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
Conditions
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.
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.
Interventions
DRUGCarfilzomib
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
BIOLOGICALRituximab
Given IV (375mg/m\^2)
DRUGCyclophosphamide
Given IV (750mg/m\^2)
DRUGDoxorubicin hydrochloride
Given IV (50mg/m\^2)
DRUGVincristine sulfate
Given IV (1.4mg/m\^2)
DRUGPrednisone
Given PO (100mg)
DRUGPegfilgrastim
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.
DRUGAcyclovir
PO (400mg)
Sponsors
Case Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase II Dose (Phase I) | Through cycle 6 (each cycle is 21 days) | Highest dose administered when no more than 1 out of 6 patients experience lose limiting toxicity below the maximally administered dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (Phase II) | 31 months after treatment | PFS will be estimated using a Kaplan-Meier curve. Progression-free Survival (PFS) is defined as the time from entry onto study until lymphoma progression or death from any cause. Participants was evaluated utilizing RECIST v1.0 criteria at baseline, 3 months after beginning treatment, end of treatment (6 cycles of therapy), and at 6 month, 12 month, and 24 month follow up visit. RECIST v1.0 criteria for Malignant Lymphoma use the following categories of response: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Relapse and Progression (PD). |
| Overall Survival (Phase II) | 31 months after treatment | Overall survival will be estimated with a Kaplan-Meier curve. Overall survival is defined as the time from entry onto study until lymphoma progression or death from any cause. |
| Complete Response Rate (Phase II) | 31 months after treatment | The percentage 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 |
| Partial Response Rate (Phase II) | 31 months after treatment | The percentage 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I CR-CHOP Level -2 Dose level -2:
Carfilzomib: 11 mg/m\^2 on day 1 and 2 every 21 days, cycles 1-6
CHOP: Standard dose on day 3 every 21 days Rituximab standard dose on Day 2 | 0 |
| Phase I CR-CHOP Level -1 Dose Level -1:
Carfilzomib: 15 mg/m\^2 on days 1 and 2 every 21 days, cycles 1-6
CHOP: Standard dose on day 3 every 21 days Rituximab standard dose on Day 2 | 0 |
| Phase I CR-CHOP Dose Level 1 Dose Level 1:
Carfilzomib: 20 mg/m\^2 days 1,2 every 21 days, cycles 1-6
CHOP: Standard dose on day 3 every 21 days Rituximab standard dose on Day 2 | 9 |
| Phase I CR-CHOP Dose Level 2 Dose Level 2:
Carfilzomib: 20 mg/m\^2 days 1,2 of cycle 1 followed by 27 mg/m\^2 days 1,2 every 21 days for cycles 2-6
CHOP: Standard dose on day 3 every 21 days Rituximab standard dose on Day 2 | 3 |
| Phase I CR-CHOP Dose Level 3 Dose Level 3:
Carfilzomib: 20 mg/m\^2 days 1,2 of cycle 1 followed by 36 mg/m\^2 days 1,2 every 21 days for cycles 2-6
CHOP: Standard dose on day 3 every 21 days Rituximab standard dose on Day 2 | 3 |
| Phase I CR-CHOP Dose Level 4 Dose Level 4:
Carfilzomib: 20 mg/m\^2 days 1,2 of cycle 1 followed by 45 mg/m\^2 days 1,2 every 21 days for cycles 2-6
CHOP: Standard dose on day 3 every 21 days Rituximab standard dose on Day 2 | 3 |
| Phase I CR-CHOP Dose Level 5 Dose Level 5:
Carfilzomib: 20 mg/m\^2 days 1,2 of cycle 1 followed by 56 mg/m\^2 days 1,2 every 21 days for cycles 2-6
CHOP: Standard dose on day 3 every 21 days Rituximab standard dose on Day 2 | 6 |
| Phase II CR-CHOP Dose Level 5 Dose Level 5:
Carfilzomib: 20 mg/m\^2 days 1,2 of cycle 1 followed by 56 mg/m\^2 days 1,2 every 21 days for cycles 2-6
CHOP: Standard dose on day 3 every 21 days Rituximab standard dose on Day 2 | 24 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Phase I CR-CHOP Dose Level 2 | Phase I CR-CHOP Dose Level 3 | Phase I CR-CHOP Dose Level 4 | Phase I CR-CHOP Dose Level 1 | Phase I CR-CHOP Dose Level 5 | Phase II CR-CHOP Dose Level 5 | Total |
|---|---|---|---|---|---|---|---|
| Age, Customized 20-29 years old | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Age, Customized 30-39 years old | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Age, Customized 40-49 years old | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 4 Participants |
| Age, Customized 50-59 years old | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 5 Participants | 12 Participants |
| Age, Customized 60-69 years old | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 5 Participants | 10 Participants |
| Age, Customized 70-79 years old | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 10 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 3 Participants | 9 Participants | 6 Participants | 23 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 3 Participants | 9 Participants | 6 Participants | 24 Participants | 48 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 3 participants | 9 participants | 6 participants | 24 participants | 48 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 7 Participants | 2 Participants | 8 Participants | 23 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants | 16 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 0 / 0 | 1 / 9 | 1 / 3 | 1 / 3 | 0 / 3 | 0 / 6 | 2 / 24 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 8 / 9 | 3 / 3 | 3 / 3 | 3 / 3 | 6 / 6 | 22 / 24 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 | 2 / 9 | 2 / 3 | 1 / 3 | 1 / 3 | 1 / 6 | 8 / 24 |
Outcome results
Primary
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.
Time frame: Through cycle 6 (each cycle is 21 days)
Population: The number of subjects that were on the phase I cohort.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab, Combination Chemotherapy, Carfilzomib | Recommended Phase II Dose (Phase I) | Days 1, 2 of cycle 1 | 20 mg/m^2 |
| Rituximab, Combination Chemotherapy, Carfilzomib | Recommended Phase II Dose (Phase I) | Days 1, 2 every 21 days for cycles 2-6 | 56 mg/m^2 |
Secondary
Complete Response Rate (Phase II)
The percentage 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
Time frame: 31 months after treatment
Population: 24 participants were enrolled to Phase II.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab, Combination Chemotherapy, Carfilzomib | Complete Response Rate (Phase II) | 70 percentage of participants |
Secondary
Overall Survival (Phase II)
Overall survival will be estimated with a Kaplan-Meier curve. Overall survival is defined as the time from entry onto study until lymphoma progression or death from any cause.
Time frame: 31 months after treatment
Population: 24 participants were enrolled to Phase II.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab, Combination Chemotherapy, Carfilzomib | Overall Survival (Phase II) | 87 % of participants analyzed |
Secondary
Partial Response Rate (Phase II)
The percentage 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.
Time frame: 31 months after treatment
Population: 24 participants were enrolled in Phase II.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab, Combination Chemotherapy, Carfilzomib | Partial Response Rate (Phase II) | 19 percentage of participants |
Secondary
Progression Free Survival (Phase II)
PFS will be estimated using a Kaplan-Meier curve. Progression-free Survival (PFS) is defined as the time from entry onto study until lymphoma progression or death from any cause. Participants was evaluated utilizing RECIST v1.0 criteria at baseline, 3 months after beginning treatment, end of treatment (6 cycles of therapy), and at 6 month, 12 month, and 24 month follow up visit. RECIST v1.0 criteria for Malignant Lymphoma use the following categories of response: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Relapse and Progression (PD).
Time frame: 31 months after treatment
Population: 24 participants were enrolled in Phase II.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab, Combination Chemotherapy, Carfilzomib | Progression Free Survival (Phase II) | 79 percentage of participants |