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Carfilzomib, Rituximab, and Combination Chemotherapy in Treating Patients With Diffuse Large B-Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT02073097
Recruitment Status : Recruiting
First Posted : February 27, 2014
Last Update Posted : May 3, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Case Comprehensive Cancer Center

Brief Summary:
This phase I/II trial studies the side effects and best dose of carfilzomib when given together with rituximab and combination chemotherapy and to see how well they work in treating patients with 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 by finding cancer cells and helping kill them. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not known if carfilzomib in combination with R-CHOP is better or worse than R-CHOP alone in treating patients with diffuse large b-cell lymphoma.

Condition or disease Intervention/treatment Phase
Contiguous Stage II Adult Diffuse Large Cell Lymphoma Noncontiguous Stage II 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 Drug: carfilzomib Biological: rituximab Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: vincristine sulfate Drug: prednisone Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety of carfilzomib in combination with rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) (CR-CHOP) in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and identify a recommended phase II dose (RP2D). (Phase I)

SECONDARY OBJECTIVES:

I. To determine if CR-CHOP improves the rates of 1-year progression free survival (PFS) and overall survival (OS) in non-germinal center (non-GC) DLBCL patients relative to historical controls treated with R-CHOP(Phase II) II. To determine response rates (complete and partial remission) in non-GC DLBCL patients treated with CR-CHOP and compare to historical controls treated with R-CHOP.

III. Because a proportion (~10%) of patients classified as non-GC by immunohistochemical (IHC) algorithms may not have the activated B-cells (ABC) subtyped of DLBCL, an exploratory secondary objective will compare the PFS, OS and response rates of the ABC subgroup of patients with DLBCL as determined by the Gene Expression Profiling with those of the overall group of non-GC DLBCL.

OUTLINE: This is a phase I, dose-escalation study of carfilzomib followed by a phase II study.

Patients receive rituximab intravenously (IV) over at least 90 minutes, cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV over 3-5 minutes, vincristine sulfate IV over 1 minute on day 1, and prednisone orally (PO) on days 1-5. Patients also receive carfilzomib IV over 30 minutes on days 1, 2, 8 and 9. Courses repeat every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and at 6, 12, and 24 months.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Carfilzomib in Combination With R-CHOP (CR-CHOP) for Patients With Diffuse Large B-cell Lymphoma
Actual Study Start Date : October 1, 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: rituximab, combination chemotherapy, carfilzomib
Patients receive rituximab IV over at least 90 minutes, cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV over 3-5 minutes, vincristine sulfate IV over 1 minute on day 1, and prednisone PO on days 3-7. Patients also receive carfilzomib IV over 30 minutes on days 1, 2, 8 and 9. Courses repeat every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: carfilzomib
Given IV
Other Names:
  • Kyprolis
  • PR-171

Biological: rituximab
Given IV
Other Names:
  • IDEC-C2B8
  • IDEC-C2B8 monoclonal antibody
  • Mabthera
  • MOAB IDEC-C2B8
  • Rituxan

Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana

Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF

Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS

Drug: prednisone
Given PO
Other Names:
  • DeCortin
  • Deltra




Primary Outcome Measures :
  1. Recommended Phase II dose (Phase I) [ Time Frame: 21 days ]
    Highest dose administered when no more than 1 out of 6 patients experience lose limiting toxicity below the maximally administered dose.


Secondary Outcome Measures :
  1. Progression Free Survival (Phase II) [ Time Frame: 30 days after treatment ]
    The number of days until Progression-free Survival (PFS) when PFS is defined as the time from entry onto study until lymphoma progression or death from any cause. PFS will be estimated using a Kaplan-Meier curve.

  2. Overall Survival (Phase II) [ Time Frame: 30 days after treatment ]
    The number of days patients are alive from entry onto study until lymphoma progression or death from any cause. Overall survival will be estimated with a Kaplan-Meier curve

  3. Complete Response Rate (Phase II) [ Time Frame: 30 days after treatment ]
    The number of patients with a complete response as defined by a complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy

  4. Partial Response Rate (Phase II) [ Time Frame: 30 days after treatment ]
    The number of patients with a partial response as defined a >50% decrease in the sum of the product of the diameter of up to six of the largest nodes; no increase in the any node, liver, or spleen; no new sites of disease.



