PS-341 Alone and PS-341 Plus EPOCH Chemotherapy to Treat Non-Hodgkin's Lymphoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00054665
• Collaborator: (none)
• Enrollment: 50
• Locations: 2
• Arms: 2
• Duration (Months): 76.9
• Patients Per Site: 25
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study will examine the safety and effectiveness of an experimental drug called Bortezomib (PS-341), given alone and in combination with a chemotherapy regimen called Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin and Filgrastim (EPOCH), in treating non-Hodgkin's B-cell lymphoma. In the laboratory, PS-341 kills lymphoma cells and makes them more sensitive to chemotherapy. The EPOCH treatment regimen includes the drugs doxorubicin, etoposide, vincristine, cyclophosphamide, prednisone, and filgrastim.

Patients 18 years of age and older with an aggressive non-Hodgkin's lymphoma that has relapsed after treatment or is not responding to chemotherapy may be eligible for this study. Candidates will be screened with a medical history and physical examination. Other tests that may be required include blood and urine tests; lung function studies; imaging tests such as magnetic resonance imaging, computed tomography and x-rays; and biopsy (surgical removal of a small tissue sample) of tumor, bone marrow, or other tissue.

Upon entering the study, all participants will receive PS-341. The drug is given as a 3- to 5-second intravenous (through a vein) injection twice a week for 2 weeks. This is followed by a 1-week rest. Each 3-week period comprises one treatment cycle. The number of cycles a patient receives depends on how well he or she responds to the drug. Patients who do not have a complete remission or whose tumor grows on this therapy will be offered PS-341 in combination with up to six cycles of EPOCH chemotherapy. The treatment for patients taking

PS-341 plus EPOCH is as follows:

• PS-341, given by 3- to 5-second intravenous (IV) injection on days 1 and 4 of each cycle.

• Doxorubicin, etoposide, and vincristine, given by continuous IV infusion over 4 days, beginning on day 1 and ending on day 5 of each cycle. The drugs are delivered through a lightweight portable infusion pump to an indwelling IV catheter (plastic tube) in a vein.

• Cyclophosphamide, given by IV infusion over 15 minutes on day 5 of each cycle.

• Prednisone, given by mouth (pills) twice a day on days 1 through 5 of each cycle.

• Filgrastim, given by injection under the skin starting on day 6 of each cycle and continuing until the white blood cell count increases or until day 19 of the cycle.

Patients also take a combination of antibiotics 3 days a week during EPOCH to prevent infection while resistance is lowered because of the chemotherapy. Etoposide, doxorubicin, and cyclophosphamide doses are adjusted as needed, based on white blood cell counts of the previous cycle. The first patients in the study will receive a low dose of PS-341. The dose will be increased in subsequent small groups of patients as long as the preceding dose is well tolerated.

Drug therapy for patients who are candidates for bone marrow transplant will be tailored to permit transplantation. Patients who are not eligible for or who choose not to have a bone marrow transplant will be followed at the National Institutes of Health (NIH) every 3 months the first year, every 4 months the second year, every 6 months the third year, and then once a year until their disease progresses or the study ends. Patients may have tumor and bone marrow biopsies, blood draws, and computed tomography (CT) scans periodically to evaluate disease status and drug side effects.

Condition or Disease	Intervention/Treatment	Phase
B-Cell Lymphoma	Drug: PS-341; Drug: Etoposide; Drug: Doxorubicin; Drug: Vincristine; Drug: Cyclophosphamide; Drug: Prednisone; Drug: Filgrastim	Phase 2

Detailed Description

Diffuse large B-cell lymphomas (DLBCL) have been molecularly sub-classified into germinal center like B-cell (GCB) and activated B-cell like (ABC) DLBCL. Clinically, the ABC subtype has a significantly higher rate of drug resistance and lower survival. The ABC subtype has overexpression of nuclear factor-kappa B (NF-kB) with transcriptional activation of B cell lymphoma 2 (bcl-2), which may account for the drug resistance. The ability of NF-kB to inhibit responses to cancer therapeutic agents may also contribute to the refractory clinical behavior of ABC subtype, and inhibition of NF-kB can synergize with the chemotherapy to kill tumor cells. This protocol aims to study the affect of NF-kB inhibition, through proteasome inhibition by PS-341, on response to PS-341 and PS-341 with EPOCH chemotherapy in DLBCL. It will also assess the affect of PS-341 on NF-kB and BCL-2 tumor expression by microarray, and provide information on the specificity of PS-341.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: PS-341 and PS-341 + Epoch Chemotherapy and Molecular Profiling in Relapsed or Refractory Diffuse Large B-Cell Lymphomas
• Study Start Date: Feb 1, 2003
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: PS-341 Alone 1.3 mg/m^2 intravenous injection days 1, 4, 8, 11 every 3 weeks	Drug: PS-341; 1.3 mg/m^2 intravenous injection days 1, 4, 8, 11 every 3 weeks; Other Names: Velcade Bortezomib LDB-341 MLN-341
Experimental: Part B: PS-341 & EPOCH PS-341: level 1: 0.5 mg/m^2 intravenous (IV) days 1, 4; level 2: 1.0 mg/m^2 IV days 1, 4; level 3: 1.5 mg/m^2 IV days 1, 4; level 4: 1.7 mg/m^2 IV days 1, 4. EPOCH: Etoposide: 50 mg/m^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion; Doxorubicin: 10 mg/m^2 day CIV days 1-4, 96 hour infusion; Vincristine: 0.4 mg/m^2 day CIV days 1-4, 96 hour infusion; Cyclophosphamide: 750 mg/m^2 day IV day 5 bolus; Prednisone: 60 mg/m^2 by mouth twice a day days 1-5; Filgrastim: 300 micrograms subcutaneously days 6 to absolute neutrophil count recovery greater than or equal to 5000/mm^3. Repeat cycles every 21 days.	Drug: PS-341; 1.3 mg/m^2 intravenous injection days 1, 4, 8, 11 every 3 weeks; Other Names: Velcade Bortezomib LDB-341 MLN-341 ; Drug: Etoposide; 50 mg/m^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion. Repeat cycle every 21 days.; Other Names: Vepesid VP-16 ; Drug: Doxorubicin; 10 mg/m^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.; Other Names: Adriamycin ; Drug: Vincristine; 0.4 mg/m^2 day CIV days 1-4, 96 hour infusion. Repeat cycle every 21 days.; Other Names: Oncovin ; Drug: Cyclophosphamide; 750 mg/m^2 day IV day 5 bolus. Repeat cycle every 21 days.; Other Names: Cytoxan ; Drug: Prednisone; 60 mg/m^2 by mouth twice a day days 1-5. Repeat cycle every 21 days.; Other Names: Deltasone ; Drug: Filgrastim; 300 micrograms subcutaneously days 6 to absolute neutrophil count recovery greater than or equal to 5000/mm^3. Repeat cycle every 21 days.; Other Names: Neupogen

Outcome Measures

Primary Outcome Measures

1. Clinical Response Rate [18 weeks]

   Clinical Response Rate is the number of participants with a partial and complete response assessed by the criteria for lymphoma. A complete response is complete 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. Partial response is a greater than or equal to 50% decrease 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

2. Number of Participants With Adverse Events [43 months]

   Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• ELIGIBILITY CRITERIA:

Large B-cell lymphoma (subtypes: DLBCL (diffuse large B-cell lymphoma);

mediastinal (thymic) large B-cell lymphoma;

transformed large B-cell lymphoma;

follicular grade IIIB large B-cell lymphoma;

intravascular large B-cell lymphoma).

Confirmed pathological diagnosis at the treating institution.

Prior anthracycline-based treatment.

Age greater than or equal to 18 years.

Available tumor tissue for biopsy.

Eastern Cooperative Oncology Group (ECOG) performance 2 or better.

Major organ function: Absolute neutrophil count (ANC) greater than or equal to 1,000/microliters,

Platelet greater than or equal to 50,000/microliters,

creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than 60 cc/min;

serum glutamic pyruvic transaminase (SGPT) less than 5 x upper limit of normal;

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 percent unconjugated; unless impairment due to organ involvement by lymphoma.

Informed consent and willingness to use contraception by both men and women.

Not pregnant or nursing because of an unknown potential for teratogenic or abortifacient effects.

Both male and female patients must be willing to use adequate contraception.

Human immunodeficiency virus (HIV) serology negative.

HIV positive patients receiving combination anti-retroviral therapy are excluded from the study because of positive pharmacokinetic interactions with PS-341 or the combination of PS-341 and EPOCH.

Additionally, the biology of HIV associated DLBCL's is often quite different from HIV negative disease due to involvement of Epstein Barr Virus (EBV).

Hepatitis B surface antigen negative.

No symptomatic cardiac disease or cardiac ejection fraction less than 40 percent (in patients receiving EPOCH).

No active central nervous system (CNS) lymphoma.

No systemic cytotoxic or experimental treatments within 4 weeks of treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Cancer Institute (NCI)	Bethesda	Maryland	United States	20892
2	Roswell Parck Cancer Institute	Buffalo	New York	United States	14263

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Wyndham Wilson, M.D., National Cancer Institute, National Institutes of Health

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page
• CTCv2.0

Publications

• Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649-83. Review.
• Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, Shovlin M, Jaffe ES, Janik JE, Staudt LM, Wilson WH. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009 Jun 11;113(24):6069-76. doi: 10.1182/blood-2009-01-199679. Epub 2009 Apr 20.

• Responsible Party: Wyndham Wilson, Dr. Wyndham Wilson, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00054665
• Other Study ID Numbers: 030096; 03-C-0096; NCT00057902
• First Posted: Feb 6, 2003
• Last Update Posted: Sep 11, 2012
• Last Verified: Aug 1, 2012

• Keywords provided by Wyndham Wilson, Dr. Wyndham Wilson, National Cancer Institute (NCI): BCL-2; NFK-B; Drug Resistance; Translational; Lymphoma; Large B-Cell Lymphoma
• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell; Prednisone; Cyclophosphamide; Doxorubicin; Etoposide; Vincristine; Bortezomib

Study Results

Participant Flow

Pre-assignment Detail	1 patient was deemed ineligible and did not receive any treatment. In addition, per the protocol, patients who require an immediate treatment response for medical reasons will only receive part B of the protocol. This decision will be made by the principal investigator in consultation with the associate investigators (e.g. participants can skip A)

Arm/Group Title	Part A: PS-341 Alone	Part B: PS-341 & EPOCH
Arm/Group Description	1.3 mg/m^2 intravenous bolus injection over 3-5 seconds every 3 weeks.Per the protocol, patients who require an immediate treatment response for medical reasons will only receive part B of the protocol. This decision will be made by the principal investigator in consultation with the associate investigators.	PS-341 1.3 mg/m^2 intravenous bolus injection over 3-5 seconds every 3 weeks. EPOCH (etoposide 50 mg/m^2 day continuous intravenous infusion days 1-4, doxorubicin 10 mg/m^2 day continuous intravenous infusion days 1-4, vincristine 0.4 mg/m^2/day continuous intravenous infusion days 1-4, cyclophosphamide 750 mg/m^2 intravenous bolus day 5, prednisone 60 mg/m^2 by mouth days 1-5, and filgrastim 300 micrograms subcutaneously day 6 to absolute neutrophil count (ANC) recovery >/= 5000/mm^3.Per the protocol, patients who require an immediate treatment response for medical reasons will only receive part B of the protocol. This decision will be made by the principal investigator in consultation with the associate investigators.
Period Title: Part A
STARTED	23	0
COMPLETED	23	0
NOT COMPLETED	0	0
Period Title: Part A
STARTED	0	44
COMPLETED	0	44
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm A & B: PS-341 and PS-341 & EPOCH
Arm/Group Description	Part A: PS-341 Alone 1.3 mg/m^2 intravenous injection days 1, 4, 8, 11 every 3 weeks Part B: PS-341 & EPOCH PS-341: level 1: 0.5 mg/m^2 intravenous (IV) days 1, 4; level 2: 1.0 mg/m^2 IV days 1, 4; level 3: 1.5 mg/m^2 IV days 1, 4; level 4: 1.7 mg/m^2 IV days 1, 4. EPOCH: Etoposide: 50 mg/m^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion; Doxorubicin: 10 mg/m^2 day CIV days 1-4, 96 hour infusion; Vincristine: 0.4 mg/m^2 day CIV days 1-4, 96 hour infusion; Cyclophosphamide: 750 mg/m^2 day IV day 5 bolus; Prednisone: 60 mg/m^2 by mouth twice a day days 1-5; Filgrastim: 300 micrograms subcutaneously days 6 to absolute neutrophil count recovery greater than or equal to 5000/mm^3. Repeat cycles every 21 days
Overall Participants	50
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	36 72%
>=65 years	14 28%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.04 (16.46)
Sex: Female, Male (Count of Participants)
Female	14 28%
Male	36 72%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2%
Not Hispanic or Latino	48 96%
Unknown or Not Reported	1 2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 8%
White	45 90%
More than one race	0 0%
Unknown or Not Reported	1 2%
Region of Enrollment (participants) [Number]
United States	50 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Response Rate
Description	Clinical Response Rate is the number of participants with a partial and complete response assessed by the criteria for lymphoma. A complete response is complete 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. Partial response is a greater than or equal to 50% decrease 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
Time Frame	18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part A: PS-341 Alone	Part B: PS-341 & EPOCH
Arm/Group Description	1.3 mg/m^2 intravenous injection days 1, 4, 8, 11 every 3 weeks	PS-341: level 1: 0.5 mg/m^2 intravenous (IV) days 1, 4; level 2: 1.0 mg/m^2 IV days 1, 4; level 3: 1.5 mg/m^2 IV days 1, 4; level 4: 1.7 mg/m^2 IV days 1, 4. EPOCH: Etoposide: 50 mg/m^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion; Doxorubicin: 10 mg/m^2 day CIV days 1-4, 96 hour infusion; Vincristine: 0.4 mg/m^2 day CIV days 1-4, 96 hour infusion; Cyclophosphamide: 750 mg/m^2 day IV day 5 bolus; Prednisone: 60 mg/m^2 by mouth twice a day days 1-5; Filgrastim: 300 micrograms subcutaneously days 6 to absolute neutrophil count recovery greater than or equal to 5000/mm^3. Repeat cycle every 21 days.
Measure Participants	23	44
Partial response	1 2%	7 NaN
Complete response	0 0%	8 NaN

2. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part A: PS-341 Alone	Part B: PS-341 & EPOCH
Arm/Group Description	Part A: 1.3 mg/m^2 intravenous injection days 1, 4, 8, 11 every 3 weeks	Part B: PS-341: level 1: 0.5 mg/m^2 intravenous (IV) days 1, 4; level 2: 1.0 mg/m^2 IV days 1, 4; level 3: 1.5 mg/m^2 IV days 1, 4; level 4: 1.7 mg/m^2 IV days 1, 4. EPOCH: Etoposide: 50 mg/m^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion; Doxorubicin: 10 mg/m^2 day CIV days 1-4, 96 hour infusion; Vincristine: 0.4 mg/m^2 day CIV days 1-4, 96 hour infusion; Cyclophosphamide: 750 mg/m^2 day IV day 5 bolus; Prednisone: 60 mg/m^2 by mouth twice a day days 1-5; Filgrastim: 300 micrograms subcutaneously days 6 to absolute neutrophil count recovery greater than or equal to 5000/mm^3. Repeat cycle every 21 days.
Measure Participants	23	44
Number [Participants]	23 46%	44 NaN

Adverse Events

Arm/Group Title	Part A: PS-341 Alone		Part B: PS-341 & EPOCH
Arm/Group Description	PS-341 1.3 mg/m^2 intravenous injection days 1, 4, 8, 11 every 3 weeks		PS-341: level 1: 0.5 mg/m^2 intravenous (IV) days 1, 4; level 2: 1.0 mg/m^2 IV days 1, 4; level 3: 1.5 mg/m^2 IV days 1, 4; level 4: 1.7 mg/m^2 IV days 1, 4. EPOCH: Etoposide: 50 mg/m^2 day continuous intravenous infusion (CIV) days 1-4, 96 hour infusion; Doxorubicin: 10 mg/m^2 day CIV days 1-4, 96 hour infusion; Vincristine: 0.4 mg/m^2 day CIV days 1-4, 96 hour infusion; Cyclophosphamide: 750 mg/m^2 day IV day 5 bolus; Prednisone: 60 mg/m^2 by mouth twice a day days 1-5; Filgrastim: 300 micrograms subcutaneously days 6 to absolute neutrophil count recovery greater than or equal to 5000/mm^3. Repeat cycles every 21 days.
All Cause Mortality
	Part A: PS-341 Alone		Part B: PS-341 & EPOCH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Part A: PS-341 Alone		Part B: PS-341 & EPOCH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/24 (87.5%)		40/44 (90.9%)
Blood and lymphatic system disorders
Hemoglobin	6/24 (25%)	18	17/44 (38.6%)	39
Leukocytes (total WBC)	7/24 (29.2%)	8	17/44 (38.6%)	43
Leukocytes (total WBC) for BMT studies, if specified in the protocol.	1/24 (4.2%)	1	0/44 (0%)	0
Lymphopenia	5/24 (20.8%)	8	13/44 (29.5%)	25
Neutrophils/granulocytes (ANC/AGC)	5/24 (20.8%)	6	21/44 (47.7%)	41
Platelets	12/24 (50%)	27	33/44 (75%)	80
Transfusion: Platelets	1/24 (4.2%)	1	12/44 (27.3%)	22
Transfusion: pRBCs	1/24 (4.2%)	1	13/44 (29.5%)	19
Cardiac disorders
Vasovagal episode	1/24 (4.2%)	1	0/44 (0%)	0
Hypotension	4/24 (16.7%)	7	11/44 (25%)	13
Prolonged QTc interval (QTc > 0.48 seconds)	0/24 (0%)	0	1/44 (2.3%)	1
Ventricular arrhythmia (PVCs/bigeminy/trigeminy/ventricular tachycardia)	0/24 (0%)	0	1/44 (2.3%)	1
Ear and labyrinth disorders
Inner ear/hearing	0/24 (0%)	0	1/44 (2.3%)	1
Eye disorders
Ocular/Visual-Other (Specify, periorbital edema)	1/24 (4.2%)	1	0/44 (0%)	0
Gastrointestinal disorders
Anorexia	4/24 (16.7%)	4	8/44 (18.2%)	8
Constipation	1/24 (4.2%)	3	6/44 (13.6%)	6
Diarrhea patients without colostomy	7/24 (29.2%)	9	11/44 (25%)	16
Nausea	7/24 (29.2%)	8	12/44 (27.3%)	17
Stomatitis/pharyngitis (oral/pharyngeal mucositis)	2/24 (8.3%)	2	8/44 (18.2%)	14
Taste disturbance (dysgeusia)	3/24 (12.5%)	3	6/44 (13.6%)	6
Vomiting	1/24 (4.2%)	1	5/44 (11.4%)	7
Abdominal pain or cramping	3/24 (12.5%)	3	5/44 (11.4%)	6
Dehydration	0/24 (0%)	0	1/44 (2.3%)	1
Dysphagia, esophagitis, odynophagia (painful swallowing)	0/24 (0%)	0	1/44 (2.3%)	1
Flatulence	0/24 (0%)	0	1/44 (2.3%)	1
Gastrointestinal-Other	0/24 (0%)	0	2/44 (4.5%)	2
Ileus (or neuroconstipation)	0/24 (0%)	0	1/44 (2.3%)	1
Rectal bleeding/hematochezia	0/24 (0%)	0	2/44 (4.5%)	2
General disorders
Edema	1/24 (4.2%)	1	5/44 (11.4%)	6
Fatigue (lethargy, malaise, asthenia)	8/24 (33.3%)	9	10/44 (22.7%)	14
Fever (in the absence of neutropenia, where neutropenia is defined as AGC<	3/24 (12.5%)	3	3/44 (6.8%)	3
Rigors, chills	1/24 (4.2%)	1	0/44 (0%)	0
Sweating (diaphoresis)	1/24 (4.2%)	1	0/44 (0%)	0
Weight loss	0/24 (0%)	0	2/44 (4.5%)	2
Pain-Other (Specify, testicular)	0/24 (0%)	0	1/44 (2.3%)	1
Constitutional Symptoms-Other (Specify, generalized weakness)	0/24 (0%)	0	1/44 (2.3%)	1
Hepatobiliary disorders
Alkaline phosphatase	1/24 (4.2%)	1	3/44 (6.8%)	5
Hypoalbuminemia	1/24 (4.2%)	1	9/44 (20.5%)	11
SGOT (AST) (serum glutamic oxaloacetic transaminase)	2/24 (8.3%)	4	4/44 (9.1%)	5
SGPT (ALT) (serum glutamic pyruvic transaminase)	3/24 (12.5%)	3	3/44 (6.8%)	4
Bilirubin	0/24 (0%)	0	3/44 (6.8%)	4
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	1/24 (4.2%)	1	0/44 (0%)	0
Infections and infestations
Febrile neutropenia	0/24 (0%)	0	5/44 (11.4%)	6
Infection	0/24 (0%)	0	9/44 (20.5%)	12
Infection with unknown ANC	0/24 (0%)	0	1/44 (2.3%)	1
Infection without neutropenia	0/24 (0%)	0	7/44 (15.9%)	13
Investigations
Partial thromboplastin time (PTT)	3/24 (12.5%)	3	4/44 (9.1%)	5
Prothrombin time (PT)	1/24 (4.2%)	1	1/44 (2.3%)	1
Bicarbonate	0/24 (0%)	0	1/44 (2.3%)	1
Metabolism and nutrition disorders
Hypocalcemia	1/24 (4.2%)	1	4/44 (9.1%)	8
Hypoglycemia	1/24 (4.2%)	2	0/44 (0%)	0
Hypokalemia	1/24 (4.2%)	2	5/44 (11.4%)	6
Hypomagnesemia	2/24 (8.3%)	3	4/44 (9.1%)	6
Hyponatremia	1/24 (4.2%)	2	4/44 (9.1%)	5
Hyperglycemia	0/24 (0%)	0	10/44 (22.7%)	14
Hypermagnesemia	0/24 (0%)	0	1/44 (2.3%)	1
Hyperuricemia	0/24 (0%)	0	3/44 (6.8%)	4
Hypophosphatemia	0/24 (0%)	0	2/44 (4.5%)	2
Musculoskeletal and connective tissue disorders
Arthralgia (joint pain)	1/24 (4.2%)	1	1/44 (2.3%)	1
Myalgia (muscle pain)	3/24 (12.5%)	4	1/44 (2.3%)	1
Muscle weakness (not due to neuropathy)	0/24 (0%)	0	7/44 (15.9%)	8
Bone pain	0/24 (0%)	0	3/44 (6.8%)	3
Chest pain (non-cardiac and non-pleuritic)	0/24 (0%)	0	1/44 (2.3%)	1
Nervous system disorders
Ataxia (incoordination)	1/24 (4.2%)	1	1/44 (2.3%)	1
Dizziness/lightheadedness	2/24 (8.3%)	3	4/44 (9.1%)	7
Neuropathy - motor	1/24 (4.2%)	1	2/44 (4.5%)	2
Neuropathy-sensory	5/24 (20.8%)	5	8/44 (18.2%)	10
Syncope (fainting)	1/24 (4.2%)	2	1/44 (2.3%)	1
Headache	1/24 (4.2%)	1	1/44 (2.3%)	1
Neuropathic pain	1/24 (4.2%)	4	1/44 (2.3%)	1
Neurology-Other (Specify)	0/24 (0%)	0	4/44 (9.1%)	4
Psychiatric disorders
Insomnia	0/24 (0%)	0	3/44 (6.8%)	3
Mood alteration-anxiety agitation	0/24 (0%)	0	1/44 (2.3%)	1
Renal and urinary disorders
Creatinine	0/24 (0%)	0	1/44 (2.3%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/24 (0%)	0	1/44 (2.3%)	2
Dyspnea (shortness of breath)	0/24 (0%)	0	4/44 (9.1%)	5
Hiccoughs (hiccups, singultus)	0/24 (0%)	0	1/44 (2.3%)	1
Voice changes/stridor/larynx (e.g., hoarseness, loss of voice, laryngitis)	0/24 (0%)	0	1/44 (2.3%)	1
Hypoxia	0/24 (0%)	0	1/44 (2.3%)	1
Pulmonary-Other (Specify, wheezing)	0/24 (0%)	0	2/44 (4.5%)	2
Skin and subcutaneous tissue disorders
Bruising (in absence of grade 3 or 4 thrombocytopenia)	1/24 (4.2%)	2	0/44 (0%)	0
Rash/desquamation	3/24 (12.5%)	3	0/44 (0%)	0
Urticaria (hives, welts, wheals)	1/24 (4.2%)	2	0/44 (0%)	0
Nail changes	0/24 (0%)	0	1/44 (2.3%)	1
Pruritus	0/24 (0%)	0	1/44 (2.3%)	1
Other (Not Including Serious) Adverse Events
	Part A: PS-341 Alone		Part B: PS-341 & EPOCH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/24 (100%)		44/44 (100%)
Blood and lymphatic system disorders
Hemoglobin	5/24 (20.8%)	5	26/44 (59.1%)	40
Leukocytes (total WBC)	5/24 (20.8%)	5	25/44 (56.8%)	48
Lymphopenia	6/24 (25%)	8	14/44 (31.8%)	22
Neutrophils/granulocytes (ANC/AGC)	2/24 (8.3%)	2	26/44 (59.1%)	46
Platelets	4/24 (16.7%)	10	14/44 (31.8%)	26
Transfusion: pRBCs	1/24 (4.2%)	1	18/44 (40.9%)	21
Transfusion: Platelets	0/24 (0%)	0	3/44 (6.8%)	3
Cardiac disorders
Phlebitis (superficial)	1/24 (4.2%)	1	1/44 (2.3%)	1
Sinus tachycardia	0/24 (0%)	0	4/44 (9.1%)	4
Supraventricular arrhythmias (SVT/atrial fibrillation/flutter)	0/24 (0%)	0	2/44 (4.5%)	2
Hypertension	0/24 (0%)	0	1/44 (2.3%)	1
Hypotension	0/24 (0%)	0	4/44 (9.1%)	5
Pericardial effusion/pericarditis	0/24 (0%)	0	1/44 (2.3%)	1
Thrombosis/embolism	0/24 (0%)	0	3/44 (6.8%)	3
Endocrine disorders
Hot flashes/flushes	0/24 (0%)	0	2/44 (4.5%)	2
Eye disorders
Dry eye	0/24 (0%)	0	1/44 (2.3%)	1
Gastrointestinal disorders
Anorexia	7/24 (29.2%)	7	7/44 (15.9%)	8
Constipation	7/24 (29.2%)	7	9/44 (20.5%)	13
Dehydration	1/24 (4.2%)	1	6/44 (13.6%)	7
Diarrhea patients without colostomy	3/24 (12.5%)	6	6/44 (13.6%)	6
Dyspepsia/heartburn	2/24 (8.3%)	2	2/44 (4.5%)	2
Flatulence	1/24 (4.2%)	1	4/44 (9.1%)	4
Mouth dryness	2/24 (8.3%)	2	1/44 (2.3%)	1
Nausea	2/24 (8.3%)	4	13/44 (29.5%)	15
Taste disturbance (dysgeusia)	2/24 (8.3%)	3	3/44 (6.8%)	3
Vomiting	3/24 (12.5%)	4	7/44 (15.9%)	9
Rectal bleeding/hematochezia	1/24 (4.2%)	1	1/44 (2.3%)	1
Abdominal pain or cramping	6/24 (25%)	9	7/44 (15.9%)	8
Dysphagia, esophagitis, odynophagia (painful swallowing)	0/24 (0%)	0	2/44 (4.5%)	2
Gastrointestinal-Other (Specify)	0/24 (0%)	0	3/44 (6.8%)	5
Stomatitis/pharyngitis (oral/pharyngeal mucositis)	0/24 (0%)	0	19/44 (43.2%)	26
General disorders
Edema	6/24 (25%)	6	2/44 (4.5%)	3
Fatigue (lethargy, malaise, asthenia)	1/24 (4.2%)	1	10/44 (22.7%)	12
Fever	3/24 (12.5%)	4	9/44 (20.5%)	11
Weight gain	1/24 (4.2%)	1	0/44 (0%)	0
Pain due to radiation	1/24 (4.2%)	1	0/44 (0%)	0
Pain-Other (Specify)	1/24 (4.2%)	2	3/44 (6.8%)	3
Constitutional Symptoms-Other (Specify, disease progression)	0/24 (0%)	0	1/44 (2.3%)	1
Rigors, chills	0/24 (0%)	0	1/44 (2.3%)	1
Sweating (diaphoresis)	0/24 (0%)	0	2/44 (4.5%)	2
Weight loss	0/24 (0%)	0	6/44 (13.6%)	6
Hepatobiliary disorders
Alkaline phosphatase	3/24 (12.5%)	3	4/44 (9.1%)	4
Hypoalbuminemia	3/24 (12.5%)	4	21/44 (47.7%)	25
Hyperglycemia	4/24 (16.7%)	6	15/44 (34.1%)	21
Bilirubin	0/24 (0%)	0	7/44 (15.9%)	7
SGOT (aspartate aminotransferase (AST)) (serum glutamic oxaloacetic transaminase)	0/24 (0%)	0	4/44 (9.1%)	4
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	1/24 (4.2%)	1	2/44 (4.5%)	2
Infections and infestations
Infection (documented clinically or microbiologically) with grade 3 or 4	1/24 (4.2%)	1	7/44 (15.9%)	9
Infection without neutropenia	5/24 (20.8%)	12	5/44 (11.4%)	6
Infection with unknown ANC	1/24 (4.2%)	1	0/44 (0%)	0
Febrile neutropenia	0/24 (0%)	0	6/44 (13.6%)	7
Injury, poisoning and procedural complications
Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia	1/24 (4.2%)	1	1/44 (2.3%)	1
Hemorrhage-Other (Specify, L. eye)	1/24 (4.2%)	1	0/44 (0%)	0
Investigations
Prothrombin time (PT)	1/24 (4.2%)	1	3/44 (6.8%)	5
Partial thromboplastin time (PTT)	0/24 (0%)	0	8/44 (18.2%)	8
SGPT (alanine aminotransferase (ALT)) (serum glutamic pyruvic transaminase)	0/24 (0%)	0	9/44 (20.5%)	11
Bicarbonate	0/24 (0%)	0	1/44 (2.3%)	2
Metabolism and nutrition disorders
Amylase	1/24 (4.2%)	1	0/44 (0%)	0
Hypercalcemia	2/24 (8.3%)	2	2/44 (4.5%)	2
Hyperkalemia	2/24 (8.3%)	2	2/44 (4.5%)	3
Hypermagnesemia	1/24 (4.2%)	1	9/44 (20.5%)	13
Hypernatremia	1/24 (4.2%)	1	3/44 (6.8%)	3
Hypocalcemia	4/24 (16.7%)	5	16/44 (36.4%)	20
Hypoglycemia	3/24 (12.5%)	4	1/44 (2.3%)	1
Hypokalemia	1/24 (4.2%)	2	15/44 (34.1%)	24
Hypomagnesemia	2/24 (8.3%)	2	14/44 (31.8%)	20
Hyponatremia	1/24 (4.2%)	1	18/44 (40.9%)	24
Hypophosphatemia	0/24 (0%)	0	7/44 (15.9%)	8
Lipase	0/24 (0%)	0	1/44 (2.3%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness (not due to neuropathy)	1/24 (4.2%)	1	2/44 (4.5%)	2
Bone pain	3/24 (12.5%)	4	8/44 (18.2%)	8
Chest pain (non-cardiac and non-pleuritic)	1/24 (4.2%)	1	2/44 (4.5%)	2
Myalgia (muscle pain)	5/24 (20.8%)	6	12/44 (27.3%)	14
Musculoskeletal-Other (Specify, degenerative changes-L. spine)	1/24 (4.2%)	1	0/44 (0%)	0
Arthralgia (joint pain)	0/24 (0%)	0	6/44 (13.6%)	8
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain (onset or exacerbation of tumor pain due to treatment)	2/24 (8.3%)	2	0/44 (0%)	0
Nervous system disorders
Dizziness/lightheadedness	1/24 (4.2%)	1	4/44 (9.1%)	4
Insomnia	2/24 (8.3%)	2	4/44 (9.1%)	4
Neuropathy-sensory	2/24 (8.3%)	2	12/44 (27.3%)	13
Tremor	1/24 (4.2%)	1	0/44 (0%)	0
Headache	2/24 (8.3%)	2	4/44 (9.1%)	4
Confusion	0/24 (0%)	0	2/44 (4.5%)	2
Depressed level of consciousness	0/24 (0%)	0	1/44 (2.3%)	1
Neurologic-Other (Specify)	0/24 (0%)	0	1/44 (2.3%)	1
Syncope (fainting)	0/24 (0%)	0	2/44 (4.5%)	2
Vertigo	0/24 (0%)	0	1/44 (2.3%)	1
Neuropathic pain (e.g. jaw pain, neurologic pain, phantom pain, limb pain, post-infectious neuralgi	0/24 (0%)	0	2/44 (4.5%)	3
Psychiatric disorders
Mood alteration-depression	0/24 (0%)	0	1/44 (2.3%)	1
Renal and urinary disorders
Dysuria (painful urination)	1/24 (4.2%)	1	0/44 (0%)	0
Urinary frequency/urgency	1/24 (4.2%)	1	0/44 (0%)	0
Creatinine	0/24 (0%)	0	6/44 (13.6%)	9
Incontinence	0/24 (0%)	0	1/44 (2.3%)	1
Urinary retention	0/24 (0%)	0	1/44 (2.3%)	1
Reproductive system and breast disorders
Pelvic pain	2/24 (8.3%)	3	0/44 (0%)	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/24 (4.2%)	1	0/44 (0%)	0
Cough	3/24 (12.5%)	4	4/44 (9.1%)	4
Dyspnea (shortness of breath)	3/24 (12.5%)	3	0/44 (0%)	0
Pleural effusion (non-malignant)	1/24 (4.2%)	1	3/44 (6.8%)	3
Apnea	0/24 (0%)	0	1/44 (2.3%)	1
Dyspnea (shortness of breath)	0/24 (0%)	0	10/44 (22.7%)	11
Hiccoughs (hiccups, singultus)	0/24 (0%)	0	1/44 (2.3%)	2
Hypoxia	0/24 (0%)	0	4/44 (9.1%)	4
Pulmonary-Other (Specify, wheezing)	0/24 (0%)	0	2/44 (4.5%)	2
Voice changes/stridor/larynx (e.g., hoarseness, loss of voice, laryngitis)	0/24 (0%)	0	2/44 (4.5%)	2
Skin and subcutaneous tissue disorders
Pruritus	1/24 (4.2%)	1	2/44 (4.5%)	2
Rash/desquamation	1/24 (4.2%)	1	4/44 (9.1%)	4
Alopecia	0/24 (0%)	0	6/44 (13.6%)	6
Nail changes	0/24 (0%)	0	1/44 (2.3%)	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.