Carfilzomib, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Stage I-IV Diffuse Large B-cell Lymphoma

NCT01959698 | Active Not Recruiting Phase 1 Results DMC

• 3 other identifiers: I 240813NCI-2013-01784R01CA136907
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I/Ib trial studies the side effects and best dose of carfilzomib when given together with rituximab, ifosfamide, carboplatin, and etoposide and to see how well it works in treating patients with stage I-IV diffuse large B-cell lymphoma that has returned (relapsed) or that has not responded to treatment (refractory). Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as ifosfamide, carboplatin, and etoposide, also work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving carfilzomib with rituximab, ifosfamide, carboplatin, and etoposide may be a better treatment for diffuse large B-cell lymphoma.

Conditions

CD20 Positive; Recurrent Diffuse Large B-Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma; Stage I Diffuse Large B-Cell Lymphoma; Stage III Diffuse Large B-Cell Lymphoma; Stage IV Diffuse Large B-Cell Lymphoma; Stage II Diffuse Large B-Cell Lymphoma

Outcome Measures

Primary Outcomes (2)

• Overall Response Rate (PR + CR)

  Overall response rate (CR and PR) after 3 cycles of C R ICE in patients age of 18 to 75 with relapsed/refractory CD20-positive DLBCL treated with rituximab-based immunochemotherapy (e.g., R-CHOP, R-EPOCH, R-HyperCVAD, etc.) induction. Response was based on a Modified Cheson Criteria with Complete response (CR): All lesions with a longest diameter ≤ 15 mm or short axis ≤ 10 mm (Not palpable during the clinical examination, No visible nodule on imaging, And disappearance of all non-nodal target lesions Or in case of hypermetabolic disease on the baseline PET scan, negative PET scan whatever the appearance of lesions on CT) and Partial Response (PR): ≥ 50 % of sum of the products of the diameters (SPD) of target lesions or in the case of hypermetabolic lesions on the baseline PET scan, persistence of at least one PET-positive site without progression of other lesions on CT (≥ 50 % of SPD of target lesions (or longest diameter if a single nodule) No clinically enlarged liver or spleen)

  The time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented, assessed up to 12 weeks

• MTD Defined as the Dose of Carfilzomib Added to Standard R-ICE Chemotherapy Which, if Exceeded, Would Put the Patient at an Undesirable Risk of Medically Unacceptable Dose-limiting Toxicities (Phase I)

  28 days

Secondary Outcomes (5)

• Complete Response Rate According to the International Working Group Response Criteria as Reported by the Revised Cheson Criteria

  Up to 5 years

• Overall Survival

  From the start of treatment until death for any reason, assessed up to 5 years

• Pharmacokinetics (PK)/Pharmacodynamics (PD) of Carfilzomib and Standard R-ICE Combination Therapy in Adult Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma

  Pre-dose, just prior to the end of the infusion; and at 15 minutes, 30 minutes, 1, 2, 4, 6 hours post infusion on course 1, day 1, then at 24 hours post course 1 infusion on course 1, day 2 (prior to day 2 infusion)

• Progression-free Survival

  Up to 5 years

• Toxicity of the Addition of Carfilzomib to R-ICE at the MTD, Assessed by the CTEP Version 4.0 of the NCI CTCAE

  Up to 5 years

Other Outcomes (3)

• Degree of Proteasome Inhibition Determined by Enzymatic Assay for Chymotrypsin-like Activity

  Days 1-3 of course 1

• Ex Vivo Analysis of Sensitivity of Primary Tumor Cells to Various Combinations of Carfilzomib Versus Bortezomib +/- Rituximab

  Baseline

• Functional Activity of Patients Peripheral Blood Mononuclear "Effector" Cells

  Baseline

Study Arms (1)

Treatment (carfilzomib, rituximab, chemotherapy)

EXPERIMENTAL

Patients receive carfilzomib IV over 10-30 minutes on days 1, 2, 8, and 9; rituximab IV over 3-8 hours on day 3; etoposide IV over 1 hour on days 4-6; carboplatin IV over 1 hour on day 5; and ifosfamide IV over 24 hours on day 5. Treatment repeats every 21-28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Drug: Carboplatin; Drug: Carfilzomib; Drug: Etoposide; Drug: Ifosfamide; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Biological: Rituximab

Interventions

Ifosfamide DRUG

Given IV

Also known as: Asta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942

Treatment (carfilzomib, rituximab, chemotherapy)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (carfilzomib, rituximab, chemotherapy)

Pharmacological Study OTHER

Correlative studies

Treatment (carfilzomib, rituximab, chemotherapy)

Carboplatin DRUG

Given IV

Also known as: Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplat, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo

Treatment (carfilzomib, rituximab, chemotherapy)

Carfilzomib DRUG

Given IV

Also known as: Kyprolis, PR-171

Treatment (carfilzomib, rituximab, chemotherapy)

