EPOCH-R Chemotherapy Plus Bortezomib to Treat Mantle Cell Lymphoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00114738
• Collaborator: (none)
• Enrollment: 53
• Location: 1
• Arms: 4
• Anticipated Duration (Months): 205.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study will evaluate the effectiveness of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin-rituximab (EPOCH-R) chemotherapy plus bortezomib for treating mantle cell lymphoma, a cancer of white blood cells called lymphocytes. EPOCH-R consists of the drugs prednisone, etoposide, doxorubicin and vincristine, with the addition of a new drug called rituximab. In a recent study of patients with newly diagnosed mantle cell lymphoma, 92 percent had a complete remission of their disease after treatment with EPOCH-R. This study will test whether adding bortezomib as "maintenance therapy" once chemotherapy is finished will lengthen the time before the disease relapses and improve the overall cure rate.

Patients 18 years of age and older with mantle cell lymphoma may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, electrocardiogram, multi-gated acquisition scan (MUGA) or echocardiogram, imaging studies and biopsy to determine the extent of disease, and possible colonoscopy.

Participants undergo treatment in three parts, as follows:

• Part 1: Bortezomib alone: Patients receive 4 doses of bortezomib over 3 weeks. The drug is injected into a vein over about 30 seconds.

• Part 2: EPOCH-R chemotherapy plus bortezomib: This phase of treatment begins 3 to 4 weeks after completing Part 1. Treatment is given on an outpatient basis in six 3-week cycles, with all drugs administered over the first 5 days of each cycle. Patients take prednisone by mouth on days 1 to 5 and etoposide, doxorubicin, and vincristine as a 96-hour infusion through a vein over days 1 to 5. The infused drugs are delivered through a lightweight, portable infusion pump. Rituximab is given by vein over several hours on day 1 immediately before the chemotherapy infusion begins. Bortezomib is given by vein over 30 seconds on day 1 before the rituximab and again on day 4. Cyclophosphamide is given by vein over about 15 minutes on day 5 immediately after the chemotherapy infusion is completed. Patients are taught how to self inject granulocyte colony stimulating factor (G-CSF), a drug that helps boost white cell counts after chemotherapy. They inject the drug under the skin (like an insulin shot) for 10 days of each cycle beginning day 6. Patients also take an antibiotic to help prevent infection during chemotherapy.

• Part 3: Bortezomib alone: After completing EPOCH-R-B therapy, patients are randomly assigned to receive or not to receive bortezomib alone. The drug is given in 2 doses over 5 days, with a break of 16 days before the next dose. These 3-week cycles continue for up to 18 months or until the disease comes back or worsens. Patients who are assigned to the group that does not receive bortezomib will be offered the drug if their disease relapses.

During therapy, patients have tests performed on their bone marrow, tumor tissue, blood or other fluids to look at different genes and proteins that may be involved in the development of their lymphoma or the reaction of the immune system. A tissue biopsy is done before treatment begins and a day after treatment starts. Disease progress is followed with computed tomography (CT) scans and blood tests. When treatment is completed, patients whose cancer has disappeared are scheduled for periodic follow-up examinations and tests. Those whose disease remains or recurs may be offered participation in another protocol if an appropriate one is available or are returned to the care of their local physician.

...

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Mantle Cell; Mantle Cell Lymphoma	Drug: Rituximab (R); Biological: EPOCH; Drug: Bortezomib (B); Drug: Bortezomib; Drug: Bortezomib or observation	Phase 2

Detailed Description

Background:

Mantle cell lymphoma (MCL) presents a clinical challenge because it is aggressive and incurable with chemotherapy. Therefore novel treatment approaches are needed.

MCL has overexpression of NF-kappa B (NF-kappa B), a transcription factor that affects cell growth and survival, and cyclin D1 that affects cell cycle and growth. These proteins appear to be involved in the pathogenesis of MCL.

Bortezomib, a proteasome inhibitor that inhibits NF-kappa B and cyclin D1, has demonstrated activity in patients with relapsed or refractory MCL.

Dose-adjusted-etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin-rituximab (EPOCH-R) has excellent activity in MCL, with a complete response (CR) rate of 92%, but patients eventually relapse.

Objective:

Determine the progression free survival (PFS) and overall survival (OS) of dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab,bortezomib (DA-EPOCH-RB) followed by bortezomib maintenance versus observation.

Eligibility:

Diagnosis of mantle cell lymphoma.

No prior treatment except for local radiation or a short course of steroids for control of symptoms,

Age greater than or equal to 18 years old.

Adequate major organ function unless impairment is due to lymphoma.

Study Design:

To assess the clinical activity and biological effects of bortezomib, patients will initially receive one cycle of bortezomib alone with sequential tumor biopsies for microarray analysis.

All patients will then receive Dose-adjusted (DA)-EPOCH-RB for 6 cycles, and if they have at least a PR, this will be followed by randomization to either immediate bortezomib maintenance x 18 months, or to observation, followed by bortezomib if progression occurs. This study has as a primary goal, to describe progression free survival (PFS) and overall survival of early bortezomib maintenance versus observation following induction with bortezomib followed by DA-EPOCH-RB. Important secondary goals are to assess response and toxicity to bortezomib alone or DA-EPOCH-RB, to evaluate time to progression after receiving bortezomib following progression on an observation arm, and to assess the biological effects of bortezomib on untreated MCL.

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Study of Dose-Adjusted EPOCH-Rituximab-Bortezomib (EPOCH-R-B) Induction Followed by Bortezomib Maintenance Versus Observation in Untreated Mantle Cell Lymphoma With Microarray Profiling and Proteomics
• Actual Study Start Date: Jun 15, 2005
• Actual Primary Completion Date: Aug 11, 2016
• Anticipated Study Completion Date: Aug 11, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: EPOCH-R + Bortezomib Combo chemo etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-Rituxan (R) + Bortezomib (B)	Drug: Rituximab (R); Rituximab is given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and bortezomib every 3 weeks for 6 cycles.; Other Names: Rituxan ; Biological: EPOCH; EPOCH is given with Rituximab and bortezomib every 3 weeks for 6 cycles.; Drug: Bortezomib; Bortezomib is given with EPOCH and rituximab every 6 weeks for 12 cycles.; Other Names: Velcade
Experimental: Bortezomib "window" Bortezomib alone	Drug: Bortezomib (B); Bortezomib is given alone for one cycle.; Other Names: Velcade
Active Comparator: Bortezomib maintenance Bortezomib maintenance	Drug: Bortezomib; Bortezomib is given with EPOCH and rituximab every 6 weeks for 12 cycles.; Other Names: Velcade
Other: Observation At the beginning of part C patients are randomized to receive bortezomib maintenance or observation without bortezomib.	Drug: Bortezomib or observation; At the beginning of Part C, patients are randomized to receive bortezomib maintenance or be observed w/o bortezomib.; Other Names: Velcade

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [up to 5 years]

   Time interval from start of treatment to documented evidence of disease progression. Progression is defined by at least one of the following: ≥50% increase in the sum of the products of at least two lymph nodes, appearance of new lymph nodes, ≥50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin, appearance of new palpable hepatomegaly or splenomegaly that was not previously present, and ≥50% increase in the absolute number of circulating lymphocytes.The primary evaluation will be a Kaplan-Meier analysis with a two tailed log rank test.

2. Median Overall Survival (OS) [up to 9.9 years]

   Overall Survival is the time between the first day of treatment to the day of death. The primary evaluation will be a Kaplan-Meier analysis with a two tailed log rank test.

3. Overall Progression Free Survival [up to 9.9 years]

   Time interval from start of treatment to documented evidence of disease progression. Progression is defined by at least one of the following: ≥50% increase in the sum of the products of at least two lymph nodes, appearance of new lymph nodes, ≥50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin, appearance of new palpable hepatomegaly or splenomegaly that was not previously present, and ≥50% increase in the absolute number of circulating lymphocytes.

4. Overall Survival [up to 9.9 years]

   Overall Survival is the time between the first day of treatment to the day of death. The primary evaluation will be a Kaplan-Meier analysis with a two tailed log rank test.

Secondary Outcome Measures

1. Count of Participants With Serious and Non-Serious Adverse Events [Date treatment consent signed to date off study, approximately 143 months and 7 days]

   Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

2. Clinical Response [up to 22 weeks after initiation of therapy]

   Clinical response is assessed by the response criteria for lymphomas and is defined as a fraction of patients who have a complete response (CR) or a complete response (CR) + partial response (PR). A complete response is disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities (e.g. lactate dehydrogenase) definitely assignable to the lymphoma. Partial response is ≥50% decreased in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Progressive disease is defined by at least one of the following: ≥50% increase in the sum of the products of at least two lymph nodes appearance of new lymph nodes, ≥50% increase in the size of the liver and/or spleen, ≥50% increase in the absolute number of circulating lymphocytes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• ELIGIBILITY CRITERIA:

Diagnosis of mantle cell lymphoma (confirmed at National Cancer Institute (NCI)). All variants are eligible.

Age greater than or equal to 18 years.

No prior treatment except for local radiation or a short course of steroids for control of symptoms.

All stages of disease.

Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 3.

Adequate major organ function (serum creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than 50 ml/min; bilirubin less than 2 mg/dl (total) except less than 5 mg/dl in patients with Gilbert's syndrome as defined by greater than 80% unconjugated; Absolute neutrophil count (ANC) greater than 1000 and platelets greater than 75,000) unless impairment due to organ involvement by lymphoma.

No myocardial infarction within 6 months prior to enrollment or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiogram (ECG) abnormality at Screening has to be documented by the investigator as not medically relevant.

No grade 2 greater than or equal to peripheral neuropathy within 14 days before enrollment.

Ability to give informed consent.

Human immunodeficiency virus (HIV) antibody negative.

Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Female subject is not pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-human chorionic gonadotropin (hCG)) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women

Male subject agrees to use an acceptable method for contraception for the duration of the study.

No history of a prior invasive malignancy in past 5 years

No known involvement of central nervous system by lymphoma

No history of hypersensitivity to boron or mannitol.

Patient has not received other investigational drugs with 14 days before enrollment.

No serious medical or psychiatric illness likely to interfere with participation in this clinical study.

Exclusion for fludeoxyglucose (FDG) scan is anyone exceeding the weight limit of the scanner (350 lb).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Wyndham H Wilson, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Sep 6, 2018

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Campo E, Raffeld M, Jaffe ES. Mantle-cell lymphoma. Semin Hematol. 1999 Apr;36(2):115-27. Review.
• Hiddemann W, Unterhalt M, Herrmann R, Wöltjen HH, Kreuser ED, Trümper L, Reuss-Borst M, Terhardt-Kasten E, Busch M, Neubauer A, Kaiser U, Hanrath RD, Middeke H, Helm G, Freund M, Stein H, Tiemann M, Parwaresch R. Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group. J Clin Oncol. 1998 May;16(5):1922-30.
• Velders GA, Kluin-Nelemans JC, De Boer CJ, Hermans J, Noordijk EM, Schuuring E, Kramer MH, Van Deijk WA, Rahder JB, Kluin PM, Van Krieken JH. Mantle-cell lymphoma: a population-based clinical study. J Clin Oncol. 1996 Apr;14(4):1269-74.

• Responsible Party: Wyndham Wilson, M.D., Principal Investigator, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00114738
• Other Study ID Numbers: 050170; 05-C-0170; NCT00131976
• First Posted: Jun 17, 2005
• Last Update Posted: Oct 18, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Keywords provided by Wyndham Wilson, M.D., Principal Investigator, National Cancer Institute (NCI): Proteasome Inhibition; NF-Kappa-B; Gene Expression Signature; Cyclin D1; Translational Studies; Lymphoma; Mantle Cell Lymphoma; MCL
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Rituximab; Bortezomib

Study Results

Participant Flow

Arm/Group Title	Bortezomib Then Bortezomib + DA-EPOCH-R Induction	Bortezomib Maintenance	Observation
Arm/Group Description	Bortezomib is given alone for one cycle, then combo chemo etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-Rituxan (R) + Bortezomib (B) is given every 3 weeks for 6 cycles.	Bortezomib alone is given in 3 week cycles. 3-week cycles continue up to 18 months or until the disease comes back or worsens.	Participants are observed without treatment.
Period Title: Bortezomib Then Bortezomib + Induction
STARTED	53	0	0
Started With Bortezomib Alone	47	0	0
Skipped Bortezomib Alone	6	0	0
COMPLETED	51	0	0
NOT COMPLETED	2	0	0
Period Title: Bortezomib Then Bortezomib + Induction
STARTED	51	0	0
COMPLETED	30	0	0
NOT COMPLETED	21	0	0
Period Title: Bortezomib Then Bortezomib + Induction
STARTED	0	14	16
COMPLETED	0	14	16
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All Participants who received at least one dose of Bortezomib alone followed by EPOCH-R+B chemotherapy. Bortezomib (B): Bortezomib is given alone for one cycle. Combo chemo etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-Rituxan (R) + Bortezomib (B) Rituximab (R): Rituximab is given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and bortezomib every 3 weeks for 6 cycles. EPOCH: EPOCH is given with Rituximab and bortezomib every 3 weeks for 6 cycles. Bortezomib (B): Bortezomib is given alone for one cycle. Bortezomib or observation: At the beginning of Part C, patients are randomized to receive bortezomib maintenance or be observed w/o bortezomib.
Overall Participants	53
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	39 73.6%
>=65 years	14 26.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.85 (8.7)
Sex: Female, Male (Count of Participants)
Female	12 22.6%
Male	41 77.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 7.5%
Not Hispanic or Latino	46 86.8%
Unknown or Not Reported	3 5.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 3.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 3.8%
White	49 92.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	53 100%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	Time interval from start of treatment to documented evidence of disease progression. Progression is defined by at least one of the following: ≥50% increase in the sum of the products of at least two lymph nodes, appearance of new lymph nodes, ≥50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin, appearance of new palpable hepatomegaly or splenomegaly that was not previously present, and ≥50% increase in the absolute number of circulating lymphocytes.The primary evaluation will be a Kaplan-Meier analysis with a two tailed log rank test.
Time Frame	up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib Maintenance	Observation	Not Randomized
Arm/Group Description	Bortezomib maintenance Bortezomib: Bortezomib is given with EPOCH and rituximab every 3 weeks for 6 cycles.	Observation without bortezomib	Twenty-three patients were not randomized. Sixteen due to neuropathy and seven due to "other" reasons.
Measure Participants	14	16	23
Median (95% Confidence Interval) [Months]	27.2	33.5	7.8

2. Primary Outcome

Title	Median Overall Survival (OS)
Description	Overall Survival is the time between the first day of treatment to the day of death. The primary evaluation will be a Kaplan-Meier analysis with a two tailed log rank test.
Time Frame	up to 9.9 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EPOCH-R+Bortezomib
Arm/Group Description	Combo chemo etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-Rituxan (R) + Bortezomib (B) Rituximab (R): Rituximab is given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and bortezomib every 3 weeks for 6 cycles. EPOCH: EPOCH is given with Rituximab and bortezomib every 3 weeks for 6 cycles. Bortezomib (B): Bortezomib is given alone for one cycle.
Measure Participants	53
Median (95% Confidence Interval) [Months]	80.4

3. Primary Outcome

Title	Overall Progression Free Survival
Description	Time interval from start of treatment to documented evidence of disease progression. Progression is defined by at least one of the following: ≥50% increase in the sum of the products of at least two lymph nodes, appearance of new lymph nodes, ≥50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin, appearance of new palpable hepatomegaly or splenomegaly that was not previously present, and ≥50% increase in the absolute number of circulating lymphocytes.
Time Frame	up to 9.9 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EPOCH-R+Bortezomib
Arm/Group Description	Combo chemo etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-Rituxan (R) + Bortezomib (B) Rituximab (R): Rituximab is given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and bortezomib every 3 weeks for 6 cycles. EPOCH: EPOCH is given with Rituximab and bortezomib every 3 weeks for 6 cycles. Bortezomib (B): Bortezomib is given alone for one cycle.
Measure Participants	53
Median (95% Confidence Interval) [Months]	29.3

4. Primary Outcome

Title	Overall Survival
Description	Overall Survival is the time between the first day of treatment to the day of death. The primary evaluation will be a Kaplan-Meier analysis with a two tailed log rank test.
Time Frame	up to 9.9 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib Maintenance	Observation	Not Randomized
Arm/Group Description	Bortezomib maintenance Bortezomib: Bortezomib is given with EPOCH and rituximab every 3 weeks for 6 cycles.	Observation without bortezomib	Twenty-three patients were not randomized. Sixteen due to neuropathy and seven due to "other" reasons.
Measure Participants	14	16	23
Median (95% Confidence Interval) [Months]	78.6	87.5	31.6

5. Secondary Outcome

Title	Count of Participants With Serious and Non-Serious Adverse Events
Description	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time Frame	Date treatment consent signed to date off study, approximately 143 months and 7 days

Outcome Measure Data

Analysis Population Description

Participants are grouped together in one arm/group because most adverse events occurred during Part B, in which all participants received drug.

Arm/Group Title	EPOCH-R+Bortezomib
Arm/Group Description	Combo chemo etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-Rituxan (R) + Bortezomib (B) Rituximab (R): Rituximab is given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and bortezomib every 3 weeks for 6 cycles. EPOCH: EPOCH is given with Rituximab and bortezomib every 3 weeks for 6 cycles. Bortezomib (B): Bortezomib is given alone for one cycle.
Measure Participants	53
Count of Participants [Participants]	53 100%

6. Secondary Outcome

Title	Clinical Response
Description	Clinical response is assessed by the response criteria for lymphomas and is defined as a fraction of patients who have a complete response (CR) or a complete response (CR) + partial response (PR). A complete response is disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities (e.g. lactate dehydrogenase) definitely assignable to the lymphoma. Partial response is ≥50% decreased in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Progressive disease is defined by at least one of the following: ≥50% increase in the sum of the products of at least two lymph nodes appearance of new lymph nodes, ≥50% increase in the size of the liver and/or spleen, ≥50% increase in the absolute number of circulating lymphocytes.
Time Frame	up to 22 weeks after initiation of therapy

Outcome Measure Data

Analysis Population Description

Participants are grouped together in one arm/group because this is the arm/group in which all participants received drug.

Arm/Group Title	EPOCH-R+Bortezomib
Arm/Group Description	Combo chemo etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-Rituxan (R) + Bortezomib (B) Rituximab (R): Rituximab is given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and bortezomib every 3 weeks for 6 cycles. EPOCH: EPOCH is given with Rituximab and bortezomib every 3 weeks for 6 cycles. Bortezomib (B): Bortezomib is given alone for one cycle.
Measure Participants	53
Overall Response (CR+PR)	92.5
Complete Response	86.7
Stable Disease	3.8
Progressive Disease	1.9
Not Evaluable	1.9

Adverse Events

Time Frame	date treatment consent signed to date off study, approximately 143 months and 7 days
Adverse Event Reporting Description	Participants are grouped together in one arm/group because most adverse events occurred during Part B, in which all participants received drug.
Arm/Group Title	EPOCH-R+Bortezomib
Arm/Group Description	Combo chemo etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-Rituxan (R) + Bortezomib (B) Rituximab (R): Rituximab is given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and bortezomib every 3 weeks for 6 cycles. EPOCH: EPOCH is given with Rituximab and bortezomib every 3 weeks for 6 cycles. Bortezomib (B): Bortezomib is given alone for one cycle.
All Cause Mortality
	EPOCH-R+Bortezomib
	Affected / at Risk (%)	# Events
Total	1/53 (1.9%)
Serious Adverse Events
	EPOCH-R+Bortezomib
	Affected / at Risk (%)	# Events
Total	21/53 (39.6%)
Blood and lymphatic system disorders
Hemoglobin	1/53 (1.9%)	1
Platelets	1/53 (1.9%)	1
Gastrointestinal disorders
Constipation	1/53 (1.9%)	1
Diarrhea	1/53 (1.9%)	1
Esophagitis	1/53 (1.9%)	1
Hemorrhage, GI::Peritoneal cavity	1/53 (1.9%)	1
Obstruction, GI::Colon	1/53 (1.9%)	1
Obstruction, GI::Small bowel NOS	1/53 (1.9%)	2
Pain::Abdomen NOS	1/53 (1.9%)	2
Perforation, GI::Colon	1/53 (1.9%)	1
General disorders
Death not associated with CTCAE term::Disease progression NOS	1/53 (1.9%)	1
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	1/53 (1.9%)	1
Infections and infestations
Febrile neutropenia	9/53 (17%)	11
Infection with normal ANC or Grade 1 or 2 neutrophils::Lung (pneumonia)	1/53 (1.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Skin (cellulitis)	1/53 (1.9%)	1
Infection with unknown ANC::Lung (pneumonia)	1/53 (1.9%)	1
Metabolism and nutrition disorders
Creatinine	1/53 (1.9%)	1
Musculoskeletal and connective tissue disorders
Fracture	1/53 (1.9%)	1
Pain::Bone	1/53 (1.9%)	1
Nervous system disorders
Dizziness	1/53 (1.9%)	1
Hemorrhage, CNS	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	1/53 (1.9%)	1
Other (Not Including Serious) Adverse Events
	EPOCH-R+Bortezomib
	Affected / at Risk (%)	# Events
Total	53/53 (100%)
Blood and lymphatic system disorders
Edema: head and neck	1/53 (1.9%)	1
Edema: limb	27/53 (50.9%)	41
Hemoglobin	53/53 (100%)	392
Leukocytes (total WBC)	53/53 (100%)	345
Lymphopenia	53/53 (100%)	451
Neutrophils/granulocytes (ANC/AGC)	53/53 (100%)	271
PTT (Partial Thromboplastin Time)	16/53 (30.2%)	27
Pain::Lymph node	1/53 (1.9%)	1
Petechiae/purpura (hemorrhage/bleeding into skin or mucosa)	2/53 (3.8%)	2
Platelets	53/53 (100%)	419
Cardiac disorders
Cardiac General - Other (cardiac tamponade)	1/53 (1.9%)	1
Cardiac ischemia/infarction	1/53 (1.9%)	1
Hypertension	1/53 (1.9%)	1
Hypotension	15/53 (28.3%)	21
Left ventricular systolic dysfunction	1/53 (1.9%)	1
Pain::Cardiac/heart	1/53 (1.9%)	1
Pain::Pericardium	1/53 (1.9%)	1
Palpitations	3/53 (5.7%)	3
Supraventricular and nodal arrhythmia::Sinus bradycardia	2/53 (3.8%)	2
Supraventricular and nodal arrhythmia::Sinus tachycardia	4/53 (7.5%)	6
Supraventricular and nodal arrhythmia::Supraventricular arrhythmia NOS	1/53 (1.9%)	1
Ventricular arrhythmia::Ventricular tachycardia	1/53 (1.9%)	1
Ear and labyrinth disorders
Tinnitus	2/53 (3.8%)	2
Eye disorders
Ascites (non-malignant)	2/53 (3.8%)	2
Dry eye syndrome	2/53 (3.8%)	2
Hemorrhage/Bleeding - Other vitreous hemorrhage)	1/53 (1.9%)	1
Ophthalmoplegia/diplopia (double vision)	1/53 (1.9%)	1
Vision-blurred vision	1/53 (1.9%)	1
Vision-flashing lights/floaters	1/53 (1.9%)	1
Vision-photophobia	1/53 (1.9%)	1
Watery eye (epiphora, tearing)	11/53 (20.8%)	14
Gastrointestinal disorders
Constipation	32/53 (60.4%)	50
Diarrhea	30/53 (56.6%)	49
Distension/bloating, abdominal	6/53 (11.3%)	7
Dry mouth/salivary gland (xerostomia)	4/53 (7.5%)	4
Dysphagia (difficulty swallowing)	5/53 (9.4%)	5
Esophagitis	1/53 (1.9%)	1
Flatulence	3/53 (5.7%)	3
Gastrointestinal - Other (hiccups)	1/53 (1.9%)	1
Heartburn/dyspepsia	9/53 (17%)	9
Hemorrhage, GI::Anus	1/53 (1.9%)	1
Hemorrhage, GI::Colon	1/53 (1.9%)	1
Hemorrhage, GI::Rectum	1/53 (1.9%)	1
Hemorrhoids	1/53 (1.9%)	2
Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation)	1/53 (1.9%)	1
Mucositis/stomatitis (clinical exam)::Oral cavity	23/53 (43.4%)	46
Mucositis/stomatitis (clinical exam)::Stomach	3/53 (5.7%)	3
Mucositis/stomatitis (functional/symptomatic)::Oral cavity	11/53 (20.8%)	12
Nausea	27/53 (50.9%)	58
Obstruction, GI::Ileum	1/53 (1.9%)	1
Pain::Abdomen NOS	12/53 (22.6%)	14
Pain::Oral cavity	1/53 (1.9%)	1
Pain::Rectum	1/53 (1.9%)	1
Proctitis	1/53 (1.9%)	1
Prolapse of stoma, GI	1/53 (1.9%)	1
Taste alteration (dysgeusia)	13/53 (24.5%)	17
Vomiting	12/53 (22.6%)	15
Gastrointestinal - Other (Stomatitis)	2/53 (3.8%)	3
Gastrointestinal - Other (Stomatitis - Ulcer on tongue)	1/53 (1.9%)	1
Gastrointestinal - Other (Thrush)	1/53 (1.9%)	1
Gastrointestinal - Other (Stomatitis/pharyngitis)	1/53 (1.9%)	1
General disorders
Constitutional Symptoms - Other (early satiety	1/53 (1.9%)	1
Fatigue (asthenia, lethargy, malaise)	35/53 (66%)	54
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	14/53 (26.4%)	14
Flu-like syndrome	1/53 (1.9%)	1
Insomnia	18/53 (34%)	21
Rigors/chills	9/53 (17%)	11
Sweating (diaphoresis)	5/53 (9.4%)	6
Weight gain	1/53 (1.9%)	1
Weight loss	8/53 (15.1%)	13
Pain - Other (pain Lt biopsy site)	1/53 (1.9%)	1
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	2/53 (3.8%)	4
Infections and infestations
Febrile neutropenia (fever of unknown origin	13/53 (24.5%)	15
Infection	1/53 (1.9%)	1
Infection	2/53 (3.8%)	4
Infection	1/53 (1.9%)	2
Infection	1/53 (1.9%)	1
Infection	1/53 (1.9%)	1
Infection	1/53 (1.9%)	2
Infection	1/53 (1.9%)	1
Infection	1/53 (1.9%)	1
Infection	3/53 (5.7%)	3
Infection	1/53 (1.9%)	1
Infection - Other (sinusitis)	1/53 (1.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Abdomen NOS	1/53 (1.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Bladder (urinary)	1/53 (1.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Eye NOS	1/53 (1.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Lung (pneumonia)	1/53 (1.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Mucosa	1/53 (1.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Nerve-peripheral	1/53 (1.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Oral cavity-gums (gingivitis)	3/53 (5.7%)	5
Infection with normal ANC or Grade 1 or 2 neutrophils::Sinus	1/53 (1.9%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils::Skin (cellulitis)	4/53 (7.5%)	6
Infection with normal ANC or Grade 1 or 2 neutrophils::Urinary tract NOS	2/53 (3.8%)	2
Infection with unknown ANC::Soft tissue NOS	1/53 (1.9%)	1
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase)	19/53 (35.8%)	39
AST, SGOT(serum glutamic oxaloacetic transaminase)	16/53 (30.2%)	28
Metabolism and nutrition disorders
Acidosis (metabolic or respiratory)	1/53 (1.9%)	1
Albumin, serum-low (hypoalbuminemia)	36/53 (67.9%)	92
Alkaline phosphatase	16/53 (30.2%)	22
Anorexia	17/53 (32.1%)	21
Bicarbonate, serum-low	3/53 (5.7%)	3
Bilirubin (hyperbilirubinemia)	13/53 (24.5%)	23
CPK (creatine phosphokinase)	2/53 (3.8%)	2
Calcium, serum-high (hypercalcemia)	4/53 (7.5%)	9
Calcium, serum-low (hypocalcemia)	20/53 (37.7%)	69
Creatinine	9/53 (17%)	15
Dehydration	4/53 (7.5%)	4
Glucose, serum-high (hyperglycemia)	18/53 (34%)	48
Glucose, serum-low (hypoglycemia)	6/53 (11.3%)	7
Magnesium, serum-high (hypermagnesemia)	12/53 (22.6%)	22
Magnesium, serum-low (hypomagnesemia)	13/53 (24.5%)	58
Phosphate, serum-low (hypophosphatemia)	13/53 (24.5%)	25
Potassium, serum-high (hyperkalemia)	6/53 (11.3%)	9
Potassium, serum-low (hypokalemia)	13/53 (24.5%)	24
Proteinuria	1/53 (1.9%)	1
Sodium, serum-high (hypernatremia)	7/53 (13.2%)	8
Sodium, serum-low (hyponatremia)	20/53 (37.7%)	44
Uric acid, serum-high (hyperuricemia)	7/53 (13.2%)	10
Musculoskeletal and connective tissue disorders
Arthritis (non-septic)	1/53 (1.9%)	1
Muscle weakness, generalized or specific area (not due to neuropathy)::Extremity-lower	1/53 (1.9%)	1
Muscle weakness, generalized or specific area (not due to neuropathy)::Whole body/generalized	4/53 (7.5%)	5
Pain::Back	11/53 (20.8%)	11
Pain::Bone	32/53 (60.4%)	61
Pain::Chest wall	1/53 (1.9%)	1
Pain::Chest/thorax NOS	1/53 (1.9%)	1
Pain::Extremity-limb	7/53 (13.2%)	9
Pain::Joint	10/53 (18.9%)	10
Pain::Muscle	9/53 (17%)	12
Seroma	1/53 (1.9%)	1
Pain - Other (pain R arm)	1/53 (1.9%)	1
Pain - Other (pain in extremity)	1/53 (1.9%)	1
Pain - Other (arm)	1/53 (1.9%)	1
Pain - Other (extremities)	1/53 (1.9%)	1
Nervous system disorders
Ataxia (incoordination)	1/53 (1.9%)	1
Cognitive disturbance	1/53 (1.9%)	1
Confusion	2/53 (3.8%)	3
Dizziness	21/53 (39.6%)	26
Laryngeal nerve dysfunction	3/53 (5.7%)	5
Memory impairment	1/53 (1.9%)	1
Mood alteration::Agitation	1/53 (1.9%)	1
Mood alteration::Anxiety	4/53 (7.5%)	4
Mood alteration::Depression	4/53 (7.5%)	4
Neurology - Other (autonomic neuropathy)	3/53 (5.7%)	4
Neuropathy: motor	8/53 (15.1%)	9
Neuropathy: sensory	52/53 (98.1%)	93
Pain - Other (Specify, Jaw-GCSF)	8/53 (15.1%)	11
Pain::Head/headache	15/53 (28.3%)	20
Pain::Neuralgia/peripheral nerve	12/53 (22.6%)	18
Somnolence/depressed level of consciousness	1/53 (1.9%)	1
Syncope (fainting)	3/53 (5.7%)	3
Neurology - Other (fall)	1/53 (1.9%)	1
Pain - Other (neuropathic)	1/53 (1.9%)	1
Renal and urinary disorders
Cystitis	1/53 (1.9%)	2
Pain::Kidney	1/53 (1.9%)	1
Pain::Urethra	1/53 (1.9%)	2
Urinary frequency/urgency	3/53 (5.7%)	3
Urinary retention (including neurogenic bladder)	1/53 (1.9%)	1
Urine color change	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	12/53 (22.6%)	18
Atelectasis	1/53 (1.9%)	1
Bronchospasm, wheezing	1/53 (1.9%)	1
Cough	10/53 (18.9%)	12
Dyspnea (shortness of breath)	16/53 (30.2%)	22
FEV(1)	1/53 (1.9%)	1
Hemorrhage, pulmonary/upper respiratory::Nose	4/53 (7.5%)	4
Hiccoughs (hiccups, singultus)	2/53 (3.8%)	9
Hypoxia	1/53 (1.9%)	3
Pain::Throat/pharynx/larynx	1/53 (1.9%)	1
Pleural effusion (non-malignant)	4/53 (7.5%)	4
Pulmonary/Upper Respiratory - Other (tachypnea)	1/53 (1.9%)	1
Voice changes/dysarthria (e.g., hoarseness, loss or alteration in voice, laryngitis)	4/53 (7.5%)	4
Pain - Other (sore throat)	1/53 (1.9%)	1
Skin and subcutaneous tissue disorders
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	1/53 (1.9%)	1
Dermatology/Skin - Other (folliculitis)	1/53 (1.9%)	1
Dry skin	6/53 (11.3%)	6
Hair loss/alopecia (scalp or body)	40/53 (75.5%)	48
Injection site reaction/extravasation changes	3/53 (5.7%)	3
Nail changes	7/53 (13.2%)	7
Pruritus/itching	2/53 (3.8%)	3
Rash/desquamation	16/53 (30.2%)	18
Rash: acne/acneiform	3/53 (5.7%)	3
Rash: hand-foot skin reaction	1/53 (1.9%)	1
Skin breakdown/decubitus ulcer	2/53 (3.8%)	2
Urticaria (hives, welts, wheals)	1/53 (1.9%)	1
Pain - Other (skin/shingles)	1/53 (1.9%)	1
Surgical and medical procedures
Intra-operative injury::Muscle	1/53 (1.9%)	1
Pain - Other (surgical site)	1/53 (1.9%)	1
Vascular disorders
Phlebitis (including superficial thrombosis)	2/53 (3.8%)	2
Thrombosis/embolism (vascular access-related)	4/53 (7.5%)	4
Thrombosis/thrombus/embolism	6/53 (11.3%)	8
Vessel injury-vein::Extremity-upper	1/53 (1.9%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.