BR in Patients With CLL With Comorbidities and/or Renal Dysfunction

NCT01832922 | Completed Phase 1 DMC

• 2 other identifiers: D130673P30CA023108-31S4
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 2

Brief Summary

This is a non-randomized, open label, dose-ranging study of Bendamustine and Rituximab (BR) in patients with previously untreated or relapsed/refractory Chronic Lymphocytic Leukemia (CLL) who have multiple comorbidities with or without renal insufficiency. These agents are FDA approved for this indication. However, full dose bendamustine is associated with significant hematologic toxicity and a high rate of infectious complications in "unfit" patients and patients with significantly impaired renal function. This study will attempt to optimize and define adequate and safe treatment protocols for these patients with comorbidities and/or renal dysfunction. The study will accrue two independent patient cohorts which will follow a standard Phase I design. Patients with CLL who have significant comorbidities with or without minor renal dysfunction (CrCL\>40 mL/min) will be accrued onto Cohort 1 of the study. Patients with significant renal dysfunction (CrCL\<40 mL/min) will be accrued onto Cohort 2. Once the maximum tolerated dose (MTD) is determined, two expansion cohorts will be enrolled. There will be a treatment period of up to six 28-day cycles. On C1D1 all qualifying patients will provide samples for biomarker analysis. Six patients without renal dysfunction and 6 to 9 patients with renal dysfunction will also provide samples for bendamustine PK analysis. Accrual of both patient cohorts will occur simultaneously and will take place at two centers: Norris Cotton Cancer Center (NCCC) and Dana-Farber Cancer Institute (DFCI). Coordination of accrual to the study cohorts will be centralized at NCCC by Dr. Alexey V. Danilov.

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma

Keywords

bendamustine; rituximab; Chronic Lymphocytic Leukemia; comorbidities; renal insufficiency

Outcome Measures

Primary Outcomes (1)

• Number of participants with adverse events

  To evaluate the safety (MTD) of bendamustine in combination with rituximab in patients with CLL who have multiple comorbidities and/or significant renal dysfunction.

  within the first 30 days of treatment

Secondary Outcomes (1)

• tumor response to treatment

  3 years

Other Outcomes (2)

• plasma bendamustine concentration versus time

  Days 1 and 2

• biomarker levels at baseline

  prior to Day 1

Study Arms (2)

Significant Comorbidiities

EXPERIMENTAL

Significant comorbidities as defined by Cumulative Illness Rating Score (CIRS) of ≥7.

Drug: Bendamustine; Drug: Rituximab

Significant renal dysfunction

ACTIVE COMPARATOR

Significant renal dysfunction defined as CrCL 15-40 mL/min, but not receiving dialysis.

Drug: Bendamustine; Drug: Rituximab

Interventions

Bendamustine DRUG

Also known as: Treanda

Significant Comorbidiities; Significant renal dysfunction

Rituximab DRUG

Also known as: Rituxan

Significant Comorbidiities; Significant renal dysfunction

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or flow cytometry confirmed diagnosis of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) according to NCI-WG 1996 guidelines (41). The malignant B cells must co-express CD5 with CD19 or CD20. Patients who lack CD23 expression on their leukemia cells should be examined for (and found NOT to have) either t(11;14) or cyclin D1 overexpression, to rule out mantle cell lymphoma.
• Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring treatment:
• A minimum of any one of the following constitutional symptoms:
• Unintentional weight loss \>10% within the previous 6 months prior to screening.
• Extreme fatigue (unable to work or perform usual activities).
• Fevers of greater than 100.5 F for ≥2 weeks without evidence of infection.
• Night sweats without evidence of infection.
• Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia or thrombocytopenia.
• Massive (ie, \>6 cm below the left costal margin), progressive or symptomatic splenomegaly.
• Massive nodes or clusters (ie, \> 10 cm in longest diameter) or progressive lymphadenopathy.
• Progressive lymphocytosis with an increase of \>50% over a 2-month period, or an anticipated doubling time of less than 6 months.
• Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids.
• Prior treatment: Patients have not had prior treatment of CLL OR Previously treated relapsed CLL patients must have received not more than 3 prior therapies for CLL. Prior bendamustine and rituximab are allowed.
• Patients must have ECOG performance status 0-3.
• Patients must have a Cumulative Illness Risk Score \[CIRS\]≥7 with at least one grade 3-4 category \[CLL will not be considered a comorbidity\]; or estimated creatinine clearance (CrCL) using the Cockcroft-Gault equation ≥15 mL/min but ≤40 ml/min (Appendix 1: CCI Criteria).

You may not qualify if:

• Recent therapeutic intervention including a) prior nitrosoureas or mitomycin C within 6 weeks; b) therapeutic anticancer antibodies (including rituximab) within 4 weeks; c) radio- or toxin-immunoconjugates within 10 weeks; d) all other chemotherapy, radiation therapy within 3 weeks prior to initiation of therapy.
• Inadequate recovery from adverse events related to prior therapy to grade ≤1 (excluding Grade 2 alopecia and neuropathy).
• Bendamustine-refractory (no response to a regimen containing bendamustine) or relapse following treatment with a bendamustine-containing regimen within 6 months of treatment with that regimen.
• Chronic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent or chronic use of other immunosuppressive agents (azathioprine, methotrexate, tacrolimus, cyclosporine). Stem cell transplant recipients must have no evidence of active graft-versus-host disease.
• History of prior malignancy except: a) Malignancy treated with curative intent and no known active disease present for ≥ 2 years prior to initiation of therapy on current study; b) adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; c) adequately treated in situ carcinomas (eg, cervical, esophageal, etc.) without evidence of disease; d) asymptomatic prostate cancer managed with "watch and wait" strategy.
• Known Richter's transformation.
• Advanced renal failure (estimated CrCL \< 15 mL/min) or on dialysis.
• Human Immunodeficiency Virus (HIV) or Hepatitis C antibody positivity, or active hepatitis B.
• Major surgery (requiring general anesthesia) within 30 days prior to initiation of therapy.
• Uncontrolled bacterial, viral, or fungal infection.
• Inability to adhere to the study schedule or the required follow-up.

Sponsors & Collaborators

• Dartmouth-Hitchcock Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center

Lebanon, New Hampshire, 03750, United States

Location

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Renal Insufficiency

Interventions

Bendamustine Hydrochloride; Rituximab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Alexey V Danilov, MD

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine and of Pharmacology and Toxicology

Study Record Dates

• First Submitted: April 12, 2013
• First Posted: April 16, 2013
• Study Start: April 1, 2013
• Primary Completion: April 27, 2015
• Study Completion: November 28, 2016
• Last Updated: March 30, 2018

Record last verified: 2018-03

Locations

US (2)