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An Open Label, Single-Arm, Phase 1b/2 Study of the Safety and Efficacy of Combination Treatment With Lenalidomide, Bortezomib, Dexamethasone and Siltuximab (CNTO 328) in Subjects With Newly Diagnosed, Previously Untreated Multiple Myeloma Requiring Systemic Chemotherapy


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Myeloma

Thank you

Trial Information

An Open Label, Single-Arm, Phase 1b/2 Study of the Safety and Efficacy of Combination Treatment With Lenalidomide, Bortezomib, Dexamethasone and Siltuximab (CNTO 328) in Subjects With Newly Diagnosed, Previously Untreated Multiple Myeloma Requiring Systemic Chemotherapy


The Study Drugs:

Siltuximab is designed to block IL-6, which is a protein that plays an important role in the
survival of myeloma cancer cells. This may slow the growth of cancer cells or cause the
cancer cells to die.

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

Lenalidomide is designed to kill the myeloma cells and may change the body's immune system.
It may also interfere with the development of tiny blood vessels that help support tumor
growth. This may slow the growth of cancer cells.

Dexamethasone is a corticosteroid that is similar to a natural hormone made by your body.
Dexamethasone is often given to MM patients in combination with other chemotherapy to treat
cancer.

Study Groups:

If you are found to be eligible to take part in this study, based on when you join the study
you will be enrolled in the Phase I or Phase II portion. If you are in Phase I, you will be
assigned to a dose level of Siltuximab based on when you join this study. Up to 2 dose
levels of Siltuximab will be tested. Three (3) to 6 participants will be enrolled at each
dose level. The first group of participants will receive the highest dose level. If
intolerable side effects are seen in the first group, the next group will receive a lower
dose.

All participants will receive the same dose level of bortezomib, lenalidomide, and
dexamethasone.

After the highest tolerable dose level is found, up to an extra 54 participants will receive
the study drugs at this dose level in the Phase II part of the study.

Study Drug Administration:

Each cycle is 21 days.

Induction Therapy:

On Days 1, 4, 8, and 11 of Cycle 1 up to Cycle 8 (induction therapy), you will receive
bortezomib by vein over 5-10 seconds.

On Days 1-14 of every cycle, you will take lenalidomide by mouth 1 time each day. Swallow
lenalidomide capsules whole with 1 cup (about 8 ounces) of water. Do not break, chew, or
open the capsules.

On Day 1 of every cycle, you will receive Siltuximab by vein over 1 hour.

On Days 1, 2, 4, 5, 8, 9, 11, and 12 of Cycles 1-8 (induction therapy), you will take
dexamethasone by mouth 1 time a day. After 8 cycles, you may continue to take dexamethasone
if the doctor thinks it is needed. Dexamethasone should be taken with food.

You can take the study drugs any time during the day but you should take them at the same
time every day.

If you miss a dose of lenalidomide, take it as soon as you remember on the same day. If you
miss taking your dose for the entire day, take your regular dose the next scheduled day (do
NOT take double your regular dose to make up for the missed dose). If you take more than
the prescribed dose of lenalidomide, you should seek emergency medical care if needed and
contact the study staff right away.

You will be given a study drug dosing calendar for each cycle to record the lenalidomide
and dexamethasone you will be taking at home. Please bring the dosing calendar and pill
bottles to your study visit at the beginning of each new cycle.

If the doctor thinks it is in your best interest, you may have a stem cell transplant
anytime after 4 cycles of induction therapy You will sign a separate consent form that will
describe the procedure and the risks in detail.

Maintenance Phase:

If you want to delay the stem cell transplant, after 4-8 cycles, you will begin the
maintenance phase.

During the maintenance phase:

- You will take lenalidomide on Days 1-14 of each cycle.

- You will receive bortezomib by vein on Days 1 and 8 of each cycle.

- You will take dexamethasone by mouth on Days 1 and 8 of each cycle.

- You will receive Siltuximab by vein on Day 1 of every cycle.

Study Visits:

On Day 1 of Cycle 1:

- You will have a physical exam, including measurement of your height, weight and vital
signs.

- Your medical history will be updated.

- You will be asked to list any drugs you may be taking and if you have had any side
effects.

- Your performance status will be recorded.

- You will have an ECG.

- You will complete 2 questionnaires about your day-to-day activities and quality of
life. They should take about 5 minutes each to complete.

- If you are able to become pregnant, you will have a blood (about 1 teaspoon) pregnancy
test.

On Day 1 of Cycles 2-8:

- You will have a physical exam, including measurement of your height, weight and vital
signs.

- Your performance status will be recorded.

- You will be asked to list any drugs you may be taking and if you have had any side
effects.

- Blood (about 5 tablespoons) will be drawn for routine tests.

- Blood (about 1 teaspoon) and/or urine will be collected to check the status of the
disease. If urine is collected, you will collect the urine over 24 hours. You will be
provided with a container to collect the urine in.

- You will have a neurological exam (Cycles 2-8).

- Blood (about 2 tablespoons) will be drawn for research about how to better treat
myeloma.

