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

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ClinicalTrials.gov Identifier: NCT02187133
Recruitment Status : Recruiting
First Posted : July 10, 2014
Last Update Posted : March 15, 2018
Sponsor:
Collaborator:
National Comprehensive Cancer Network
Information provided by (Responsible Party):
C. Babis Andreadis, University of California, San Francisco

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Lymphoma, Non-Hodgkin Lymphoma Drug: Carfilzomib Drug: Bendamustine Drug: Rituximab Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of carfilzomib when combined with bendamustine (bendamustine hydrochloride) and rituximab in patients with relapsed or refractory non-Hodgkin's lymphoma.

SECONDARY OBJECTIVES:

I. To evaluate the preliminary antitumor activity of carfilzomib with bendamustine and rituximab in patients with non-Hodgkin lymphoma (dose escalation) and with specific non-Hodgkin lymphoma (NHL) subtypes (dose expansion).

OUTLINE: This is a dose-escalation study of carfilzomib.

Patients receive carfilzomib intravenously (IV) over 30 minutes twice weekly on days 1, 2, 8, 9, 15, and 16 or weekly on days 2, 9, and 16; bendamustine hydrochloride IV over 60 minutes on days 1 and 2; and rituximab IV over 30-90 minutes on day 9 (course 1 only) and day 1 (subsequent courses). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 weeks for 6 months, every 3 months for 6 months, and then every 6 months thereafter.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 2014
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Treatment
Patients receive carfilzomib IV over 30 minutes twice weekly on days 1, 2, 8, 9, 15, and 16 or weekly on days 2, 9, and 16; bendamustine hydrochloride IV over 60 minutes on days 1 and 2; and rituximab IV over 30-90 minutes on day 9 (course 1 only) and day 1 (subsequent courses). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: Carfilzomib

Given IV; DL (Dose Level)

Twice Weekly

DL -1 and DL1: 15 mg/m^2

Weekly

DL 1.5: 20,27,27 mg/m^2

DL 2: 20,36,36 mg/m^2

DL 3: 20,56,56 mg/m^2

DL 4: 20,70,70 mg/m^2

Other Names:
  • Kyprolis
  • PR-171

Drug: Bendamustine

Given IV; DL (Dose Level)

DL -1: 75 mg/m^2

DL 1,1.5, 2, 3, and 4: 90 mg/m^2

Other Names:
  • Bendamustine Hydrochloride
  • Cytostasan Hydrochloride
  • Levact
  • Ribomustin
  • Treanda

Drug: Rituximab
Given IV; 375 mg/m^2
Other Names:
  • C2B8 Monoclonal Antibody
  • Rituxan
  • RTXM83




Primary Outcome Measures :
  1. 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 ]
  2. Assessing the tolerability of carfilzomib when combined with bendamustine and rituximab in patients with relapsed or refractory non-Hodgkin's Lymphoma. [ Time Frame: Up to 2 years ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]

Other Outcome Measures:
  1. Analyzing overall survival in patients treated with carfilzomib when combined with bendamustine and rituximab [ Time Frame: Up to 2 years ]
  2. Evaluating the relationship between antitumor activity of carfilzomib and bendamustine with markers of activation of the terminal unfolded protein response (UPR) or modulation of the apoptotic pathway in primary tumor tissue. [ Time Frame: Up to 2 years ]
  3. Evaluating the relationship between toxicity of carfilzomib and bendamustine with markers of activation of the terminal unfolded protein response (UPR) or modulation of the apoptotic pathway in primary tumor tissue. [ Time Frame: Up to 2 years ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 or more 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
  • 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 for at least 90 days after the last dose of carfilzomib, and must agree not to donate sperm for at least 90 days after the last dose of carfilzomib

Adequate bone marrow function:

  • Absolute neutrophil count ≥ 1.0 × 10^9/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 × 10^9/L or≥ 50× 10^9/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

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 C infection, defined as presence of HCV antibody.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02187133


Contacts
Contact: Charalambos Andreadis, M.D. 877-827-3222 cancertrials@ucsf.edu
Contact: Erika Cavallone 877-827-3222 cancertrials@ucsf.edu

Locations
United States, California
University of California, San Diego Recruiting
San Diego, California, United States, 92093
Contact: Jesika Reiner       jreiner@ucsd.edu   
Principal Investigator: Matthew Wieduwilt, MD         
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Erika Cavallone    877-827-3222    cancertrials@ucsf.edu   
Sponsors and Collaborators
University of California, San Francisco
National Comprehensive Cancer Network
Investigators
Principal Investigator: Charalambos Andreadis, M.D. University of California, San Francisco

Responsible Party: C. Babis Andreadis, Associate Professor of Clinical Medicine, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02187133     History of Changes
Other Study ID Numbers: 14251
NCI-2015-00775 ( Other Identifier: Clinical Trials Reporting Program (CTRP) )
First Posted: July 10, 2014    Key Record Dates
Last Update Posted: March 15, 2018
Last Verified: March 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by C. Babis Andreadis, University of California, San Francisco:
Relapsed
Refractory

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Bendamustine Hydrochloride
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action