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Rituxan/Bendamustine/PCI-32765 in Relapsed DLBCL, MCL, or Indolent Non-Hodgkin's Lymphoma

Primary Purpose

Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
BTK inhibitor PCI-32765
rituximab
bendamustine hydrochloride
pharmacogenomic studies
pharmacological study
laboratory biomarker analysis
Sponsored by
Kami Maddocks, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Histologically confirmed B-cell NHL of the following subtypes: follicular, marginal zone (nodal, splenic, or extranodal), Waldenstrom's macroglobulinemia, diffuse large B-cell (DLCL) or mantle cell lymphoma (MCL) according to 2008 World Health Organization (WHO) criteria that is relapsed or refractory after at least 1 prior therapy

    • Patients with DLCL must be relapsed or refractory after previous autologous stem cell transplant unless transplant is contraindicated
    • Patients with MCL, follicular lymphoma (FL), marginal zone lymphoma, or Waldenstrom's macroglobulinemia are eligible after >= 1 prior therapies; however, patients with MCL who are not eligible for stem cell transplant (due to age or other co-morbidities) or refuse up-front stem cell transplantation may receive study treatment as their first-line therapy
  • Body weight >= 40 kg
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Agreement to use contraception during the study and for 30 days after the last dose of study drug if sexually active and able to bear children
  • Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty
  • Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations)

Exclusion Criteria:

  • Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient has been disease free for at least 2 years or which will not limit survival to < 2 years (Note: these cases must be discussed with the Principal Investigator)
  • A life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of PCI-32765 PO, or put the study outcomes at undue risk
  • Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
  • Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
  • Any immunotherapy, chemotherapy, radiotherapy, or experimental therapy within 3 weeks before first dose of study drug (corticosteroids for disease-related symptoms allowed but require 1-week washout before study drug administration)
  • Use of medications known to prolong QTc interval or that may be associated with Torsades de Pointes are prohibited within 7 days of starting study drug and during treatment
  • Central nervous system (CNS) involvement by lymphoma
  • Grade >= 2 toxicity (other than alopecia) related to prior anticancer therapy including radiation
  • Known history of human immunodeficiency virus (HIV), active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV surface antigen positive), carriers of HBV (surface antigen and surface antibody negative, but HBV core antibody positive), or any uncontrolled active systemic infection
  • Major surgery within 4 weeks before first dose of study drug
  • Previous serious infusion reactions or hypersensitivity to rituximab or bendamustine not controlled or prevented by steroid pre-medication
  • Creatinine > 2.0 mg/dL
  • Total bilirubin > 1.5 x upper limit of normal (ULN) (unless due to Gilbert's disease)
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN
  • Absolute neutrophil count (ANC) < 1000/mm^3
  • Platelets < 50,000/mm^3
  • Lactating or pregnant

Sites / Locations

  • Ohio State University Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (enzyme inhibitor, chemo, monoclonal antibody)

Arm Description

Patients receive BTK inhibitor PCI-32765 PO QD on days 1-28. Patients also receive rituximab IV on day 1 and bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may continue receiving BTK inhibitor PCI-32765 PO in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Maximum tolerated dose (MTD) as determined by the incidence of dose limiting toxicities (DLT) of BTK inhibitor PCI-32765 when given in combination with rituximab and bendamustine hydrochloride
MTD is defined as the highest dose Level at which =< 1 of 6 patients experienced a DLT.

Secondary Outcome Measures

Frequency, severity, and relatedness of adverse events
Laboratory shift tables containing counts and percentages will be prepared by treatment assignment, laboratory parameter, and time. Summary tables will be prepared for each laboratory parameter. Figures of changes in laboratory parameters over time will be generated.
Overall response rate
The point estimate of the rate will be calculated for the per protocol analysis set. The response rate 95% confidence interval estimates also will be derived. Association between the correlation markers and response will be explored using graphical and descriptive analysis.
Duration of response
From time measurement criteria are met for complete response(CR)or partial response(PR)until the first date that recurrent or progressive disease occurs. Median duration of overall response will be assessed with 95% confidence interval.
Identification of germinal center versus nongerminal center DLCL
Determined by immunohistochemistry in patients with DLCL enrolled in the dose escalation portion of the study and in the DLCL expansion cohort.
Correlation of PGx with response and toxicity
Data will be evaluated with pharmacokinetics and clinical outcomes to identify significant associations and potential PGx biomarkers.

