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

Information source: Roswell Park Cancer Institute
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Contiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Stage I Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma

Intervention: carfilzomib (Drug); rituximab (Biological); etoposide (Drug); carboplatin (Drug); ifosfamide (Drug); pharmacological study (Other); laboratory biomarker analysis (Other)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Roswell Park Cancer Institute

Official(s) and/or principal investigator(s):
Francisco J. Hernandez-Ilizaliturri, MD, Principal Investigator, Affiliation: Roswell Park Cancer Institute

Summary

This phase I/II 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 relapsed or refractory diffuse large B-cell lymphoma. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. 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 or by stopping them from dividing. Giving carfilzomib with rituximab, ifosfamide, carboplatin, and etoposide may be an effective treatment for diffuse large B-cell lymphoma.

Clinical Details

Official title: Phase I/II Study of Carfilzomib Plus Rituximab Plus Ifosfamide Plus Carboplatin Plus Etoposide (C-R-ICE) in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL)

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

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)

Best overall response rate (PR + CR) (Phase II)

Secondary outcome:

Complete response rate according to the International Working Group Response criteria as reported by the revised Cheson criteria

Toxicity of the addition of carfilzomib to R-ICE at the MTD, assessed by the CTEP 4ersion 4.0 of the NCI CTCAE

Overall survival

Progression-free survival

Pharmacokinetics (PK)/pharmacodynamics (PD) of carfilzomib and standard R-ICE combination therapy in adult patients with relapsed/refractory diffuse large B-cell lymphoma

Detailed description: PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) and examine the dose-limiting toxicities of carfilzomib when administered in combination with rituximab, ifosfamide, carboplatin, and etoposide (C-R-ICE) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). (Phase I) II. To assess the toxicity of dose regimen using the Cancer Therapy Evaluation Program (CTEP) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE version 4. 0). (Phase I) III. To evaluate the safety of carfilzomib (given at maximum tolerated dose [MTD] as determined in Phase I of this study) in combination with R-ICE salvage therapy in relapsed/refractory DLBCL patients. (Phase II) IV. To achieve an overall response rate (complete response [CR] and partial response [PR]) of 70% after 3 cycles of C-R-ICE in patients between the ages of 18 to 75 with relapsed/refractory cluster of differentiation (CD)20-positive DLBCL previously treated with rituximab-based immunochemotherapy (e. g., rituximab, cyclophosphamide, doxorubicin, vincristine [vincristine sulfate], and prednisone [R-CHOP], rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin [REPOCH], rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine [R-HyperCVAD], etc.) induction. (Phase II) SECONDARY OBJECTIVES: I. To determine the feasibility of successful mobilization of autologous stem cells (i. e., minimum of 2 x 10^6 CD34+ cells/kg should be collected) to be used for autologous stem cell transplant (ASCT). II. To determine toxicities associated with C-R-ICE salvage therapy. III. To determine the time to progression (TTP), progression-free survival (PFS), and overall survival (OS) followed by ASCT; disease-free survival in CR patients. IV. To determine the pharmacokinetics/pharmacodynamics relationship between carfilzomib's degree of proteasome inhibition and response rate along with the time course of thrombocytopenia. V. To study differences in clinical outcomes between germinal center B-cell-like (GCB) and non-GCB relapsed/refractory DLBCL following therapy with carfilzomib and R-ICE. VI. Correlative translational research studies to include: phenotypic/genotypic analysis and functional activity (i. e., antibody-dependent cellular cytotoxicity [ADCC] and complement-mediated cytotoxicity [CMC]) of patient's peripheral blood mononuclear "effector" cells (PBMC), as well as ex vivo analysis of sensitivity of primary tumor cells to various combinations of carfilzomib versus bortezomib +/- rituximab; enzymatic assay for chymotrypsin-like activity to determine the degree of proteasome inhibition in primary DLBCL patient samples and patient PBMC specimens; explorative analysis to identify potential factors predictive of response to therapy will be performed. OUTLINE: This is a phase I, dose-escalation study of carfilzomib, followed by a phase II study. Patients receive carfilzomib intravenously (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. After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 2 years, and then annually for 2 years.

Eligibility

Minimum age: 18 Years. Maximum age: 74 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Histological confirmation of relapsed/refractory CD20 positive diffuse large B-cell

lymphoma

- A tissue block or unstained slides will be submitted to the Roswell Park Cancer

Institute (RPCI) Pathology Department for central pathology review; in addition immunohistochemistry (IHC) for CD20, antigen identified by monoclonal antibody Ki-67 (Ki67), CD10, B-cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2), Bcl-6, and melanoma associated antigen (mutated) 1 (MUM-1) staining will be performed

- Cell of origin will be determined according to the Han's algorithm

- A fresh tumor biopsy for correlative studies is required as part of

participation in this study

- 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.)

- Patients may have received other monoclonal immunotherapy, radiation therapy, or

bortezomib

- >= 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

- Adequate hepatic function with serum alanine aminotransferase (ALT)/aspartate

aminotransferase (AST) =< 3. 5 times the upper limit of normal in the absence of a history of Gilbert's disease (or pattern consistent with Gilbert's) 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

- Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and

to practice contraception; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

- Male subjects must agree to practice contraception

- No known hypersensitivity to murine products

- Patients must have normal baseline cardiac function based upon echocardiogram or

gated blood pool scan (multigated acquisition scan [MUGA]) with an ejection fraction >= 50%

- Patients who test positive for hepatitis C (HepC) antibodies (Ab) are eligible

provided all of the following criteria are met: bilirubin =< 2 x upper limit of normal; ALT/AST =< 3 x upper limit of normal; and clinical evaluation to rule out cirrhosis

- Specific guidelines will be followed regarding inclusion of relapsed/refractory DLBCL

based on hepatitis B serological testing as follows:

- Hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb)

negative, hepatitis B surface antibody (HBsAb) positive patients are eligible

- Patients who test positive for HBsAg are ineligible (regardless of other

hepatitis B serologies)

- Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status)

should have a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing done and protocol eligibility determined as follows:

- If HBV DNA is positive, the subject will be excluded from the study

- If HBV DNA is negative, the subject may be included but must undergo at

least every 2 months HBV DNA polymerase chain reaction (PCR) testing from the start of treatment throughout the duration the treatment course Exclusion Criteria:

- 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

- Active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma

or known CNS parenchymal lymphoma; a lumbar puncture demonstrating DLBCL at the time of registration to this study is not exclusion for study enrollment

Locations and Contacts

Roswell Park Cancer Institute, Buffalo, New York 14263, United States; Recruiting
Roswell Park, Phone: 877-275-7724, Email: ASKRPCI@roswellpark.org
Francisco J. Hernandez-Ilizaliturri, MD, Principal Investigator
Additional Information

Starting date: April 2014
Last updated: August 11, 2015

Page last updated: August 23, 2015

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