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Phase I Dose-Escalation Study of Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in Recurrent B Cell Lymphoma

Phase 1
18 Years
Not Enrolling
B-Cell Lymphoma, B-Cell Leukemia

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Trial Information

Phase I Dose-Escalation Study of Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 in Recurrent B Cell Lymphoma

Inclusion Criteria:

- Women and men ≥ 18 years of age. There is no experience with this drug in a
pediatric population.

- Body weight ≥ 40 kg.

- Recurrent surface immunoglobulin positive B cell non-Hodgkin's lymphoma (NHL)
according to WHO classification, including small lymphocytic lymphoma/ chronic
lymphocytic leukemia (SLL/CLL) lymphoplasmacytic lymphoma, including Waldenström's
Macroglobulinemia (WM), and pre-identified DLBCL ABC subtype oFor the DLBCL-ABC
cohort, documented, activated B-cell subtype by either immunohistochemistry or tissue
microarray analysis.

- Measurable disease (for NHL, bidimensional disease ≥ 2 cm diameter in at least one
dimension, for CLL ≥ 5000 leukemia cells/mm3, for WM presence of immunoglobulin M
paraprotein with a minimum IgM level ≥ 1000 mg/dL and infiltration of bone marrow by
lymphoplasmacytic cells), and pre-identified DLBCL ABC subtype by
immunohistochemistry (IHC).

- Have failed ≥ 1 previous treatment for lymphoma and no standard therapy is available.
Patients with diffuse large B cell lymphoma must have failed, refused or be
ineligible for autologous stem cell transplant.

- ECOG performance status of ≤ 1.

- Ability to swallow oral capsules without difficulty.

- Willing and able to sign a written informed consent.

Exclusion Criteria:

- More than four prior systemic therapies (not counting maintenance rituximab), except
for CLL patients. Salvage therapy/conditioning regimen leading up to autologous bone
marrow transplantation is considered to be one regimen (This inclusion criterion does
not apply to the DLBCL-ABC cohort).

- Prior allogeneic bone marrow transplant.

- Immunotherapy, chemotherapy, radiotherapy or experimental therapy within 4 weeks
before first day of study drug dosing.

- Major surgery within 4 weeks before first day of study drug dosing.

- CNS involvement by lymphoma.

- Active opportunistic infection or treatment for opportunistic infection within 4
weeks before first day of study drug dosing.

- History of malabsorption.

- Laboratory abnormalities:

- Creatinine > 1.5 × institutional upper limit of normal (ULN)

- Total bilirubin > 1.5 x institutional ULN (unless elevated from documented
Gilbert's syndrome)

- AST or ALT > 2.5 × institutional ULN

- Platelet count < 75,000/µL (unless patients have CLL and bone-marrow
involvement, provided they are not transfusion-dependent)

- Absolute neutrophil count (ANC) < 1500/µL (unless patients have CLL and
bone-marrow involvement)

- Hgb < 8.0 g/dL

- Uncontrolled illness including but not limited to: ongoing or active infection,
symptomatic congestive heart failure (New York Heart Association Class III or IV
heart failure), unstable angina pectoris, cardiac arrhythmia, and psychiatric illness
that would limit compliance with study requirements.

- Risk factors for, or use of medications known to prolong QTc interval or that may be
associated with Torsades de Pointes within 7 days of treatment start.

- QTc prolongation (defined as a QTc > 450 msecs) or other significant ECG
abnormalities including 2nd degree AV block type II, 3rd degree AV block, or
bradycardia (ventricular rate less than 50 beats/min). If the screening ECG has a QTc
> 450 msecs, the ECG can be submitted for a centralized, cardiologic evaluation.

- History of myocardial infarction, acute coronary syndromes (including unstable
angina), coronary angioplasty and/or stenting within the past 6 months.

- Known HIV infection.

- Hepatitis B sAg or Hepatitis C positive.

- Other medical or psychiatric illness or organ dysfunction which, in the opinion of
the investigator, would either compromise the patient's safety or interfere with the
evaluation of the safety of the study agent.

- Pregnant or lactating women (female patients of child-bearing potential must have a
negative serum pregnancy test within 14 days of first day of drug dosing, or, if
positive, a pregnancy ruled out by ultrasound).

- Women of child-bearing potential or sexually active men, unwilling to use adequate
contraceptive protection during the course of the study.

- History of prior cancer < 2 years ago, except for basal cell or squamous cell
carcinoma of the skin, cervical cancer in situ or other in situ carcinomas.

Type of Study:


Study Design:

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

Outcome Measure:

Dose limiting toxicity assessment for each patient.

Outcome Time Frame:

At the end of the first 35 day cycle

Safety Issue:


Principal Investigator

Thorsten Graef, MD, PhD

Investigator Role:

Study Director

Investigator Affiliation:



United States: Food and Drug Administration

Study ID:




Start Date:

February 2009

Completion Date:

July 2012

Related Keywords:

  • B-Cell Lymphoma
  • B-Cell Leukemia
  • PCI-32765
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Lymphoma, B-Cell
  • Burkitt Lymphoma
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, B-Cell, Diffuse
  • Lymphoma, Follicular
  • Lymphoma, Mantle Cell
  • Leukemia, Lymphoid
  • Leukemia, B-Cell
  • Waldenstrom macroglobulinemia
  • Bruton's Tyrosine Kinase
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, B-Cell
  • Lymphoma
  • Lymphoma, B-Cell



Stanford University School of Medicine Stanford, California  94305-5317
University of Chicago Chicago, Illinois  60637
National Cancer Institute Bethesda, Maryland  20892-1922
University of Texas, MD Anderson Houston, Texas  77030
New York Prebyterian Hospital Cornell Medical Center New York, New York  10065
Willamette Valley Cancer Institute/Research Ctr Eugene, Oregon  97401
University of Vermont College of Medicine Burlington, Vermont  05405
Northwest Cancer Specialists, Vancouver Cancer Center Vancouver, Washington  98684
Yakima Valley Memorial Hospital/North Star Lodge Cancer Ctr Yakima, Washington  98902