Full Information

First Posted
November 1, 2011
Last Updated
June 27, 2022
Sponsor
Kami Maddocks, MD
Collaborators
Pharmacyclics LLC.
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1. Study Identification

Unique Protocol Identification Number
NCT01479842
Brief Title
Rituxan/Bendamustine/PCI-32765 in Relapsed DLBCL, MCL, or Indolent Non-Hodgkin's Lymphoma
Official Title
A Phase I, Dose-escalation Trial of Rituxan and Bendamustine in Combination With Bruton's Tyrosine Kinase Inhibitor, PCI-32765, in Patients With Relapsed Diffuse Large B-cell Lymphoma, Mantle Cell Lymphoma, or Indolent Non-Hodgkin's Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 7, 2011 (Actual)
Primary Completion Date
March 28, 2014 (Actual)
Study Completion Date
December 31, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Kami Maddocks, MD
Collaborators
Pharmacyclics LLC.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I trial studies the side effects and best dose of BTK inhibitor PCI-32765 when given together with rituximab and bendamustine hydrochloride in treating patients with recurrent non-Hodgkin lymphoma (NHL). BTK inhibitor PCI-32765 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving BTK inhibitor PCI-32765 together with rituximab and bendamustine hydrochloride may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVES: I. Identify the specific toxicities and a recommended phase 2 dose of PCI-32765 (BTK inhibitor PCI-32765) orally (PO) in combination with rituximab and bendamustine (bendamustine hydrochloride) (i.e., "combination therapy") in patients with relapsed and refractory B-cell NHL. SECONDARY OBJECTIVES: I. Evaluate the activity of combined rituximab, bendamustine, and PCI-32765 in patients with relapsed and refractory B-cell NHL as measured by response rate and duration of response. II. Identify potential marker(s) predictive of response to the combination therapy. III. Correlate pharmacogenetic (PGx) findings with patient response and toxicity. OUTLINE: This is a dose-escalation study of BTK inhibitor PCI-32765. Patients receive BTK inhibitor PCI-32765 PO once daily (QD) on days 1-28. Patients also receive rituximab intravenously (IV) on day 1 and bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may continue receiving BTK inhibitor PCI-32765 PO in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 4 months for up to 2 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Nodal Marginal Zone B-cell Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Splenic Marginal Zone Lymphoma, Waldenstrom Macroglobulinemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (enzyme inhibitor, chemo, monoclonal antibody)
Arm Type
Experimental
Arm Description
Patients receive BTK inhibitor PCI-32765 PO QD on days 1-28. Patients also receive rituximab IV on day 1 and bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may continue receiving BTK inhibitor PCI-32765 PO in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
BTK inhibitor PCI-32765
Other Intervention Name(s)
Bruton's tyrosine kinase inhibitor PCI-32765, PCI-32765
Intervention Description
Given PO
Intervention Type
Biological
Intervention Name(s)
rituximab
Other Intervention Name(s)
IDEC-C2B8, IDEC-C2B8 monoclonal antibody, Mabthera, MOAB IDEC-C2B8, Rituxan
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
bendamustine hydrochloride
Other Intervention Name(s)
bendamustin hydrochloride, bendamustine, cytostasan hydrochloride, Treanda
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
pharmacogenomic studies
Other Intervention Name(s)
Pharmacogenomic Study
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Maximum tolerated dose (MTD) as determined by the incidence of dose limiting toxicities (DLT) of BTK inhibitor PCI-32765 when given in combination with rituximab and bendamustine hydrochloride
Description
MTD is defined as the highest dose Level at which =< 1 of 6 patients experienced a DLT.
Time Frame
during first course of therapy
Secondary Outcome Measure Information:
Title
Frequency, severity, and relatedness of adverse events
Description
Laboratory shift tables containing counts and percentages will be prepared by treatment assignment, laboratory parameter, and time. Summary tables will be prepared for each laboratory parameter. Figures of changes in laboratory parameters over time will be generated.
Time Frame
up to 30 days after last dose of treatment
Title
Overall response rate
Description
The point estimate of the rate will be calculated for the per protocol analysis set. The response rate 95% confidence interval estimates also will be derived. Association between the correlation markers and response will be explored using graphical and descriptive analysis.
Time Frame
up to 24 months post treatment
Title
Duration of response
Description
From time measurement criteria are met for complete response(CR)or partial response(PR)until the first date that recurrent or progressive disease occurs. Median duration of overall response will be assessed with 95% confidence interval.
Time Frame
up to 24 months post treatment
Title
Identification of germinal center versus nongerminal center DLCL
Description
Determined by immunohistochemistry in patients with DLCL enrolled in the dose escalation portion of the study and in the DLCL expansion cohort.
Time Frame
screening or cycle 1 day 1 predose
Title
Correlation of PGx with response and toxicity
Description
Data will be evaluated with pharmacokinetics and clinical outcomes to identify significant associations and potential PGx biomarkers.
Time Frame
screening or cycle 1 day 1 predose

