Multiple Myeloma
Conditions
Keywords
multiple myeloma, refractory, relapsed, bortezomib, doxil
Brief summary
This is a phase II, multicenter, open label, nonrandomized study to evaluate the efficacy and safety of lenalidomide at a dose of 10 mg/dose in combination with bortezomib at 1.0 mg/m2/dose, pegylated liposomal doxorubicin (PLD) at 4.0 mg/m2/dose, and intravenous (IV) dexamethasone at 40 mg/dose in adult patients with relapsed/refractory multiple myeloma (MM). The study consists of a screening period, followed by up to eight 28 day open label treatment cycles, a final assessment to occur 28 days after the end of the last treatment cycle, and a follow-up period.
Detailed description
Studies have shown that combinations of PLD and bortezomib have striking synergy in preclinical studies and impressive response rates (73 & 89%) in early clinical trials for MM patients with relapsed/refractory disease as well as first-line therapy. In addition, the efficacy of PLD with bortezomib in anthracycline-insensitive patients has been greater than single-agent bortezomib when comparing across studies. The immunomodulatory drugs, thalidomide and lenalidomide, target the tumor cell microenvironment, are antiangiogenic, have an immune activation effect and also exert a direct cytotoxic effect on myeloma cells. A phase 1 clinical study by our group also demonstrated that low dose PLD, administered at a more frequent dosing schedule, in combination with bortezomib, and dexamethasone (DVD regimen) is well tolerated and associated with high response rates and durable responses. In this phase II prospective trial, we will evaluate this regimen and show that this change enhances the DVD-R regimen's safety and efficacy for patients with relapsed/refractory MM.
Interventions
DRUGDVD-R
40 mg dexamethasone will be administered IV on Days 1, 4, 8, and 11 of each cycle. 1.0 mg/m2 Bortezomib will be administered IV over 3 to 5 seconds followed by a standard saline flush, on Days 1, 4, 8, and 11 immediately following the dexamethasone infusion. 4.0 mg/m2 PLD will be given as a 90 minute infusion on Day 1 of Cycle 1 and subsequent doses may be administered over 30 to 60 minutes on Days 4, 8 and 11 of Cycle 1 and on Days 1, 4, 8, and 11 of each subsequent cycle, following the bortezomib administration. 10 mg/day lenalidomide will be administered PO on days 1-14 of a 28-day treatment cycle, followed by a 14-day rest period, following the PLD administration.
Sponsors
Celgene Corporation
Oncotherapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Has a diagnosis of multiple myeloma (MM) based on standard criteria (Durie 1986) 2. Currently has MM with measurable disease (serum m protein \> 1.0g/dl and/or 24 hr urine m protein \> 200mg/24 hr) 3. Currently has progressive MM that has relapsed or is refractory 4. Voluntarily signed an informed consent 5. Age 18 years 6. Eastern Cooperative Oncology Group (ECOG) performance \< 2 7. Life-expectancy \> 3 months 8. Laboratory test results within these ranges: * Absolute neutrophil count (ANC) 1.5 x 109/L; if the bone marrow is extensively infiltrated (\> 70% plasma cells) then 1.0 x 109/L * Platelet count 75 x 109/L; if the bone marrow is extensively infiltrated (\> 70% plasma cells) then 50 x 109/L * Hg \> 8 g/dL * Calculated or measured creatinine clearance \> 30 mL/minute. * Total bilirubin 2.0 x upper limit of normal (ULN) * Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) 3 x ULN or 5 x ULN if hepatic metastases are present * Serum potassium within the normal range 9. Disease free of prior malignancies for 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast 10. Registered into the mandatory RevAssist® program, willing and able to comply with the requirements of RevAssist®. 11. Females of childbearing potential must have a negative serum or urine pregnancy test and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control. 12. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid (ASA) may use warfarin or low molecular weight heparin)
Exclusion criteria
1. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes syndrome 2. Plasma cell leukemia 3. Grade 2 peripheral neuropathy within 14 days before enrollment 4. Impaired cardiac function or clinically significant cardiac diseases, including myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) Class II or greater heart failure, Uncontrolled angina, clinically significant pericardial disease, severe uncontrolled ventricular arrhythmias, echocardiogram or Multigated acquisition(MUGA) scan evidence of left ventricular ejection fraction (LVEF) below institutional normal within 28 days prior to enrollment, electrocardiographic (ECG) 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. 5. Severe hypercalcemia, i.e., serum calcium 12 mg/dL (3.0 mmol/L) corrected for albumin 6. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form 7. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study 8. Undergone major surgery within 28 days prior enrollment or has not recovered from side effects of such therapy (Kyphoplasty is not considered to be a major surgery; however, the investigator is to discuss enrollment of a patient with a recent history of kyphoplasty with the medical monitor). 9. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide) 10. Received the following prior therapy: * Chemotherapy within 3 weeks of enrollment (6 wks for nitrosoureas) * Corticosteroids (\>10 mg/day prednisone or equivalent) within 3 weeks of enrollment * Immunotherapy or antibody therapy as well as thalidomide, lenalidomide, arsenic trioxide or bortezomib within 21 days before enrollment * Radiation therapy within 28 days before enrollment, except localized radiation therapy * Use of any other experimental drug or therapy within 28 days of enrollment 11. Known hypersensitivity to compounds of similar to thalidomide, doxorubicin, bortezomib, boron or mannitol. 12. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs 13. Concurrent use of other anti-cancer agents or treatments 14. Known positivity for human immunodeficiency virus (HIV) or hepatitis B or C; baseline testing for HIV and hepatitis B or C is not required
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| International Myeloma Working Group (IMWG) Response Criteria | Up to 7.5 months (eight 28-day cycles) | The investigator will evaluate each patient for response to therapy according to criteria augmented from those developed by Bladé et al., 1998 presented below (Table 7-1). Assessment of disease response will be performed prior to drug administration on Day 1 of Cycles 2 8 and at the End of Study Treatment visit. If a patient is determined to have complete response (CR), very good partial response (VGPR), partial response (PR), or minor response (MR), then assessment of disease response is to be performed 4 weeks later to confirm the response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Best Response | Up to 7.5 months (eight 28-day cycles) | — |
| Duration of Response | First evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death. | — |
| Time to First Response | Up to 7.5 months (eight 28-day cycles) | — |
| Progression-free Survival | Time from the start of treatment to progressive disease or until death | — |
| Follow-up Time | Follow-up visits for disease progression and overall survival every 3 months after study discontinuation. After progression, follow-up visits for survival status every 6 months or until alternate therapy needs to be started or death intervenes | time that patients were monitored for disease progression and overall survival |
| Time to Progression | Time from the start of treatment to progressive disease | — |
Countries
United States
Participant flow
Recruitment details
This study enrolled patients from eight different clinical sites sites in the United States. Data was collected from September 2009 until July 25, 2011
Participants by arm
| Arm | Count |
|---|---|
| DVD-R Single Arm Dose schematic of Dexamethasone + Bortezomib + Pegylated Liposomal Doxorubicin + Lenalidomide (DVD-R) Therapy:
Per 28 Day Cycle, patients will received drug in the following order, dosing and schedule:
1\) Dexamethasone- 40 mg intravenous infusion (IV) on Days 1, 4, 8 and 11; 2) Bortezomib- 1.0 mg/m2 infused over 3 to 5 seconds followed by a standard saline flush on Days 1, 4, 8 and 11; 3) Pegylated Liposomal Doxorubicin- 4.0 mg/m2 IV as a 90 minute infusion on Day 1 of Cycle 1 and subsequent doses may be administered over 30 to 60 minutes on Days 4, 8 and 11 of Cycle 1 and on Days 1, 4, 8, and 11 of each subsequent cycle; and 4) Lenalidomide- 10 mg PO on days 1-14 | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 6 |
| Overall Study | inclusion/exclusion criteria failure | 1 |
| Overall Study | Lack of Efficacy | 9 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | DVD-R Single Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 27 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Age, Continuous | 71 years |
| International Staging System (ISS); stage (N) I (beta 2 microglobulin(B2M )<3.5 +Albumin ≥3.5) | 16 participants |
| International Staging System (ISS); stage (N) II (B2M 3.5 +albumin < 3.5; or B2M 3.5-5.5) | 14 participants |
| International Staging System (ISS); stage (N) III (B2M >5.5) | 10 participants |
| Prior treatments | 3 number of treatments |
| Serum creatinine | 1.0 mg/dL |
| Serum M-protein | 2.05 g/dL |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 25 Participants |
| Total Number of prior lines of treatment Alkylating agents | 20 number of treatments |
| Total Number of prior lines of treatment Bortezomib (BTZ) | 33 number of treatments |
| Total Number of prior lines of treatment Glucocorticoids | 35 number of treatments |
| Total Number of prior lines of treatment HDAC inhibitors (panobinostat/romidepsin) | 7 number of treatments |
| Total Number of prior lines of treatment Lenalidomide (LEN) | 19 number of treatments |
| Total Number of prior lines of treatment Other | 11 number of treatments |
| Total Number of prior lines of treatment PLD+btz+dexamethasone (dex) | 17 number of treatments |
| Total Number of prior lines of treatment PLD+btz+dex and len+ glucocorticoids | 10 number of treatments |
| Total Number of prior lines of treatment PLD or Doxorubucin | 15 number of treatments |
| Total Number of prior lines of treatment Thalidomide | 15 number of treatments |
| Total Number of prior lines of treatment Transplant (autologous) | 5 number of treatments |
| Urine-M protein | 261.1 mg/dL |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 23 / 40 |
| serious Total, serious adverse events | 10 / 40 |
Outcome results
Primary
International Myeloma Working Group (IMWG) Response Criteria
The investigator will evaluate each patient for response to therapy according to criteria augmented from those developed by Bladé et al., 1998 presented below (Table 7-1). Assessment of disease response will be performed prior to drug administration on Day 1 of Cycles 2 8 and at the End of Study Treatment visit. If a patient is determined to have complete response (CR), very good partial response (VGPR), partial response (PR), or minor response (MR), then assessment of disease response is to be performed 4 weeks later to confirm the response.
Time frame: Up to 7.5 months (eight 28-day cycles)
Population: Population analysis was carried out as per protocol. Efficacy was evaluated via a modified version of the Bladé response criteria \[complete response (CR), very good partial response (VGPR), partial response (PR), and those achieving minimal response (MR)\]
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| DVD-R Single Arm | International Myeloma Working Group (IMWG) Response Criteria | CR | 8 participants |
| DVD-R Single Arm | International Myeloma Working Group (IMWG) Response Criteria | VGPR | 4 participants |
| DVD-R Single Arm | International Myeloma Working Group (IMWG) Response Criteria | PR | 7 participants |
| DVD-R Single Arm | International Myeloma Working Group (IMWG) Response Criteria | Objective Response (CR+VGPR+PR) | 19 participants |
| DVD-R Single Arm | International Myeloma Working Group (IMWG) Response Criteria | MR | 14 participants |
| DVD-R Single Arm | International Myeloma Working Group (IMWG) Response Criteria | Clinical Benefit (CR+VGPR+PR+MR) | 33 participants |
| DVD-R Single Arm | International Myeloma Working Group (IMWG) Response Criteria | Estable disease | 4 participants |
| DVD-R Single Arm | International Myeloma Working Group (IMWG) Response Criteria | Progressive disease | 2 participants |
Secondary
Duration of Response
Time frame: First evidence of PR or better (for overall response) and MR or better (for clinical benefit response) to start of disease progression or death.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DVD-R Single Arm | Duration of Response | 12 months |
Secondary
Follow-up Time
time that patients were monitored for disease progression and overall survival
Time frame: Follow-up visits for disease progression and overall survival every 3 months after study discontinuation. After progression, follow-up visits for survival status every 6 months or until alternate therapy needs to be started or death intervenes
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DVD-R Single Arm | Follow-up Time | 11 months |
Secondary
Progression-free Survival
Time frame: Time from the start of treatment to progressive disease or until death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DVD-R Single Arm | Progression-free Survival | 9 months |
Secondary
Time to Best Response
Time frame: Up to 7.5 months (eight 28-day cycles)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DVD-R Single Arm | Time to Best Response | 2 months |
Secondary
Time to First Response
Time frame: Up to 7.5 months (eight 28-day cycles)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DVD-R Single Arm | Time to First Response | 1 months |
Secondary
Time to Progression
Time frame: Time from the start of treatment to progressive disease
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DVD-R Single Arm | Time to Progression | 9 months |