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

NCT02187133 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 14251NCI-2015-00775
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 3

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.

Conditions

Lymphoma, Non-Hodgkin; Lymphoma

Keywords

Relapsed; Refractory

Outcome Measures

Primary Outcomes (2)

• Maximally tolerated dose (MTD)

  The MTD will be the dose level immediately preceding the dose level at which \>= 2 Dose Limiting Toxicities (DLT) are observed and at which 0/3 or 1/6 participants experiences a DLT.

  Up to 1 cycle (28 days per cycle)

• Number of participants with Dose Limiting Toxicities (DLT)

  The DLT period will correspond to cycle 1 of therapy. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 will be used to assess the severity of adverse events. The causality of each AE will be assessed by the investigator for confirmation of a DLT.

  Up to 1 cycle (28 days per cycle)

Secondary Outcomes (4)

• Overall Response Rate (ORR)

  Up to 2 years

• Median Duration of Response

  Up to 2 years

• Median Progression Free Survival (PFS)

  Up to 2 years

• Median Time to Next Therapy

  Up to 2 years

Other Outcomes (3)

• Median Overall Survival

  Up to 2 years

• Correlation of antitumor activity with markers of activation of the terminal unfolded protein response (UPR) or modulation of the apoptotic pathway in primary tumor tissue.

  Up to 2 years

• Correlation of treatment-related toxicity with markers of activation of the terminal unfolded protein response (UPR) or modulation of the apoptotic pathway in primary tumor tissue.

  Up to 2 years

Study Arms (1)

Treatment

EXPERIMENTAL

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; Drug: Bendamustine; Drug: Rituximab

Interventions

Carfilzomib DRUG

Given IV; Dose Level (DL) Twice Weekly: DL -1 and DL 1: 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

Also known as: Kyprolis, PR-171

Treatment

Bendamustine DRUG

Given IV; Dose Level (DL) DL -1: 75 mg/m\^2 DL 1,1.5, 2, 3, and 4: 90 mg/m\^2

Also known as: Bendamustine Hydrochloride, Cytostasan Hydrochloride, Levacet, Ribomustin, Treanda

Treatment

Rituximab DRUG

Given IV; 375 mg/m\^2

Also known as: C2B8 Monoclonal Antibody, Rituxan, RTXM83

Treatment

Eligibility Criteria

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

You may qualify if:

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

You may not qualify if:

• 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 central nervous system (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 (HCV), defined as presence of HCV antibody.
• Unstable angina or myocardial infarction within 6 months prior Cycle 1, Day 1, New York Heart Association (NYHA) Class III or IV heart failure, left ventricular ejection fraction (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

Sponsors & Collaborators

• University of California, San Francisco: lead
• National Comprehensive Cancer Network: collaborator

Study Sites (3)

University of California, Davis

Davis, California, 95616, United States

Location

University of California, San Diego

San Diego, California, 92093, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Related Publications (1)

• Kambhampati S, Fakhri B, Ai WZ, Kaplan LD, Tuscano JM, Wieduwilt MJ, Sudhindra A, Cavallone E, Reiner J, Aoun C, Castillo M, Martinelli M, Ta T, Le D, Padilla M, Crawford E, Andreadis CB. Carfilzomib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma: A Phase I Trial. Clin Lymphoma Myeloma Leuk. 2021 Mar;21(3):139-146. doi: 10.1016/j.clml.2020.12.020. Epub 2020 Dec 24.

  PMID: 33478921 DERIVED

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Lymphoma; Recurrence

Interventions

carfilzomib; Bendamustine Hydrochloride; Rituximab

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

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

• Charalambos Andreadis, M.D.

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Clinical Medicine

Study Record Dates

• First Submitted: July 8, 2014
• First Posted: July 10, 2014
• Study Start: May 5, 2015
• Primary Completion: March 31, 2021
• Study Completion: March 31, 2021
• Last Updated: April 23, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)