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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

Phase 1
18 Years
Open (Enrolling)
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

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Trial Information

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


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.

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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Description:

MTD is defined as the highest dose Level at which =< 1 of 6 patients experienced a DLT.

Outcome Time Frame:

during first course of therapy

Safety Issue:


Principal Investigator

Kristie Blum, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University


United States: Food and Drug Administration

Study ID:




Start Date:

December 2011

Completion Date:

Related Keywords:

  • 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
  • Waldenström Macroglobulinemia
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Waldenstrom Macroglobulinemia
  • Lymphoma, B-Cell
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Mantle-Cell



Ohio State University Medical Center Columbus, Ohio  43210