoints (before start of cycles 7, 12, 18) as well as extended follow-up vistis. MRD will be measured from two body compartments-peripheral blood and bone marrow. MRD will be recorded and will be reported based on the limit of detection of the assay (to be determined). Results will be pooled and rates of MRD negativity for the assay will be recorded at each time point for the pooled patients and for each of the two body compartments that are being assessed.

OS will be determined using the time from first day of study treatment to death for each patients. Results for each patient will be pooled to derive an overall survival rate.

PFS will be defined as the time from first dose of study treatment to the first objective documentation of progressive disease (PD), the start of an alternative anticancer therapy, or death from any cause during study. Results for each patient will be pooled to derive an overall progressive free survival rate. Participants not meeting criteria for PD will be followed by telephone every 6 months for up to six years from the time of first dose.

A descriptive analysis of safety will be performed with descriptions of frequency and grade of the adverse events including adverse events of special interest such as hypertension, cardiac arrhythmias and bleeding events. The common toxicities described in the NCK common terminology criteriae for adverse events (NC CTAE v5.0) will be documented and grade in each patient at each visit throughout the trial. Rates and severity of all of these toxicity will be collected and reported.

Defined as the length of time a participant is identified as CR or VGPR until they progress. Different from PFS

Defined as the amount of time from the start of trial until the patient requires a new form of treatment to treat their WM

AstraZeneca

Sunnybrook Health Sciences Centre

Panobinostat

Histone Deacetylase Inhibitors

30 mg three days a week (Mondays, Wednesdays and Fridays).

1 cycle was 28 days

Dose modifications for attributable toxicities allowed for reduction to:

* 25 mg, 20 mg three times a week every week
* Or 20 mg three times a week every other week. No dose re-escalation was allowed.

  * The protocol was amended on 6/15/2010 because of concerns of toxicity to allow a starting dose of 25 mg; 12/36 (33%) patients were enrolled on the 25 mg dose.

LBH589

Irene Ghobrial, MD

The purpose of this research study is to assess the overall response rate of LBH589 in patients with relapsed or refractory Waldenstrom's Macroglobulinemia. LBH589 is a newly discovered compound that has killed Waldenstrom cells in laboratory studies, however, it is not known if LBH589 will show the same activity in people with Waldenstrom's Macroglobulinemia. This drug has been used in research for the treatment of other types of cancer, such as multiple myeloma.

This phase II study is designed to assess the toxicity profile and the proportion of overall response in patients with relapsed or refractory WM. This will study the effect of single agent LBH589 on response in these patients. Efficacy measures will include both objective clinical measurements and investigator-reported outcomes. Response and time to event analyses will follow the criteria set forth in the International Waldenstrom consortium recommendations. Prior to the start of the study, investigators will assess disease and perform a CT scan of the chest, abdomen and pelvis.

Response will be assessed after 2 cycles. If patients have stable disease or response, then they will continue on therapy until progression or unacceptable toxicity, being assessed every cycle until the sixth cycle and then every 3 months. Patients who show progression after 2 cycles will come off therapy and undergo event monitoring every 3 months. All responses will be assessed by M-protein quantification and immunofixation from serum and IgM monoclonal protein level. In addition, BM biopsies will be done at baseline, at the end of cycle 6 and at the end of all therapy. The protocol was amended because of concerns of toxicity to allow a starting dose of 25 mg; 12/36 (33%) patients were enrolled on the 25 mg dose.

LBH589 in Relapsed or Relapsed and Refractory Waldenstrom's Macroglobulinemia

Phase II Trial of LBH589 (Panobinostat) in Relapsed or Relapsed and Refractory Waldenstrom's Macroglobulinemia

Overall response rate is percentage of participants with complete (CR), very good partial (VGPR), partial (PR), or minimal response (MR) as best response during treatment.

CR

* Disappearance of monoclonal protein by immunofixation
* No histologic evidence of bone marrow involvement
* Resolution of any adenopathy/organomegaly (confirmed by CT scan), or signs or symptoms attributable to WM.
* Second immunofixation required for confirmation.

VGPR

-At least 90% reduction of serum monoclonal IgM concentration on protein electrophoresis.

PR

* At least 50% reduction of serum monoclonal IgM concentration on protein electrophoresis and at least 50% decrease in adenopathy/organomegaly on physical examination or on CT scan.
* No new symptoms or signs of active disease.

MR

* At least 25% but less than 50% reduction of serum monoclonal IgM by protein electrophoresis.
* No new symptoms or signs of active disease.

Progression free survival (PFS) is defined as the time from start of treatment to disease progression or death from any cause as estimated by Kaplan Meier methods. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free.

Time to progression (TTP) is defined as the time from start of treatment to progression. Patients who have not progressed are censored at the date the patient is last known to be progression free.