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically confirmed B-cell NHL of the following subtypes: follicular, marginal zone (nodal, splenic, or extranodal), Waldenstrom's macroglobulinemia, diffuse large B-cell (DLCL) or mantle cell lymphoma (MCL) according to 2008 World Health Organization (WHO) criteria that is relapsed or refractory after at least 1 prior therapy Patients with DLCL must be relapsed or refractory after previous autologous stem cell transplant unless transplant is contraindicated Patients with MCL, follicular lymphoma (FL), marginal zone lymphoma, or Waldenstrom's macroglobulinemia are eligible after >= 1 prior therapies; however, patients with MCL who are not eligible for stem cell transplant (due to age or other co-morbidities) or refuse up-front stem cell transplantation may receive study treatment as their first-line therapy Body weight >= 40 kg Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 Agreement to use contraception during the study and for 30 days after the last dose of study drug if sexually active and able to bear children Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations) Exclusion Criteria: Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient has been disease free for at least 2 years or which will not limit survival to < 2 years (Note: these cases must be discussed with the Principal Investigator) A life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of PCI-32765 PO, or put the study outcomes at undue risk Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction Any immunotherapy, chemotherapy, radiotherapy, or experimental therapy within 3 weeks before first dose of study drug (corticosteroids for disease-related symptoms allowed but require 1-week washout before study drug administration) Use of medications known to prolong QTc interval or that may be associated with Torsades de Pointes are prohibited within 7 days of starting study drug and during treatment Central nervous system (CNS) involvement by lymphoma Grade >= 2 toxicity (other than alopecia) related to prior anticancer therapy including radiation Known history of human immunodeficiency virus (HIV), active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV surface antigen positive), carriers of HBV (surface antigen and surface antibody negative, but HBV core antibody positive), or any uncontrolled active systemic infection Major surgery within 4 weeks before first dose of study drug Previous serious infusion reactions or hypersensitivity to rituximab or bendamustine not controlled or prevented by steroid pre-medication Creatinine > 2.0 mg/dL Total bilirubin > 1.5 x upper limit of normal (ULN) (unless due to Gilbert's disease) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN Absolute neutrophil count (ANC) < 1000/mm^3 Platelets < 50,000/mm^3 Lactating or pregnant
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kami Maddocks, MD
Organizational Affiliation
Ohio State University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
25355819
Citation
Maddocks K, Christian B, Jaglowski S, Flynn J, Jones JA, Porcu P, Wei L, Jenkins C, Lozanski G, Byrd JC, Blum KA. A phase 1/1b study of rituximab, bendamustine, and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma. Blood. 2015 Jan 8;125(2):242-8. doi: 10.1182/blood-2014-08-597914. Epub 2014 Oct 29.
Results Reference
result
Links:
URL
http://cancer.osu.edu
Description
Jamesline

Learn more about this trial

Rituxan/Bendamustine/PCI-32765 in Relapsed DLBCL, MCL, or Indolent Non-Hodgkin's Lymphoma

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