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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II Study of Carfilzomib in Combination With R-CHOP (CR-CHOP) for Patients With Diffuse Large B-cell Lymphoma

Conditions
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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

Intervention / Treatment
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* Drug: Carfilzomib
* Biological: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin hydrochloride
* Drug: Vincristine sulfate
* Drug: Prednisone
* Drug: Pegfilgrastim
* Drug: Acyclovir


Participation Criteria
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Eligibility Criteria
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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 CNS involvement by lymphoma. Patients at high risk for secondary CNS involvement but without neurologic symptoms suspected to be due to lymphoma are allowed to be enrolled and receive intrathecal chemotherapy including but not limited to methotrexate, cytarabine and glucocorticoids. Patients who are enrolled and subsequently identified to have pathologic confirmation of CNS involvement by lymphoma may be continued on study at the discretion of the principal investigator. 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 because Carfilzomib is a proteasome inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with Carfilzomib, breastfeeding should be discontinued if the mother is treated with Carfilzomib. These potential risks may also apply to other agents used in this study. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Carfilzomib. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. 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, or low risk melanoma if treated with definitive therapy (such as excision) and expected to have a low likelihood of recurrence. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rituximab, combination chemotherapy, carfilzomib<br>Participants receive (every 21 day cycle): Rituximab IV over at least 90 minutes on day 2 Carfilzomib IV over 30 minutes on days 1, and 2 Cyclophosphamide IV over 30-60 minutes on day 3 Doxorubicin hydrochloride IV over 3-5 minutes on day 3 Vincristine sulfate IV over 1 minute on day 3 Prednisone PO on days 3-7 any time Pegfilgrastim day 4 Acyclovir 2x per day from cycle 1, 6 months after completion of cycle 6 Courses repeat every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: Carfilzomib<br>* Given IV, according to dose level. Cohorts begin with dose level (DL)1, escalated in standard 3+3 design to identify a recommended phase 2 dose DL (-2) 11 mg/m2 on day 1 and 2 every 21 days, cycles 1-6 DL (-1) 15 mg/m2 on days 1 and 2 every 21 days, cycles 1-6 DL (1) 20 mg/m2 days 1,2 every 21 days, cycles 1-6 DL (2) 20 mg/m2 days 1,2 of cycle 1 followed by 27 mg/m2 days 1,2 every 21 days for cycles 2-6. DL (3) 20 mg/m2 days 1,2 of cycle 1 followed by 36 mg/m2 days 1,2 every 21 days for cycles 2-6. DL(4) 20 mg/m2 days 1,2 of cycle 1 followed by 45 mg/m2 days 1,2 every 21 days for cycles 2-6 DL (5) 20 mg/m2 days 1,2 of cycle 1 followed by 56 mg/m2 days 1,2 every 21 days for cycles 2-6<br>* Other names: PR-171;Biological: Rituximab<br>* Given IV (375mg/m^2)<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* Given IV (750mg/m^2)<br>* Other names: Endoxana;Drug: Doxorubicin hydrochloride<br>* Given IV (50mg/m^2)<br>* Other names: Adriamycin RDF;Drug: Vincristine sulfate<br>* Given IV (1.4mg/m^2)<br>* Other names: Vincasar PFS;Drug: Prednisone<br>* Given PO (100mg)<br>* Other names: Deltra;Drug: Pegfilgrastim<br>* 6 mg SC day 4 (every 21 days). Filgrastim 300 or 480 mcg IV/SC daily days 1-10 may be substituted if pegfilgrastim is not available. ONPROTM is also an acceptable method of administration.<br>* Other names: Recombinant methionyl human granulocyte colony-stimulating factor (G-CSF);Drug: Acyclovir<br>* PO (400mg)<br>* Other names: Zovirax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase II dose (Phase I) | Highest dose administered when no more than 1 out of 6 patients experience lose limiting toxicity below the maximally administered dose. | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (Phase II) | 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. | 30 days after treatment | 
| Overall Survival (Phase II) | 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 | 30 days after treatment | 
| Complete Response Rate (Phase II) | 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 | 30 days after treatment | 
| Partial Response Rate (Phase II) | 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. | 30 days after treatment |