- You will complete the questionnaire about your day-to-day activities

On Days 4 of Cycles 1-8:

- Your vital signs will be recorded.

- Blood (about 4 tablespoons) will be drawn for routine tests.

On Days 8 of Cycles 1-8:

- Your vital signs will be recorded.

- Blood (about 4 tablespoons) will be drawn for routine tests. During Cycle 1, this
routine blood draw will include a pregnancy test if you are able to become pregnant.

- Blood (about 2 tablespoons) will be drawn for research about how to better treat
myeloma.

- You will complete the quality-of-life questionnaire.

On Day 11 of Cycles 1-8:

-Blood (about 4 tablespoons) will be drawn for routine tests.

On Day 14 or 15 of Cycles 1-2, blood (about 4 tablespoons) will be drawn for routine tests.

At the end of induction therapy (or if you are going to have a stem cell transplant, at the
end of Cycle 4):

- You will have a physical exam.

- You will have a neurological exam.

- You will be asked to list any drugs you may be taking and if you have had any side
effects.

- Blood (about 5 tablespoons) and urine will be collected for routine tests.

- You will have a skeletal survey to check the status of the disease.

- If the disease completely responds to the study drugs, you will have a bone marrow
aspiration and/or biopsy to check the status of the response.

On Day 1 of Cycles 9 and beyond (Maintenance Therapy):

- You will have a physical exam, including measurement of your vital signs, height, and
weight.

- Your performance status will be recorded.

- You will be asked to list any drugs you may be taking and if you have had any side
effects.

- You will have a neurological exam.

- Blood (about 4 tablespoons) will be drawn for routine tests.

- Blood (about 1 teaspoon) and/or urine will be collected to check the status of the
disease. If urine is collected, you will collect the urine for 24 hours. You will be
provided with a container to collect the urine in.

- If the doctor thinks it is needed, you will have a skeletal survey to check the status
of the disease.

- If the doctor thinks it is needed, you will have an MRI scan or CT scan to check the
status of the disease.

- Blood (about 2 tablespoons) will be drawn for research about how to better treat
myeloma.

- You will complete the questionnaires about your day-to-day activities and quality of
life.

On Day 8 of Cycles 9 and beyond (Maintenance Therapy), blood (about 4 tablespoons) will be
drawn for routine tests.

Pregnancy Tests:

If you are a woman who is able to become pregnant and you have regular or no menstruation,
you will have a blood (about 1 tablespoon) or urine pregnancy test weekly for the first 28
days and then at least every 28 days.

If you are a woman who is able to become pregnant and your cycles are irregular, you will
have a blood (about 1 tablespoon) or urine pregnancy test weekly for the first 28 days then
at least every 14 days.

Length of Study:

You may stay on study for as long as the disease does not get worse, you have not
experienced intolerable side effects, and if the study doctor thinks it is in your best
interest.

End-of-Treatment Visit:

Within 1 month after the last dose of study drugs, you will have an end-of-study visit. At
this visit, the following tests and procedures will be performed:

- Your performance status will be recorded.

- You will be asked to list any drugs you may be taking and if you have had any side
effects.

- You will have a physical exam, including measurement of your height and weight.

- You will have a skeletal survey.

- You will have a bone marrow biopsy to check the status of the disease.

- Blood (about 4 tablespoon) and urine will be collected for routine tests.

Long-Term Follow-Up:

If you go off study for reasons other then the disease getting worse, blood (about 5
tablespoons) will be drawn for routine tests. This will done every 3 months for the first 2
years, every 6 months for Years 3 and 4, and yearly for Years 5 and 6. The long term visits
will be to check disease status, survival, long term side effects, and secondary cancers.

This is an investigational study. Siltuximab is not FDA approved or commercially available.
It is only being used for research at this time. Bortezomib is FDA approved and commercially
available for the front-line treatment of MM. Lenalidomide is FDA approved and commercially
available for the treatment of certain types of myelodysplastic syndrome and for use with
dexamethasone for patients with MM who have received at least 1 therapy. The use of this
drug combination to treat MM is investigational.

Up to 66 patients will take part in this multicenter study. Up to 56 will be enrolled at M.
D. Anderson.


Inclusion Criteria:



1. 1. Multiple Myeloma Diagnosis: Subject was previously diagnosed with multiple myeloma
by the International Myeloma Foundation 2003 Diagnostic Criteria: IMF Diagnostic
Criteria: DIAGNOSTIC CRITERIA: ALL 3 REQUIRED 1. Monoclonal plasma cells in the bone
marrow > 10% and/or presence of a biopsy-proven plasmacytoma 2. Monoclonal protein
present in the serum and/or urine * 3. Myeloma-related organ dysfunction (1 or more)
** ; [C] Calcium elevation in the blood S. Calcium >10.5 mg/l or upper limit of
normal ; [R] Renal insufficiency ; [A] Anemia Hemoglobin < 10 g/dl or 2 g < normal ;
[B] Lytic bone lesions or osteoporosis ***

2. Continuation from Inclusion # 1: *If no monoclonal protein is detected (non-secretory
disease), then > 30% monoclonal bone marrow plasma cells and/or a biopsy-proven
plasmacytoma required ** A variety of other types of end organ dysfunctions can
occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to
support classification of myeloma if proven to be myeloma related. *** If a solitary
(biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the sole
defining criteria, then > 30% plasma cells are required in the bone marrow.

