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Primary Treatment of Waldenstrom's Macroglobulinemia With Bortezomib (Velcade) and Rituximab (Rituxan) Followed by Autologous Stem Cell Collection


Phase 2
N/A
N/A
Open (Enrolling)
Both
Waldenstrom's Macroglobulinemia

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Trial Information

Primary Treatment of Waldenstrom's Macroglobulinemia With Bortezomib (Velcade) and Rituximab (Rituxan) Followed by Autologous Stem Cell Collection


Bortezomib is designed to block a protein that plays a role in cell function and growth,
which may cause cancer cells to die.

Rituximab is designed to attach to cancer cells, which may cause them to die.

Cyclophosphamide, vincristine, doxorubicin, and cladribine are designed to interfere with
the multiplication of cancer cells, which may slow or stop their growth and spread
throughout the body. This may cause the cancer cells to die.

Dexamethasone is designed to decrease inflammation. It is also used to treat certain forms
of cancer.

If you are found to be eligible to participate in this study, you will begin taking the
study drugs. You will be given two 35-day cycles of bortezomib and rituximab. Bortezomib
will be given through a needle in a vein over 3-5 seconds on Days 1, 8, 15, and 22.
Rituximab will also be given through a vein on Days 8 and 22. The first rituximab infusion
(by vein) usually takes 6-8 hours. Later infusions are generally shorter, taking about 4
hours to complete. While you are receiving bortezomib/rituximab (for 2-3 months),
valacyclovir (an anti-viral drug) is taken by mouth, once a day.

During the study, before each dose of bortezomib, you will have blood (about 2 teaspoons
each time) drawn for routine tests. Your vital signs will be measured. You will be asked
about any side effects you may have experienced. You will also be asked to answer the
questionnaire about any neuropathy you may have.

Stem cells are the cells from which all blood cells develop. If you respond to the first 2
cycles of bortezomib/rituximab, you will then have some of your stems cells collected. You
will have to sign a separate consent form that describes this procedure and its risks.
After the stem cell collection, 1 cycle of cladribine, cyclophosphamide, and rituximab will
be given. Cladribine will be given through a vein once a day over 2 hours on Days 1-5.
Cyclophosphamide is taken by mouth, twice a day on Days 1-5, and rituximab is given through
a vein once a week for 4 weeks.

If you do not respond to the first cycle of bortezomib/rituximab, you will be taken off the
study.

If you respond to the first but do not respond to the second cycle of bortezomib/rituximab,
you will receive a third cycle. The bortezomib/rituximab will be given in the same manner
as your first 2 cycles.

If you respond to the third cycle of bortezomib/rituximab, you will have some of your stems
cells collected. After the stem cell collection, 1 cycle of cladribine, cyclophosphamide,
and rituximab will be given. Cladribine will be given through a vein once a day over 2
hours on Days 1-5. Cyclophosphamide is taken by mouth, twice a day on Days 1-5, and
rituximab is given through a vein once a week for 4 weeks.

If you do not respond to the third cycle of bortezomib/rituximab, you will be given a
chemotherapy regimen containing the drugs rituximab, cyclophosphamide, vincristine, and
doxorubicin, together with dexamethasone. This combination is known as modified
R-Hyper-CVAD. Rituximab will be given through a vein over about 4 hours on Day 1 only.
Cyclophosphamide will be given through a vein every 12 hours on Days 1-4. Doxorubicin and
vincristine will be given through a vein continuously over 24 hours on Days 1-4.
Dexamethasone is taken by mouth daily on Days 1-4, 9-12, and 17-20.

If a partial response is seen with modified R-Hyper-CVAD, you will have some of your stem
cells collected. You will receive 1 cycle of cladribine, cyclophosphamide, and rituximab.
Cladribine will be given through a vein once a day over 2 hours on Days 1-5.
Cyclophosphamide is taken by mouth, twice a day on Days 1-5, and rituximab is given through
a vein once a week for 4 weeks.

About 1 week before the start of each cycle of chemotherapy, you will have blood (about 4-5
teaspoons) drawn for routine tests and to see how your WM is responding. You may also need
to collect your urine over 24 hours, depending on if the first test was initially positive
or not. You will also have a complete physical exam, including measurement of vital signs,
height, and weight.

If your CT scans were positive initially, you will need to have them repeated after 2 cycles
of bortezomib/rituximab and then every 6 months. Once you have a partial response confirmed
by CT scans, you will not need to repeat the CT scans anymore.

If your disease does not respond to modified R-Hyper-CVAD, you will be taken off the study.

Responding participants will be followed at least every 6 months for the first 36 months
(from the end of therapy). After that, you will be followed at least once a year unless the
disease gets worse and needs to be re-treated. For the follow-up evaluations, you will have
a physical exam, including measurement of vital signs. Blood (about 4 tablespoons) will be
drawn for routine tests. Blood (about 4-5 teaspoons) and urine (over 24 hours) will be
collected to check the status of your WM. If the x-rays and/or CT scans done at the
beginning of the study were positive, you will have repeat x-rays and/or CT scans.

For patients who have not had a partial response, follow-up evaluations will be at least
every 3 months. You will have a physical exam, including measurement of vital signs. Blood
(about 4 tablespoons) will be drawn for routine tests. Blood (about 4-5 tablespoons) and
urine (over 24 hours) will be collected to check the status of your WM.

You will be taken off the study if you do not have a partial or complete response following
3 cycles of bortezomib/rituximab and 2 cycles of modified R-Hyper-CVAD. You will be taken
off the study if the disease gets worse after all planned therapy that the study doctor
feels requires repetition. You will be taken off the study if intolerable side effects
occur. You will be taken off the study if treatment with bortezomib is delayed for more
than 2 weeks. You will be taken off the study if you develop certain other illnesses, or if
there are certain changes in your health that the study doctor decides may make further
treatment with the study drugs to be unacceptable.

