Carfilzomib With Bendamustine and Rituximab in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma
Lymphoma, Non-Hodgkin - Lymphoma
Conditions: official terms
Lymphoma - Lymphoma, Non-Hodgkin
Conditions: Keywords
Relapsed, Refractory
Study Type
Study Phase
Phase 1
Study Design
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Name: Carfilzomib Type: Drug
Name: Bendamustine Type: Drug
Name: Rituximab Type: Drug
Overall Status
This study will be conducted as a Phase Ib, open-label, non-randomized, single-institution study to evaluate the safety and tolerability of carfilzomib in combination with bendamustine and rituximab in patients with relapsed or refractory NHL and to determine the recommended phase II dose and preliminary efficacy of this combination. The study will have two phases: a dose-escalation phase to determine the maximal tolerated dose of carfilzomib in this combination where participants will be monitored for toxicity, tolerability and response and a dose-expansion phase that will determine the preliminary efficacy in patients with Mantle cell lymphoma or any other disease subtype in which there is a preliminary efficacy signal observed.

Determination of the maximum tolerated dose (MTD) will follow standard 3+3 design with escalation of the carfilzomib dose only (Table 5.2). Dose levels of carfilzomib will be 15 mg/m2, 20 mg/m2, 27 mg/m2, and 36 mg/m2 IV administered on days 1, 2, 8, 9, 15 and 16. The last 2 cohorts will have a starting carfilzomib dose of 20 mg/m2 on days 1, 2. Bendamustine will be administered at the well-tolerated dose of 90 mg/m2 IV on days 1 and 2. A dose de-escalation of bendamustine to 75 mg/m2 (cohort -1) will occur if the starting dose proves intolerable in this combination. Rituximab will be given at a dose of 375 mg/m2 on day 9 of Cycle 1 and day 1 of subsequent cycles. Rituximab will be intentionally delayed to day 9 of cycle 1 to help facilitate performance of the correlative studies.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: Inclusion Criteria:

- Histologically-confirmed B-cell non-Hodgkin's lymphoma (Mantle Cell Lymphoma, Follicular Lymphoma, Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia, Marginal Zone Lymphoma, Diffuse Large B-cell Lymphoma, and Lymphoplasmacytic Lymphoma)

- Must have relapsed or refractory disease after 2 but not more than 4 prior lines of therapy; 1 line of therapy is allowed, if it included an autologous stem cell transplant and at least 12 weeks have elapsed from Day 0. A line of therapy is defined as a course of therapy that is not interrupted by progressive disease.

- Subjects must have measurable disease of at least 1.5 cm in diameter

- Age ≥ 18 years

- Life expectancy ≥ 3 months

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Laboratory:

Adequate bone marrow function:

Absolute neutrophil count ≥ 1.0 × 109/L Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior Cycle 1, Day 1 (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines) Platelet count ≥ 75 × 109/L or≥ 50× 109/L if there is lymphoma involvement in the bone marrow, independent of platelet transfusion

Adequate hepatic function:

Serum AST/ALT ≤ 3 times the upper limit of normal Serum direct bilirubin ≤ 2 mg/dL (unless history of Gilbert's)

Adequate renal function:

Creatinine clearance (CrCl) ≥ 30 mL/minute, either measured or calculated using a standard formula (eg, Cockcroft and Gault) Uric acid If elevated, corrected to within laboratory range prior to dosing

- Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception. FCBP definition: A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months.

- Male subjects must agree to practice contraception.

Exclusion Criteria:

- Progressive disease on bendamustine within 6 months of cycle 1, Day 1

- Prior treatment with carfilzomib for lymphoma

- Patient has received other investigational drugs within 21 days prior to Cycle 1, Day 1. Exceptions allowed if greater than four half-lives of the experimental agent ).

- Prior radiation therapy or chemotherapy within 2 weeks prior Cycle 1, Day 1, monoclonal antibody therapy within 4 weeks

- Prior allogeneic transplant

- Active, uncontrolled CNS involvement by lymphoma

- Pregnant or lactating females

- Major surgery within 14 days prior Cycle 1, Day 1

- Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior Cycle 1, Day 1

- Known human immunodeficiency virus infection

- Active hepatitis B or C infection, defined as presence of HBV surface antigen or HCV antibody. Subjects who are HBVsAg antibody positive are allowed on study as long as HBVsAg is negative but will require HBV PCR monitoring per institutional standard.

- Unstable angina or myocardial infarction within 6 months prior Cycle 1, Day 1, NYHA Class III or IV heart failure, LVEF < 40%, uncontrolled angina, history of severe coronary artery disease, history of torsade de pointes, history of symptomatic pulmonary hypertension, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, QTc prolongation >450 msec, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker.

- Uncontrolled hypertension or uncontrolled diabetes within 14 days prior Cycle 1, Day 1

- Nonhematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas

- Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior Cycle 1, Day 1

- Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)

- Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment

- Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior Cycle 1, Day 1

- Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.
University of California, San Francisco
San Francisco, California, United States
Status: Recruiting
Contact: Geraldine Pelle-Day, Ph.D. - 415-476-4765 -
Start Date
December 2014
Completion Date
June 2017
University of California, San Francisco
University of California, San Francisco
Record processing date processed this data on July 28, 2015 page