Etoposide DRUG

Given IV

Also known as: Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213

Treatment (carfilzomib, rituximab, chemotherapy)

Rituximab BIOLOGICAL

Given IV

Also known as: ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, RTXM83

Treatment (carfilzomib, rituximab, chemotherapy)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological confirmation of relapsed/refractory CD20 positive diffuse large B-cell lymphoma
• Ann Arbor stage I to stage IV DLBCL at the time of relapsed/refractory disease to be eligible
• Measurable or assessable disease is required; measurable tumor size (at least one node measuring 2.25 cm\^2 in bidimensional measurement) per computed tomography (CT) scan, other radiological study, and/or physical exam
• Patients must have received at least 1 prior rituximab-based immunochemotherapy (e.g., R-CHOP, R-EPOCH, etc.)
• \>= 2 weeks since major surgery
• Patients must not have any significant toxicity associated with prior surgery, radiation therapy, chemotherapy, or immunotherapy, per principal investigator (PI) discretion
• Life expectancy \>= 3 months
• Karnofsky score (KS) \>= 50
• Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =\< 3.5 times the upper limit of normal within 14 days prior to starting therapy
• Absolute neutrophil count (ANC) \>= 1.0 x 10\^9/L within 14 days prior to starting therapy\*
• Hemoglobin \>= 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be receiving red blood cell \[RBC\] transfusions in accordance with institutional guidelines)\*
• Platelet count \>= 50 x 10\^9/L (\>= 20 x 10\^9/L if lymphoma involvement in the pretreatment bone marrow is found) within 14 days prior to starting therapy\*
• \*Note: If patient has cytopenias due to bone marrow involvement, these requirements are not applicable
• Serum creatinine of =\< 1.5 mg/dL; if creatinine \> 1.5 mg/dL creatinine clearance must be \> 60 mL/min within 7 days prior to treatment either measured or calculated using a standard Cockcroft and Gault formula
• Written informed consent in accordance with federal, local, and institutional guidelines

You may not qualify if:

• Patients with non-Hodgkin lymphoma (NHL) other than DLBCL; including "transformed" DLBCL
• Known to be seropositive for human immunodeficiency virus (HIV); an HIV test is not required for entry on this protocol, but is required if the patient is perceived to be at risk
• Positive serology for HBV defined as a positive test for HBsAg; in addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HepB DNA test will be performed and if positive the subject will be excluded
• Patients with symptomatic brain involvement
• Peripheral neuropathy of grade 2 or greater severity as defined by the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0; patients with grade 2 or higher (NCI-Common Toxicity Criteria \[CTC\]) neuropathy
• Myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemia
• Uncontrolled intercurrent illness including, but not limited to, active infection, poorly controlled hypertension, diabetes mellitus or other serious medical or psychiatric conditions that could interfere with adherence to or completion of this study
• Pregnant or breastfeeding
• Patient has received other investigational drugs within 4 weeks before enrollment
• Chemotherapy within 3 weeks of the first scheduled study treatment
• Less than 2-years disease free from another primary malignancy (other than squamous or basal cell carcinoma of the skin, "in-situ" carcinoma of the cervix or breast, superficial bladder carcinoma, or previously treated localized prostate cancer with normal prostate-specific antigen \[PSA\] levels); patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, are considered by their physician to be at less than 30% risk of relapse and at least 2 years have lapsed
• Major surgery, other than diagnostic surgery, within 2 weeks
• Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
• Medical condition requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent)
• Prior high-dose chemotherapy (HDC)-ASCT

Sponsors & Collaborators

• Amgen: collaborator
• Roswell Park Cancer Institute: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Related Publications (1)

• Lin LH, Ghasemi M, Burke SM, Mavis CK, Nichols JR, Torka P, Mager DE, Hernandez-Ilizaliturri FJ, Goey AKL. Population Pharmacokinetics and Pharmacodynamics of Carfilzomib in Combination with Rituximab, Ifosfamide, Carboplatin, and Etoposide in Adult Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma. Target Oncol. 2023 Sep;18(5):685-695. doi: 10.1007/s11523-023-00992-4. Epub 2023 Aug 26.

  PMID: 37632592 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

Carboplatin; carfilzomib; Etoposide; Ifosfamide; Rituximab; CT-P10

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Cyclophosphamide; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Senior Administrator, Compliance - Clinical Research Services
• Organization: Roswell Park Comprehensive Cancer Center

Adrienne.Groman@RoswellPark.org

716-845-2300

Study Officials

• Francisco Hernandez-ILizaliturri

  Roswell Park Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2013
• First Posted: October 10, 2013
• Study Start: April 17, 2014
• Primary Completion: June 1, 2020
• Study Completion (Estimated): December 1, 2026
• Last Updated: January 28, 2026
• Results First Posted: August 20, 2021

Record last verified: 2026-01

Locations

US (1)