Duration of response DR is defined as the time from the date of first response after treatment to the date of disease progression Patients who have died for any cause or are alive without progression are censored at the date the patient is last know to be progression-free.

Duration of response DR is defined as the time from the date of first response after treatment to the date of disease progression or death for any cause. Patients who are alive without progression are censored at the date the patient is last know to be progression-free.

Grade 3 thrombocytopenia is defined as having 25,000-50,000 /uL platelets

Grade 4 thrombocytopenia is defined as having \< 25,000 /uL platelets

Acetylated-histone-H3 levels were obtained through bone marrow biopsies and measured using established methods. This analysis aimed to analyze the association between overall response and percent change of acetylated histone h3 in samples using a paired t-test.

Brigham and Women's Hospital

Novartis

Dana-Farber Cancer Institute

Principal Investigator

Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.

30 mg three days a week (Mondays, Wednesdays and Fridays).

1 cycle was 28 days

Dose modifications for attributable toxicities allowed for reduction to:

* 25 mg, 20 mg three times a week every week
* Or 20 mg three times a week every other week. No dose re-escalation was allowed.

  * The protocol was amended on 6/15/2010 because of concerns of toxicity to allow a starting dose of 25 mg; 12/36 (33%) patients were enrolled on the 25 mg dose.

LBH589

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Median IgM

Median M Spike

Median Platelets

Median Hemoglobin

Median Beta 2 Microglobulin

Percentage of Bone Marrow Involvement

Lymph Nodes and Hepatocyte Selection Medium Assessment by CT Scan Evidence of Disease

Measure Description: Low is defined as 1 or dewer of the following:

Hemoglobin (HB) \<=11.5 g/dL Platelet (PT) \<=100 x 10\^9 / L Beta 2 Microglubin (B2M) \> 3 mg/L Immunoglobulin M (IgM) \> 7 g/dL

Intermediate is defined as over 65 years old or two of the following:

HB \<=11.5 g/dL PT \<=100 x 10\^9 / L B2M \> 3 mg/L IgM\> 7 g/dL

High is defined as more than 2 of the following:

Over 65 years old HB \<=11.5 g/dL PT \<=100 x 10\^9 / L B2M \> 3 mg/L IgM\> 7 g/dL

International Prognostic Scoring System for Waldenstrom Macroglobulinemia

Irene Ghobrial

Overall Response Rate

Median Progression Free Survival

Median Time to Progression

Median Duration of Response

Number of Participants With Grade 3 and 4 Treatment-Related Thrombocytopenia

Only three complete sample (baseline and post-therapy) were ascertained. The difference in percentage of acetylated histone h3 were not large enough to conduct the correlative analysis.

Acetylated Histone H3 and Overall Response Association

Overall Study

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

Ethnicity (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

Anti-Infective Agents

Thalidomide

Immunosuppressive Agents

Anti-Bacterial Agents

Angiogenesis Inhibitors

Growth Inhibitors

Athanasios Fassas, M.D.

The purpose of this research is to study how helpful thalidomide is in controlling the disease and to study any side effects from taking thalidomide.

Patients will receive thalidomide in the oral form each night before bed. The dose of thalidomide will be increased each week until week 7 as long as there are no significant side effects.

Routine physical examinations and blood tests will be done to monitor the effect of treatment and the toxicities encountered, if any, and provide the available treatments for side effects accordingly. Blood tests will be done to monitor the tumor response.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Bendamustine, Rituximab and Acalabrutinib in Waldenstrom's Macroglobulinemia	NCT04624906	Waldenstrom Mac...	Acalabrutinib Bendamustine Rituximab	18 Years -	Sunnybrook Health Sciences Centre
LBH589 in Relapsed or Relapsed and Refractory Waldenstrom's Macroglobulinemia	NCT00936611	Waldenstrom's M...	LBH589	18 Years -	Dana-Farber Cancer Institute
An Open-label, Phase 2 Study of ACP-196 in Subjects With Waldenström Macroglobulinemia	NCT02180724	Waldenström Mac...	Acalabrutinib (... Acalabrutinib (...	18 Years - 130 Years	Acerta Pharma BV
LBH589 in Relapsed or Relapsed and Refractory Waldenstrom's Macroglobulinemia	NCT00936611	Waldenstrom's M...	LBH589	18 Years -	Dana-Farber Cancer Institute
Anti-Angiogenesis Therapy Using Thalidomide in Patients With Waldenstrom's Macroglobulinemia	NCT00083707	Waldenstrom Mac...	Thalidomide	18 Years -	University of Arkansas
Bendamustine, Rituximab and Acalabrutinib in Waldenstrom's Macroglobulinemia	NCT04624906	Waldenstrom Mac...	Acalabrutinib Bendamustine Rituximab	18 Years -	Sunnybrook Health Sciences Centre

Spots Global Cancer Trial Database for macroglobulinemia