Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Lymphoma, Mantle-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

Mantle Cell Lymphoma

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Anti-Inflammatory Agents

Etoposide

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Prednisone

Rituximab

Vincristine

Bortezomib

Etoposide phosphate

Antineoplastic Agents, Immunological

Immunologic Factors

Combo chemo etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-Rituxan (R) + Bortezomib (B)

At the beginning of part C patients are randomized to receive bortezomib maintenance or observation without bortezomib.

Rituximab is given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) and bortezomib every 3 weeks for 6 cycles.

Rituximab (R)

EPOCH is given with Rituximab and bortezomib every 3 weeks for 6 cycles.

EPOCH

Bortezomib (B)

Bortezomib is given with EPOCH and rituximab every 6 weeks for 12 cycles.

At the beginning of Part C, patients are randomized to receive bortezomib maintenance or be observed w/o bortezomib.

Bortezomib or observation

Wyndham H Wilson, M.D.

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.

...

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.

EPOCH-R Chemotherapy Plus Bortezomib to Treat Mantle Cell Lymphoma

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

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.

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 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.

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.

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.

National Cancer Institute (NCI)

Principal Investigator

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

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.

EPOCH-R+Bortezomib

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.

All Participants

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Wyndham Wilson

Bortezomib maintenance

Bortezomib: Bortezomib is given with EPOCH and rituximab every 3 weeks for 6 cycles.

Bortezomib Maintenance

Observation

Twenty-three patients were not randomized. Sixteen due to neuropathy and seven due to "other" reasons.

Not Randomized

Progression Free Survival (PFS)

Median Overall Survival (OS)

Overall Progression Free Survival

Overall Survival

Count of Participants With Serious and Non-Serious Adverse Events

Overall Response (CR+PR)

Complete Response

Stable Disease

Progressive Disease

Not Evaluable

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

Clinical Response

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 Then Bortezomib + DA-EPOCH-R Induction

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.

Bortezomib Then Bortezomib + Induction

Screening for Randomization

Randomization

Leukemia

Leukemia, Promyelocytic, Acute

Hematologic Diseases

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Acute Graft Versus Host Disease

Acute Promyelocytic Leukemia

Arsenic Trioxide

Combination of arsenic trioxide with bortezomib in the treatment of relapsed acute promyelocytic leukemia

Vikram Mathews, MD. DM

Vikram Mathews

Biju George, MD. DM

Auro Viswabandya, MD. DM

Poonkuzhali Balasubramanian, PhD

Alok Srivastava, MD

Aby Abraham, MD. DM

The clinical outcome of relapsed acute promyelocytic leukemia (APL) is poor with current standard of care approaches. Additionally, standard of care warrants an autologous stem cell transplant to be done once molecular remission is achieved. Unfortunately, the majority of our patients cannot afford this procedure. We have previously reported the clinical outcome of relapsed patients who were managed without a stem cell transplants and showed that the event free survival at 5 years is less than 35%. Pre-clinical data reported from our laboratory demonstrates that there is significant synergy between arsenic trioxide (ATO; which is the accepted standard of care agent for relapsed APL) and Bortezomib (a proteasome inhibitor). We have evaluated this combination extensively in-vitro and this data was accepted as an oral presentation at the American Society of Hematology (ASH) meeting in 2011. More recently we have also reported the potential mechanism for this synergy (Poster at ASH 2012). We also have mouse model data which supports these findings. We plan to move this combination of ATO based therapy combined with Bortezomib to a Phase II clinical trial to validate these observations. The anticipated potential is that we will have a combination therapy that is less expensive, cost effective and safe with comparable clinical outcomes to those treated with the more expensive standard of care which includes an autologous stem cell transplant and which the majority of our patients cannot afford.

Proteasome Inhibition in Acute Promyelocytic Leukemia

Phase II Study to Evaluate the Role of Bortezomib in the Management of Relapsed Acute Promyelocytic Leukemia

Non hematological toxicity to be monitored

1. Proportion of patients that achieve molecular remission at the end of induction
2. Relapse free, event free and overall survival on long term follow up with this protocol.
3. Long term toxicity profile of this combination therapy
4. Duration of cytopenia with this combination in induction
5. Documentation of support care required and total cost of administering this regimen.
6. Performance status prior to consolidation therapy, each maintenance course and at the end of the regimen.
7. Molecular remission status on follow up for 5 years

Christian Medical College, Vellore, India

Professor of Clinical Hematology

Heart and Blood Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Monatide (IMS 3015)

Proteasome Inhibitors

8 Vaccinations on day 2 and 9 in every bortezomib treatment series

peptides derived from antiapoptotic proteins

Lene M Knudsen, M.D

Anti-apoptotic proteins from the Bcl-2 family are known to play a key role in oncogenesis and are overexpressed in myeloma cells. Studies have shown that dendritic cells exposed to proteasome inhibition present exogene antigens better than unexposed dendritic cells. Patients with relapse of multiple myeloma will be offered vaccination with peptides derived from antiapoptotic proteins from the Bcl-2 family in combination with an immunostimulatory adjuvant. The vaccination will be given in relation to treatment with the proteasome inhibitor bortezomib.

Vaccination With Peptides From Anti-apoptotic Proteins in Relapsed Multiple Myeloma

Vaccination With Peptides Derived From Anti-apoptotic Proteins From the Bcl-2 Family, Administered in Combination With Montanide ISA-51 in Relation to Treatment With Proteasome Inhibitors in Patients With Relapsed Multiple Myeloma

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
EPOCH-R Chemotherapy Plus Bortezomib to Treat Mantle Cell Lymphoma	NCT00114738	Lymphoma, Mantl... Mantle Cell Lym...	Rituximab (R) EPOCH Bortezomib (B) Bortezomib Bortezomib or o...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Proteasome Inhibition in Acute Promyelocytic Leukemia	NCT01950611	Relapsed Acute ...	Bortezomib	1 Year - 75 Years	Christian Medical College, Vellore, India
EPOCH-R Chemotherapy Plus Bortezomib to Treat Mantle Cell Lymphoma	NCT00114738	Lymphoma, Mantl... Mantle Cell Lym...	Rituximab (R) EPOCH Bortezomib (B) Bortezomib Bortezomib or o...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Vaccination With Peptides From Anti-apoptotic Proteins in Relapsed Multiple Myeloma	NCT01272466	Relapsed Multip...	peptides derive...	18 Years - 90 Years	Herlev Hospital
Proteasome Inhibition in Acute Promyelocytic Leukemia	NCT01950611	Relapsed Acute ...	Bortezomib	1 Year - 75 Years	Christian Medical College, Vellore, India

Spots Global Cancer Trial Database for proteasome inhibition