Once you are taken off the study, you will have an end-of-study visit. At this visit, a
physical exam, including measurement of vital signs, height, and weight will be performed.
You will be asked about any side effects that you may have experienced. You will be asked
to answer the questionnaire regarding any neuropathy you may have. Blood (about 4-6
teaspoons) will be drawn for routine tests and to check the status of your WM. You will
need to collect your urine over 24 hours to see how your WM is responding. If your initial
CT scans showed lesions that appear to be caused by WM, you will have a CT scan repeated at
this time.

If you have had a partial or complete response at the end of all planned therapy, you will
need to return to the clinic for follow-up visits at least once every 6 months for the first
36 months (from the end of therapy). After that, you will have follow-up visits at least
once a year, unless the disease gets worse and re-treatment is necessary. At the follow-up
visits, you will have a physical exam, including measurement of vital signs, height, and
weight. You will be asked about any side effects that you may have experienced. Blood
(about 4-6 teaspoons) will be drawn for routine tests and to check the status of your WM.
Depending on the results of your original urine tests, you may need to collect your urine
over 24 hours to see how your WM is responding. If your initial CT scans showed lesions
that appear to be caused by WM, you will have CT scans and an x-ray of your chest repeated
at this time.

This is an investigational study. Cyclophosphamide, vincristine, doxorubicin, and rituximab
are commercially available and FDA-approved for treatment of Waldenstrom's
macroglobulinemia. Bortezomib, dexamethasone, cladribine, and the drug combinations used in
this study have been authorized for use in research only. Bortezomib has been FDA approved
and it is registered in Europe for the treatment of multiple myeloma patients who have
received at least one prior therapy. Tests/procedures that are required for this study are
considered to be part of your routine medical care. Up to 38 patients will be enrolled in
this study. All will be enrolled at M. D. Anderson.


Inclusion Criteria:



1. Patients with symptomatic macroglobulinemic lymphoma who have had no prior treatment,
or whose prior treatment has been limited to steroids and/or alpha-interferon, are
eligible. Macroglobulinemic lymphoma includes patients with either biopsy proven
clonal lymphocytic or lymphoplasmacytic proliferation and monoclonal IgM. Also
included are symptomatic patients with clonal proliferation producing a pathologic
monoclonal IgM that causes cryoglobulinemia, peripheral neuropathy or cold agglutinin
hemolytic anemia.

2. Patients must have acceptable liver function (total bilirubin < 2.5mg/dL) and renal
function (creatinine < 2.0mg/dL). Patients with impaired renal function will only be
included if the renal failure is secondary to macroglobulinemic lymphoma (i.e. Bence
Jones proteinuria, cryoglobulinemia, ureteral obstruction due to mass) that might
reverse with improvement of disease.

3. 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.

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

5. Patients must voluntarily sign an informed consent form indicating that they are
aware of the investigational nature of the study, with the understanding that consent
may be withdrawn by the subject at any time without prejudice to future care.

6. Patient has a heart rate (HR) of greater than or equal to 50 bpm.

Exclusion Criteria:

1. Patient has a platelet count of <30x10^9/L within 28 days before enrollment unless
due to >/= 75% marrow infiltration by macroglobulinemic lymphoma or splenomegaly.

2. Patient has an absolute neutrophil count of <1.0x10^9/L within 28 days before
enrollment unless due to >/= 75% marrow infiltration by macroglobulinemic lymphoma.

3. Patient has a calculated or measured creatinine >/= to 2.0mg/dL on baseline
evaluation. Patients with impaired renal function will only be included if the renal
failure is secondary to macroglobulinemic lymphoma (i.e. Bence Jones proteinuria,
cryoglobulinemia, ureteral obstruction due to mass).

4. Patient has >/= Grade 2 peripheral neuropathy on baseline evaluation.

5. Myocardial infarction within 6 months prior to enrollment or has New York Heart
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 ECG
abnormality at Screening has to be documented by the investigator as not medically
relevant.

6. Patient has hypersensitivity to boron, mannitol, or murine proteins.

7. Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum or urine Beta -human chorionic
gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy
testing is not required for post-menopausal or surgically sterilized women.

8. Patient has received other investigational drugs within 14 days before enrollment

9. Patient has a serious medical or psychiatric illness that is likely to interfere with
participation in this clinical study.

10. Eastern Cooperative Oncology Group (ECOG) performance status of > 2.

11. Patient with a "currently active" second malignancy, other than non-melanoma skin
cancer and carcinoma in situ of the cervix, should not be enrolled. Patients are not
considered to have a "currently active" malignancy if they have completed therapy for
a prior malignancy, are disease free from prior malignancies for > 5 years and are
considered by their physician to be at less than 30 % risk of relapse.

12. Patient with a lifetime cumulative dose of > 450 mg/m^2 of anthracyclines.

13. Patients with an active hepatitis B infection.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall response rate to Bortezomib-Rituximab, and autologous stem cell collection rate after induction therapy with Bortezomib-Rituximab

Outcome Time Frame:

Within 1 week prior to the start of each cycle of chemotherapy and every 3 months thereafter until Partial Recovery (PR) achieved

Safety Issue:

No

Principal Investigator

Sheeba Thomas, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

2005-0733

NCT ID:

NCT00492050

Start Date:

August 2006

Completion Date:

Related Keywords:

  • Waldenstrom's Macroglobulinemia
  • Waldenstrom's Macroglobulinemia
  • Macroglobulinemic Lymphoma
  • Stem Cell Collection
  • Bortezomib
  • LDP-341
  • MLN341
  • PS-341
  • Velcade
  • Rituximab
  • Rituxan
  • Waldenstrom Macroglobulinemia

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030