3. Patient must not have been previously treated with any prior systemic therapy for the
treatment of multiple myeloma. Prior treatment of hypercalcemia or spinal cord
compression with corticosteroids does not disqualify the patient (the dose should not
exceed the equivalent of 160 mg of dexamethasone in a 2 week period). Bisphosphonates
are permitted

4. Patients treated with local radiotherapy with or without concomitant exposure to
steroids, for pain control or management of cord/nerve root compression, are
eligible. One week must have lapsed since last date of radiotherapy, which is
recommended to be a limited field. Patients who require concurrent radiotherapy
should have start of the protocol therapy (Cycle 1 Day 1) deferred until the
radiotherapy is completed and one week have passed since the last date of therapy.

5. Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.

6. Females of childbearing potential (FCBP) must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 mIU/mL 10 - 14 days prior to therapy
and repeated again within 24 hours of prescribing lenalidomide and must either commit
to continued abstinence from heterosexual intercourse or begin TWO acceptable methods
of birth control, one highly effective method and one additional effective method AT
THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also
agree to ongoing pregnancy testing. Men must agree to use a latex condom during
sexual contact with a FCBP even if they have had a successful vasectomy. All patients
must be counseled at a minimum of every 28 days about pregnancy precautions and risks
of fetal exposure.

7. Age >/= 18 years at the time of signing Informed Consent.

8. All necessary baseline studies for determining eligibility must be obtained within 28
days prior to enrollment.

9. Subject has a ECOG performance status of 0-2.

10. All study participants must be registered into the mandatory RevAssist® program, and
be willing and able to comply with the requirements of RevAssist®.

11. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients
intolerant to ASA may use warfarin or low molecular weight heparin).

12. Subject must be able to adhere to the study visit schedule and other protocol
requirements.

Exclusion Criteria:

1. Patient has >/=Grade 2 peripheral neuropathy on clinical examination within 14 days
before enrollment.

2. Renal insufficiency (Creatinine Clearance <30 mL/min by Cockroft-Gault formula).

3. Subjects with evidence of mucosal or internal bleeding and/or platelet refractory
(i.e., unable to maintain a platelet count >/= 50,000 cells/mm^3).

4. Subjects with an absolute neutrophil count (ANC) < 1000 cells/mm^3. Growth factors
may not be used to meet ANC eligibility criteria.

5. Total bilirubin > 1.5 mg/dL

6. Subjects with a hemoglobin < 8.0 g/dL (Transfusion are permitted).

7. Aspartate transaminase (AST) (serum glutamic oxaloacetic transaminase, SGOT) and
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase, SGPT) >/= 2 *
Upper Limits of Normal (ULN)

8. 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.

9. Clinically relevant active infection requiring intravenous antibiotics

10. Serious co-morbid medical conditions such as uncontrolled chronic obstructive or
chronic restrictive pulmonary disease, and cirrhosis.

11. Any condition, including laboratory abnormalities, that in the opinion of the
Investigator places the subject at unacceptable risk if he/she were to participate in
the study.

12. Female subject is pregnant or breast-feeding.

13. Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

14. Uncontrolled diabetes mellitus (Fasting Blood Sugar > 400 mg/dl despite medical
treatment)

15. Hypersensitivity to acyclovir or similar anti-viral drug

16. Known history of POEMS syndrome (plasma cell dyscrasia with polyneuropathy,
organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes).

17. Patients with known history of HIV, Hep B and C.

18. Hypersensitivity to boron or mannitol, or compounds containing these components

19. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study
treatment

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum Tolerated Dose (MTD) of Siltuximab

Outcome Description:

Maximum tolerated dose (MTD) defined as follows: At first dose level, if greater than 1 out of 3 patients or greater than 1 out of 6 patients experience dose limiting toxicity (DLT), the dose level exceeds the maximum tolerated dose (MTD). Dose limiting toxicity (DLT) defined as toxicities graded in severity according to the guidelines outlined in the NCI-CTCAE version 4.0.

Outcome Time Frame:

21 days

Safety Issue:

No

Principal Investigator

Jatin J. Shah, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2010-0073

NCT ID:

NCT01531998

Start Date:

May 2012

Completion Date:

Related Keywords:

  • Myeloma
  • Myeloma
  • Multiple Myeloma
  • MM
  • Newly diagnosed
  • Lenalidomide
  • CC-5013
  • Revlimid
  • Bortezomib
  • Velcade
  • LDP-341
  • MLN341
  • PS-341
  • Siltuximab
  • CNTO 328
  • Anti-IL-6 Antibody
  • Dexamethasone
  • Decadron
  • M. D. Anderson Symptom Inventory Module
  • MDASI-MM
  • Questionnaires
  • Surveys
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030