Information from the National Library of Medicine

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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:

  • Patients must have histologically confirmed diffuse large B-cell lymphoma (DLBCL); patients with previously diagnosed indolent lymphoma (follicular lymphoma and marginal zone lymphoma but not small lymphocytic lymphoma) who have transformed to DLBCL are eligible only if they have not previously been treated for indolent lymphoma. For the Phase II study, patients must have non-GC DLBCL as determined by Hans Algorithm.
  • Patients must have radiographically measurable disease
  • Patients may have received brief (<15 days) treatment with glucocorticoids and/or 1 cycle of chemotherapy such as R-CHOP [or some component(s) thereof] for the diagnosis of B-cell lymphoma provided they had all necessary staging tests performed prior to R-CHOP including CT and/or PET/CT scans, echocardiogram and bone marrow biopsy. Treatment must occur within 60 days prior to enrollment.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; performance status of 3 will be accepted if impairment is caused by DLBCL complications and improvement is expected once therapy is initiated
  • Hemoglobin ≥ 7.0 g/dl
  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelet count ≥ 100,000/mcL
  • Total bilirubin within normal institutional limits unless due to Gilbert's disease
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) ≤ 2.5 X institutional upper limit of normal
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 X institutional upper limit of normal
  • Creatinine clearance ≥ 45 mL/min calculated by Cockcroft-Gault
  • Adequate cardiac function left ventricular ejection fraction (LVEF) > 50% as assessed by echocardiogram or MUGA (Multi Gated Acquisition Scan)
  • The effects of Carfilzomib on the developing human fetus are unknown. For this reason and because chemotherapeutic agents used in this study are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) 2 weeks prior to initiation of treatment, for the duration of study participation and for 3 months after completing treatment. Should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately. Men must agree to refrain from sperm donation for at least 90 days after the last dose of carfilzomib.
  • Subjects must have the ability to understand and the willingness to sign a written informed consent document
  • International Prognostic Index must be documented:

    • ECOG performance status ≥ 2 (1 point)
    • Age ≥ 60 (1 point)
    • ≥ 2 extranodal sites (1 point)
    • Lactate dehydrogenase (LDH) > upper limit of normal (1 point)
    • Ann Arbor stage III or IV (1 point)

Exclusion Criteria:

  • Patients who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients who are receiving any other investigational agents
  • Known central nervous system (CNS) involvement by lymphoma
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to carfilzomib or other agents (R-CHOP) used in this study
  • Active congestive heart failure (New York heart Association Class III or IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within four months prior to enrollment
  • Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant or breastfeeding women are excluded from this study; breastfeeding should be discontinued if the mother is treated with carfilzomib
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin, or low-risk prostate cancer after curative therapy
  • Patients who have had major surgical procedures or significant traumatic injury within 28 days prior to study treatment
  • Patients who are reported to be of direct Asian-Pacific (China, Japan, Taiwan, Singapore, Republic of Korea, and Thailand) ancestry.

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): NCT02073097


Contacts
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Contact: Brian Hill, MD, PhD 216-445-9451 hillb2@ccf.org

Locations
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United States, Georgia
Winship Cancer Institute, Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Christopher Flowers, MD, MS    404-778-1827    crflowe@emory.edu   
Principal Investigator: Christopher Flowers, MD, MS         
United States, Ohio
University Hospitals Cleveland Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Paolo Caimi, MD    216-844-0362    paolo.caimi@uhhospitals.org   
Principal Investigator: Paolo Caimi, MD         
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Recruiting
Cleveland, Ohio, United States, 44195
Contact: Brian T. Hill, MD, PhD    216-445-9451    hillb2@ccf.org   
Principal Investigator: Brian T. Hill, MD, PhD         
Sponsors and Collaborators
Case Comprehensive Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Brian Hill, MD, PhD Case Comprehensive Cancer Center

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Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT02073097     History of Changes
Other Study ID Numbers: CASE3413
NCI-2014-00249 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CASE3413 ( Other Identifier: Case Comprehensive Cancer Center )
P30CA043703 ( U.S. NIH Grant/Contract )
First Posted: February 27, 2014    Key Record Dates
Last Update Posted: May 3, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Prednisone
Cyclophosphamide
Rituximab
Doxorubicin
Liposomal doxorubicin
Vincristine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors