Combination Study of Revlimid®, Velcade® Dexamethasone and Doxil® (RVDD)for Newly Diagnosed Multiple Myeloma
Study Details
Study Description
Brief Summary
This research study is evaluating an investigational combination of four drugs called Revlimid® (lenalidomide), Velcade® (bortezomib), Dexamethasone and Doxil® (RVDD) as a possible treatment for newly diagnosed multiple myeloma.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
During the Phase I portion of this clinical trial, the doses of Revlimid® and Doxil® will be increased until the best and safest amount (or dose) is identified in combination with Velcade® and Dexamethasone. "Investigational" means that the drug combination is still being studied and that research doctors are trying to find out more about it such as the safest dose to use, the side effects it may cause and how effective the Velcade®, Doxil®, Dexamethasone and Revlimid® investigational combination is for treating newly diagnosed multiple myeloma. In this clinical trial we are looking for the highest dose of the combination that can be given safely and see how well it works as a combination in newly diagnosed patients.
Each of these drugs, Velcade®, Doxil®, Dexamethasone and Revlimid® are approved by the FDA (U.S. Food and Drug Administration). They have not been approved in this combination for use for your type of cancer or any other type of cancer. Velcade® is currently approved by the United States Food and Drug Administration (US FDA) for the treatment of multiple myeloma patients who have received at least one prior therapy. Doxil® has recently been approved by the US FDA for multiple myeloma in combination with Velcade® in patients who have not previously received Velcade® and have received at least one prior therapy. Dexamethasone is commonly used, either alone, or in combination with other drugs, to treat multiple myeloma. Revlimid® is currently approved by the US FDA in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy.
After the Phase I clinical trial defines the safest doses of Velcade®, Doxil®, Dexamethasone and Revlimid® that can be taken together, the research study will move on to its second portion, a Phase II clinical trial. The Phase II portion of the clinical trial will test the clinical effectiveness of the best dose combination of the four drugs.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Combination Drug Therapy Patients will be treated with Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at indicated doses on day 4, Dexamethasone at 20 mg orally on days of Velcade and the day after for all dose levels, and Revlimid at indicated doses on days 1-14 in 3-week cycles for 4-8 cycles. To determine the MTD of the combination of Revlimid, Velcade, dexamethasone, and Doxil, four dose levels are planned. |
Drug: Lenalidomide
Patients will be treated with Revlimid on days 1-14 in 3-week cycles for 4-8 cycles.
Other Names:
Drug: Bortezomib
Patients will be treated with Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11
Other Names:
Drug: Dexamethasone
Patients will be treated with Dexamethasone at 20 mg orally on days of Velcade and the day after for all dose levels.
Drug: Doxil
Patients will be treated with Doxil on day 4.
|
Outcome Measures
Primary Outcome Measures
- Maximum Tolerated Dose (MTD) of Combination Therapy With VELCADE, Dexamethasone, and Doxil, (RVDD) [1 month post treatment]
Dose Level 1: 15 mg Revlimid daily on days 1-14 followed by 7-day rest every 21 days 1.3 mg/m2 Velcade daily on days 1, 4, 8 and 11 20 mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, 12* and 20 mg/m2 Doxil daily on day 4 Dose Level 2: 20 mg Revlimid daily on days 1-14 followed by 7-day rest every 21 days 1.3 mg/m2 Velcade daily on days 1, 4, 8 and 11 20 mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, 12* and 20 mg/m2 Doxil daily on day 4 Dose Level 3: 25 mg Revlimid daily on days 1-14 followed by 7-day rest every 21 days 1.3 mg/m2 Velcade daily on days 1, 4, 8 and 11 20 mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, 12* and 20 mg/m2 Doxil daily on day 4 Dose Level 4: 25 mg Revlimid daily on days 1-14 followed by 7-day rest every 21 days 1.3 mg/m2 Velcade daily on days 1, 4, 8 and 11 20 mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, 12* and 30 mg/m2 Doxil daily on day 4
Secondary Outcome Measures
- The Percentage of Patients That Achieved Partial or Complete Response to Treatment. [24 weeks (8, 21-day cycles)]
Partial Response: 50% reduction in the level of serum monoclonal protein for at least two determinations six weeks apart. If present, reduction in 24-hour urinary light chain excretion by either, greater than or equal to 90%, or to <200 mg for at least two determinations six weeks apart. 50% reduction in the size of soft tissue plasmacytomas (by clinical or radiographic examination) for at least six weeks. No increase in size or number of lytic bone lesions (development of compression fracture does not exclude response). Complete Response: Disappearance of the original monoclonal protein from the blood and urine on at least two determinations for a minimum of six weeks. <5% plasma cells in the bone marrow on at least two determinations for a minimum of six weeks. No increase in the size or number of lytic bone lesions.
Eligibility Criteria
Criteria
Inclusion Criteria
-
At least 18 years of age at the time of consent
-
Measurable disease
-
All necessary baseline studies completed
-
LVEF (left ventricular ejection fraction) greater than or equal to 50 percent by MUGA (multigated acquisition scan) or ECHO (echocardiogram)
-
Must be able to adhere to study visit schedule
Exclusion
-
Greater than or equal to grade 2 peripheral neuropathy on clinical examination within 14 days of enrollment
-
Renal insufficiency
-
Evidence of mucosal or internal bleeding and/ or platelet refractory.
-
Absolute neutrophil count less than 1000 cells/mm^2 within 14 days of enrollment.
-
Acceptable labs
-
Concomitant medications that include corticosteroids
-
Myocardial infarction within 6 months prior to enrollment, uncontrolled angina, severe uncontrolled ventricular arrhythmias
-
Clinically relevant active infection or serious medical condition that places the subject at unacceptable risk
-
Any condition, including laboratory values that places the subject at an unacceptable risk
-
Another malignancy within 3 years of enrollment, with the exception of the complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low risk prostate cancer after curative therapy
-
Hypersensitivity to bortezomib, boron, or mannitol or any of the components of DOXIL
-
Female subject that is pregnant or breastfeeding.
-
Can not have received any other investigational drugs within 14 days of enrollment
-
Serious medical or psychiatric illness
-
Uncontrolled diabetes mellitus
-
Hypersensitivity to acyclovir or similar antiviral drug
-
POEMS (plasma cell dyscrasia with polyneuropathy)
-
Known HIV
-
Known hepatitis B or C
-
Known intolerance to steroid therapy
-
Known hypersensitivity to required prophylactic mediations
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Emory University Hospital | Atlanta | Georgia | United States | 30322 |
| 2 | The University of Chicago Medical Center | Chicago | Illinois | United States | 60637 |
| 3 | Dana Farber Cancer Institute (and Massachusetts General) | Boston | Massachusetts | United States | 02115 |
| 4 | University of Michigan Comprehensive Cancer Center | Ann Arbor | Michigan | United States | 48109 |
| 5 | The Ohio State University Medical Center | Columbus | Ohio | United States | 43210 |
| 6 | Princess Margaret Hospital | Toronto | Ontario | Canada | M5G 2M9 |
Sponsors and Collaborators
- University of Michigan Rogel Cancer Center
Investigators
- Principal Investigator: Moshe Talpaz, MD, University of Michigan Rogel Cancer Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- UMCC 2007.098
- HUM 12962
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Phase I | Phase II |
|---|---|---|
| Arm/Group Description | Patients will be treated with Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at indicated doses on day 4, Dexamethasone at 20 mg orally on days of Velcade and the day after for all dose levels, and Revlimid at indicated doses on days 1-14 in 3-week cycles for 4-8 cycles. | Patients will be treated with Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at indicated doses on day 4, Dexamethasone at 20 mg orally on days of Velcade and the day after for all dose levels, and Revlimid at indicated doses on days 1-14 in 3-week cycles for 4-8 cycles. |
| Period Title: Overall Study | ||
| STARTED | 42 | 32 |
| COMPLETED | 42 | 32 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Combination Drug Therapy |
|---|---|
| Arm/Group Description | Patients will be treated with Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at indicated doses on day 4, Dexamethasone at 20 mg orally on days of Velcade and the day after for all dose levels, and Revlimid at indicated doses on days 1-14 in 3-week cycles for 4-8 cycles. |
| Overall Participants | 72 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
59
|
| Sex: Female, Male (Count of Participants) | |
| Female |
31
43.1%
|
| Male |
41
56.9%
|
Outcome Measures
| Title | Maximum Tolerated Dose (MTD) of Combination Therapy With VELCADE, Dexamethasone, and Doxil, (RVDD) |
|---|---|
| Description | Dose Level 1: 15 mg Revlimid daily on days 1-14 followed by 7-day rest every 21 days 1.3 mg/m2 Velcade daily on days 1, 4, 8 and 11 20 mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, 12* and 20 mg/m2 Doxil daily on day 4 Dose Level 2: 20 mg Revlimid daily on days 1-14 followed by 7-day rest every 21 days 1.3 mg/m2 Velcade daily on days 1, 4, 8 and 11 20 mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, 12* and 20 mg/m2 Doxil daily on day 4 Dose Level 3: 25 mg Revlimid daily on days 1-14 followed by 7-day rest every 21 days 1.3 mg/m2 Velcade daily on days 1, 4, 8 and 11 20 mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, 12* and 20 mg/m2 Doxil daily on day 4 Dose Level 4: 25 mg Revlimid daily on days 1-14 followed by 7-day rest every 21 days 1.3 mg/m2 Velcade daily on days 1, 4, 8 and 11 20 mg dexamethasone daily on Days 1, 2, 4, 5, 8, 9, 11, 12* and 30 mg/m2 Doxil daily on day 4 |
| Time Frame | 1 month post treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| A total of 74 patients were enrolled in this phase 1/2 study: 42 in phase 1. |
| Arm/Group Title | Combination Drug Therapy |
|---|---|
| Arm/Group Description | Patients will be treated with Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at indicated doses on day 4, Dexamethasone at 20 mg orally on days of Velcade and the day after for all dose levels, and Revlimid at indicated doses on days 1-14 in 3-week cycles for 4-8 cycles. |
| Measure Participants | 42 |
| Revlimid |
25
|
| VELCADE |
1.3
|
| Dexamethasone |
20
|
| Doxil |
30
|
| Title | The Percentage of Patients That Achieved Partial or Complete Response to Treatment. |
|---|---|
| Description | Partial Response: 50% reduction in the level of serum monoclonal protein for at least two determinations six weeks apart. If present, reduction in 24-hour urinary light chain excretion by either, greater than or equal to 90%, or to <200 mg for at least two determinations six weeks apart. 50% reduction in the size of soft tissue plasmacytomas (by clinical or radiographic examination) for at least six weeks. No increase in size or number of lytic bone lesions (development of compression fracture does not exclude response). Complete Response: Disappearance of the original monoclonal protein from the blood and urine on at least two determinations for a minimum of six weeks. <5% plasma cells in the bone marrow on at least two determinations for a minimum of six weeks. No increase in the size or number of lytic bone lesions. |
| Time Frame | 24 weeks (8, 21-day cycles) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 74 patients were enrolled, but 2 were not evaluable for dose limiting toxicities. 72 patients were included in this analysis. |
| Arm/Group Title | Combination Drug Therapy |
|---|---|
| Arm/Group Description | Patients will be treated with Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at indicated doses on day 4, Dexamethasone at 20 mg orally on days of Velcade and the day after for all dose levels, and Revlimid at indicated doses on days 1-14 in 3-week cycles for 4-8 cycles. |
| Measure Participants | 72 |
| Number [percentage of patients] |
96
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | Adverse events were captured collectively for the study, not by arm, because both arms received the same drugs. | |
| Arm/Group Title | Combination Drug Therapy | |
| Arm/Group Description | Patients will be treated with Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at indicated doses on day 4, Dexamethasone at 20 mg orally on days of Velcade and the day after for all dose levels, and Revlimid at indicated doses on days 1-14 in 3-week cycles for 4-8 cycles. | |
All Cause Mortality |
||
| Combination Drug Therapy | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Combination Drug Therapy | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/74 (4.1%) | |
| Infections and infestations | ||
| Pneumonia with Grade 3 or 4 Neutropenia | 1/74 (1.4%) | 1 |
| Pneumonia with Normal Absolute Neutrophil Count | 1/74 (1.4%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Lung Hemorrhage | 1/74 (1.4%) | 1 |
| Pneumonitis | 1/74 (1.4%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Combination Drug Therapy | ||
| Affected / at Risk (%) | # Events | |
| Total | 24/74 (32.4%) | |
| Blood and lymphatic system disorders | ||
| Anemia | 10/74 (13.5%) | 22 |
| Leukocytes (total WBC) | 6/74 (8.1%) | 11 |
| Lymphopenia | 5/74 (6.8%) | 12 |
| Neutrophils/granulocytes (ANC/AGC) | 4/74 (5.4%) | 5 |
| Platelets | 6/74 (8.1%) | 12 |
| Gastrointestinal disorders | ||
| Constipation | 10/74 (13.5%) | 14 |
| Diarrhea | 6/74 (8.1%) | 12 |
| Nausea | 10/74 (13.5%) | 11 |
| Taste alteration (dysgeusia) | 4/74 (5.4%) | 6 |
| General disorders | ||
| Fatigue (asthenia, lethargy, malaise) | 17/74 (23%) | 32 |
| Edema: limb | 6/74 (8.1%) | 6 |
| Metabolism and nutrition disorders | ||
| ALT, SGPT (serum glutamic pyruvic transaminase) | 6/74 (8.1%) | 9 |
| Albumin, serum-low (hypoalbuminemia) | 5/74 (6.8%) | 9 |
| Calcium, serum-low (hypocalcemia) | 6/74 (8.1%) | 12 |
| Glucose, serum-high (hyperglycemia) | 4/74 (5.4%) | 8 |
| Phosphate, serum-low (hypophosphatemia) | 4/74 (5.4%) | 9 |
| Potassium, serum-low (hypokalemia) | 5/74 (6.8%) | 6 |
| Sodium, serum-low (hyponatremia) | 5/74 (6.8%) | 5 |
| Nervous system disorders | ||
| Dizziness | 7/74 (9.5%) | 7 |
| Mood alteration | 5/74 (6.8%) | 5 |
| Neuropathy: sensory | 7/74 (9.5%) | 15 |
| Pain | 4/74 (5.4%) | 5 |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 7/74 (9.5%) | 9 |
| Dyspnea (shortness of breath) | 6/74 (8.1%) | 7 |
| Skin and subcutaneous tissue disorders | ||
| Rash/desquamation | 5/74 (6.8%) | 5 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE 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.
Results Point of Contact
| Name/Title | Dr. Moshe Talpaz |
|---|---|
| Organization | University of Michigan Comprehensive Cancer Center |
| Phone | 734-764-8195 |
| mtalpaz@umich.edu |
- UMCC 2007.098
- HUM 12962