Combination of Pentostatin, Bendamustine and Ofatumumab for Treatment of Chronic Lymphocytic Leukemia and Lymphoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Thomas Jefferson University
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Thomas Jefferson University
ClinicalTrials.gov Identifier:
NCT01352312
First received: May 10, 2011
Last updated: September 11, 2014
Last verified: September 2014
  Purpose

This is a Phase 1 study with Cohort Expansion of Pentostatin, Bendamustine and Ofatumumab (PBO) for patients with previously treated Chronic Lymphocytic Leukemia (CLL) and B-cell Non-Hodgkin's Lymphoma (B- cell NHL). The purpose of this study is to determine the optimal dose of bendamustine in combination with pentostatin and ofatumumab, and then to see how safe these three drugs work together.


Condition Intervention Phase
Chronic Lymphocytic Leukemia
B-Cell Non-Hodgkin's Lymphoma
Drug: Bendamustine
Drug: Pentostatin
Drug: Ofatumumab
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial With Cohort Expansion of Pentostatin, Bendamustine and Ofatumumab (PBO) for the Treatment of Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma

Resource links provided by NLM:


Further study details as provided by Thomas Jefferson University:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Bendamustine [ Time Frame: Up to 6 months ] [ Designated as safety issue: Yes ]
    The primary objective of this study is to determine the dose of bendamustine in combination with pentostatin and ofatumumab at which <33% of patients with relapsed Non-Hodgkin's Lymphoma (NHL) or Chronic Lymphocytic Leukemia (CLL) experience severe toxicity; and to assess the toxicity of this regimen.

  • Dose Limiting Toxicity (DLT) [ Time Frame: Through one year post-treatment ] [ Designated as safety issue: Yes ]

    Dose limiting toxicity (DLT) will be defined as any grade 4 infection, or grade ≥ 3 non-hematologic toxicity that persists for 7 days or more.

    Safety Issue?: (FDAAA) Yes



Secondary Outcome Measures:
  • Efficacy of Study Treatment Regimen [ Time Frame: 3 and 6 months ] [ Designated as safety issue: No ]
    1. CBC (complete blood count)
    2. B-cell count
    3. If a patient is in CR (complete recovery) by other criteria then bone marrow aspiration/biopsy will be performed.
    4. CT (x-ray computed tomography) scan of chest/abdomen/pelvis (optional in patients with CLL)


Estimated Enrollment: 39
Study Start Date: May 2011
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (pentostatin, bendamustine, ofatumumab)
Patients receive bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, pentostatin IV on day 1, and ofatumumab IV on day 2. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: Bendamustine
Bendamustine at the dose of 50 mg/m2 (or 70 or 90 or 40 mg/m2 depending on the dose level) daily on day 1 and 2.
Other Names:
  • Ribomustin
  • Treanda
  • SDX-105
Drug: Pentostatin
Pentostatin 4 mg/m2 on day 1 of each cycle. For patients with estimated or measured glomerular filtration rate (GFR) 30 to 60 ml/min/m2 pentostatin will be administered at the reduced dose of 2 mg/m2 on day 1 of each cycle.
Other Name: deoxycoformycin
Drug: Ofatumumab
Ofatumumab 300 mg on day 2 of first cycle. Subsequently, from cycle 2 to 6, ofatumumab 1000 mg on day 2 will be administered.
Other Names:
  • Arzerra
  • HuMax-CD20

Detailed Description:

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. There has been considerable progress in understanding the biology and treatment of CLL in the last 20 years. However, even with modern therapies, complete responses (CR) are achieved in approximately 25% of the patients with relapsed/refractory disease. Multiple studies have demonstrated that patients who achieve CR have better clinical outcomes than patients who do not achieve a CR with therapy. B-cell NHL is composed of multiple subtypes of neoplasm. These diseases are closely related to CLL in terms of natural history, biology, and responsiveness to similar therapeutic agents. These diseases are not usually cured by available chemotherapy and ultimately patients succumb to progression of resistant disease. Therefore, there is a need to develop better therapies to improve survival in patients with CLL and B-cell NHL.

Preclinical and clinical data suggests that pentostatin, bendamustine, ofatumumab are active drugs for the treatment of B-cell malignancies. In an earlier clinical trial conducted by Dr. Weiss (lead site PI), the combination of pentostatin and cyclophosphamide had very good activity in previously treated patients with B-cell neoplasms. This regimen was also better tolerated than similar fludarabine-based regimen. The response rates were improved with addition of rituximab, anti CD 20 antibody, to the above regimen. Studies have demonstrated synergy between bendamustine and purine analogs like pentostatin in killing cancer cell types of CLL and NHL. The combination of these three drugs (pentostatin, bendamustine and ofatumumab) has not been tested in clinical setting and we anticipate that the combination regimen will be more active than individual drugs alone. The aim of this trial is to find a safe dose of bendamustine to be used in combination with pentostatin and ofatumumab in patients with previously treated CLL and B-cell NHL.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Previously treated CLL or other B-cell neoplasm including small lymphocytic lymphoma, hairy cell leukemia, follicular, lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphomas, mantle cell lymphomas, lymphoplasmacytic lymphoma and diffuse large B-cell lymphoma. Patients with composite lymphoma and transformed disease will be included. Immunophenotypic (or immunohistochemical) analysis of the malignant lymphocytes should demonstrate that the cells are B-cells.
  2. Patients must have had prior cytotoxic therapy for their disease. Patients with diffuse large B-cell lymphoma must have been treated with at least 2 prior cytotoxic therapies.
  3. Age ≥ 18 years of age.
  4. ECOG performance statue 0 to 2.
  5. Reasonable life-expectancy greater than 12 weeks.
  6. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia will be eligible for treatment.
  7. Signed informed consent, which indicates the investigational nature of this study, is required.
  8. No patient may be entered onto the study without consultation with the principal investigator or his designee.

Exclusion Criteria:

  1. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
  2. No prior cytotoxic therapy for at least 4 weeks before enrollment.
  3. Currently participating in any other interventional clinical study.
  4. Other currently active malignancy.
  5. Active uncontrolled infection.
  6. History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae.
  7. Known HIV positive.
  8. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (NYHA III-IV), and uncontrolled symptomatic arrhythmia.
  9. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.
  10. Positive serology for hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.
  11. Active hepatitis C infection. If positive serology for hepatitis C (HC) defined as a positive test for HCAb, HC quantitative PCR will be performed. If PCR is positive the subject will be excluded
  12. Screening laboratory values:

    1. creatinine > 2.0 times upper normal limit and creatinine clearance < 30 ml/min/m2. Patients with creatinine > 2 times upper limit of normal will have creatinine clearance estimated. At the discretion of treating physician, creatinine clearance can be measured and that value can be used instead of calculated creatinine clearance.
    2. total bilirubin > 2 times upper normal limit (unless due to tumor involvement of liver or a known history of Gilbert's disease)
    3. ALT (alanine transaminase) > 2.5 times upper normal limit (unless due to disease involvement of liver.
  13. Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test at screening.
  14. Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence.
  15. Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01352312

Contacts
Contact: Mark Weiss, MD 215-955-8874
Contact: Clinical Research Management Office 215-955-1661

Locations
United States, Pennsylvania
Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Mark Weiss, MD    215-955-8874      
Contact: Clinical Research Management Office    215-955-1661      
Principal Investigator: Mark Weiss, MD         
Sub-Investigator: Seyfettin Onder Alpdogan, MD         
Sub-Investigator: Matthew Carabasi, MD         
Sub-Investigator: Joanne Filicko-O'Hara, MD         
Sub-Investigator: Neal Flomenberg, MD         
Sub-Investigator: Dolores Grosso, DNP, CRNP         
Sub-Investigator: Margaret Kasner, MD         
Sub-Investigator: Lisa Kearns, CRNP         
Sub-Investigator: Kathleen Murphy Matkowski, CRNP         
Sub-Investigator: John Wagner, MD         
Sub-Investigator: Ubaldo Martinez-Outschoorn, MD         
Sponsors and Collaborators
Thomas Jefferson University
GlaxoSmithKline
Investigators
Principal Investigator: Mark Weiss, MD Thomas Jefferson University
  More Information

Additional Information:
No publications provided

Responsible Party: Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT01352312     History of Changes
Other Study ID Numbers: 11P.166, 2011-23, OFT114197
Study First Received: May 10, 2011
Last Updated: September 11, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Thomas Jefferson University:
Chronic Lymphocytic Leukemia
Non-Hodgkin's Lymphoma
B-cell
leukemia
lymphoma
bendamustine
pentostatin
ofatumumab
NHL
CLL

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bendamustine
Pentostatin
Nitrogen Mustard Compounds
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Adenosine Deaminase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents

ClinicalTrials.gov processed this record on September 11, 2014