Clinical Trials /

Carfilzomib With Bendamustine and Rituximab in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

NCT02187133

Description:

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Small Lymphocytic Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Carfilzomib With Bendamustine and Rituximab in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma
  • Official Title: A Phase Ib Dose Escalation Trial of Carfilzomib in Combination With Bendamustine and Rituximab In Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 14251
  • NCT ID: NCT02187133

Conditions

  • Lymphoma, Non-Hodgkin
  • Lymphoma

Interventions

DrugSynonymsArms
CarfilzomibTreatment
BendamustineTreatment
RituximabTreatment

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalCarfilzomib: IV; Days 1, 2, 8, 9, 15, and 16. Bendamustine: IV; Days 1, and 2. Rituximab: IV; Day 9 Cycle 1, Day 1 subsequent cycles
  • Carfilzomib
  • Bendamustine
  • Rituximab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Assessing the safety of carfilzomib when combined with bendamustine and rituximab in patients with relapsed or refractory non-Hodgkin's Lymphoma.
Time Frame:Up to 2 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:To evaluate the preliminary antitumor activity of carfilzomib with bendamustine and rituximab in patients with non-Hodgkin Lymphoma (dose escalation).
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:To evaluate the preliminary antitumor activity of carfilzomib with bendamustine and rituximab in patients with specific NHL subtypes (dose expansion).
Time Frame:Up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

Trial Keywords

  • Relapsed
  • Refractory

Last Updated

January 9, 2016