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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01479842
Recruitment Status : Active, not recruiting
First Posted : November 28, 2011
Last Update Posted : November 9, 2017
Pharmacyclics LLC.
Information provided by (Responsible Party):
Kami Maddocks, Ohio State University Comprehensive Cancer Center

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.

Condition or disease Intervention/treatment Phase
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 Drug: BTK inhibitor PCI-32765 Biological: rituximab Drug: bendamustine hydrochloride Other: pharmacogenomic studies Other: pharmacological study Other: laboratory biomarker analysis Phase 1

Detailed Description:


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.


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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 48 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 7, 2011
Actual Primary Completion Date : March 2014
Estimated Study Completion Date : December 31, 2018

Arm Intervention/treatment
Experimental: Treatment (enzyme inhibitor, chemo, monoclonal antibody)
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.
Drug: BTK inhibitor PCI-32765
Given PO
Other Names:
  • Bruton's tyrosine kinase inhibitor PCI-32765
  • PCI-32765
Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • Rituxan
Drug: bendamustine hydrochloride
Given IV
Other Names:
  • bendamustin hydrochloride
  • bendamustine
  • cytostasan hydrochloride
  • Treanda
Other: pharmacogenomic studies
Correlative studies
Other Name: Pharmacogenomic Study
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Primary Outcome Measures :
  1. 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 [ Time Frame: during first course of therapy ]
    MTD is defined as the highest dose Level at which =< 1 of 6 patients experienced a DLT.

Secondary Outcome Measures :
  1. Frequency, severity, and relatedness of adverse events [ Time Frame: up to 30 days after last dose of treatment ]
    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.

  2. Overall response rate [ Time Frame: up to 24 months post treatment ]
    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.

  3. Duration of response [ Time Frame: up to 24 months post treatment ]
    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.

  4. Identification of germinal center versus nongerminal center DLCL [ Time Frame: screening or cycle 1 day 1 predose ]
    Determined by immunohistochemistry in patients with DLCL enrolled in the dose escalation portion of the study and in the DLCL expansion cohort.

  5. Correlation of PGx with response and toxicity [ Time Frame: screening or cycle 1 day 1 predose ]
    Data will be evaluated with pharmacokinetics and clinical outcomes to identify significant associations and potential PGx biomarkers.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01479842

United States, Ohio
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Kami Maddocks
Pharmacyclics LLC.
Principal Investigator: Kami Maddocks, MD Ohio State University

Additional Information:
Publications of Results:
Responsible Party: Kami Maddocks, Principal Investigator, Ohio State University Comprehensive Cancer Center Identifier: NCT01479842     History of Changes
Other Study ID Numbers: OSU-10052
NCI-2011-03293 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: November 28, 2011    Key Record Dates
Last Update Posted: November 9, 2017
Last Verified: November 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Large B-Cell, Diffuse
Waldenstrom Macroglobulinemia
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bendamustine Hydrochloride
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents