Multiple Myeloma
Conditions
Brief summary
This is an open label phase I/II trial to determine the safety and the biologic activity of the bendamustine, bortezomib and pegylated liposomal doxorubicin combination.
Detailed description
Phase I component Bortezomib 1.3 mg/m2 IV bolus, Days 1, 4, 8, and 11 Doxorubicin 30 mg/m2 IV over 1 hour, Day 4 Bendamustine escalating cohorts IV over 1 hour, Days 1 and 4 1 Cycle = 28 days Phase II component Bortezomib 1.3 mg/m2 IV bolus, Days 1, 4, 8, and 11 Doxorubicin 30 mg/m2 IV over 1 hour, Day 4 Bendamustine at MTD IV over 1 hour, Days 1 and 4 Filgrastim (if defined in MTD) 5 µg/kg/day SC, Starting day 6 until neutrophil recovery to ANC \>1000 1 Cycle = 28 days; Patients will continue treatment for a total of up to 8 cycles. ECOG Performance Status: 0-2 Hematopoietic: * Absolute neutrophil count (ANC) ≥ 1.2 x K/mm3 * Platelets ≥ 75 x K/mm3 Hepatic: * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) * AST ≤ 2.5 x ULN * ALT ≤ 2.5 x ULN Renal: * Serum creatinine \< 3.0 mg/dL Cardiovascular: * LVEF \>45% corrected by MUGA scan or echocardiogram. * No unstable angina pectoris or recent myocardial infarction (within 6 months)
Interventions
DRUGBendamustine
Phase I component: Bendamustine escalating cohorts to determine MTD, IV over 1 hour, Days 1 and 4
DRUGDoxorubicin
Phase I and II components: Pegylated liposomal doxorubicin, 30 mg/m2 IV over 1 hour, Day 4
DRUGBortezomib
Phase I and II components: Bortezomib 1.3 mg/m2 IV bolus, Days 1, 4, 8, and 11
DRUGFilgrastim
Phase II component: Filgrastim (if defined in MTD) 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000
Sponsors
Hoosier Cancer Research Network
Cephalon, Inc.
Sherif Farag, MB, BS
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
* A histologically established diagnosis of multiple myeloma with evidence of relapse or refractory disease. * Must have a detectable serum or urine M-Protein by protein electrophoresis that is at least 500 mg/dL (serum) or 1 gm/24 hours (urine), respectively, or serum free light chain level \>100 mg/l for the involved free light chain. * Must have received at least one (1) prior line of systemic treatment that has included either lenalidomide or thalidomide. * Must be willing to provide correlative blood samples.
Exclusion criteria
* Must not have received an excessive cumulative dose of anthracycline * No ≥ grade 2 peripheral neuropathy. * No cytotoxic chemotherapy within 30 days prior to registration for protocol therapy. * No autologous stem cell transplant within 6 months prior to registration for protocol therapy * No prior radiation therapy to \> 25% of bone marrow forming bones (i.e., pelvis) within 30 days prior to registration for protocol therapy. See Study Procedures Manual to calculate percent of prior radiation. * No current corticosteroid therapy in doses greater than 10 mg daily of prednisone (or equivalent) if given for management of co-morbid conditions. * No known central nervous system involvement by myeloma. * No poorly controlled intercurrent illness including, but not limited to, ongoing or active infection, poorly controlled diabetes, symptomatic congestive heart failure, cardiac arrhythmia, or psychiatric illness/social climate that in the opinion of the investigator would limit compliance with study requirements. * No patients known to be positive for HIV, or active Hepatitis A, B, or C. * No major surgery within 30 days prior to registration for protocol therapy. Placement of a venous access device within 30 days prior to registration for protocol therapy is allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: MTD of Bendamustine When Combined With Bortezomib and Pegylated Liposomal Doxorubicin. | From C1D1 up to a maximum of 7 months or until death | In the first phase, MTD of bendamustine was determined in combination with bortezomib and pegylated liposomal doxorubicin to gain a better idea of safe dosing before proceeding with the second phase to assess efficacy. Assuming myelosuppression being a dose-limiting effect that could have been overcome with growth factor support, MTD of the combination with myeloid growth factor support was also tested. |
| Phase II : Overall Response Rate | From C1D1 up to a maximum of 52 months or until death | Overall response rate (CR+PR) of bendamustine in association with bortezomib and pegylated liposomal doxorubicin was assessed in patients with relapsed or refractory Multiple Myeloma. Per modified International Myeloma Working Group criteria: Complete Response (CR) : Negative for monoclonal protein by immunofixation on the serum and urine, and Disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow ; PR : 50% or more reduction in serum M-protein and 90% or more reduction in urine M-protein or to \<200 mg/24hours or a 50% or more reduction in free light chain level ; Overall Response (OR) = CR +PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Progression-free Survival (PFS) | From C1D1 up to a maximum of 54 months until death | The time from the start of treatment of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin. to disease progression or death (regardless of cause of death), whichever comes first. Censoring date will be the last disease evaluation date.Per modified International Myeloma Working Group criteria: Progressive disease (PD) is reported if any one of the following criteria is met: Increase of 25% or more in serum or urine M-protein from baseline;Serum M-protein and/or the absolute increase must be ≥0.5 g/dL;Urine M-protein and/or absolute increase must be ≥200 mg/24 hours ; Development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas;Development of hyperc. |
| Phase I & Phase II : Toxicity of Treatment Regimen | From C1D1 until death or up to a maximum of 54 months | Toxicity profile (for all patients) were presented by rate of overall toxicity and rates of grade 3 or 4 toxicities analyzed separately and combined. |
| Phase II: Overall Survival | From C1D1 up to a maximum of 54 months or until death | The time from the start of treatment to death from any cause with last date known alive as censoring date. |
| Phase II: Duration of Survival | From C1D1 up to a maximum of 52 months | Duration of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin. from first date of at least partial response to the time of progression or death due to disease progression as events, with disease progression and death due to disease progression as events and deaths due to causes other than progression as censored. Censoring date will be the last disease evaluation date or date of death due to other causes as appropriate. |
| Phase II : Time to Progression | From C1D1 up to a maximum of 54 months or until death | The time from the start of treatment (i.e., first dose) of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin to disease progression, with disease progression and death due to disease progression as events and deaths due to causes other than progression as censored. Censoring date will be the last disease evaluation date for patient without progression/death or date of death due to other diseases for patients' deaths due to other causes.Per modified International Myeloma Working Group criteria: Progressive disease (PD) is reported if any one of the following criteria is met: Increase of 25% or more in serum or urine M-protein from baseline;Serum M-protein and/or the absolute increase must be ≥0.5 g/dL;Urine M-protein and/or absolute increase must be ≥200 mg/24 hours ; Development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas;Development of hyperc. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I Level 1 : Bendamustine at 90mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At Phase I level I, Bendamustine will be administered at 90 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle.
Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000.
Doxorubicin:
Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle.
Bortezomib:
Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle. | 3 |
| Phase I Level 2 : Bendamustine at 120mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine: At Phase I level 2, Bendamustine will be administered at 120 mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle.
Filgrastim (if defined in MTD) will be administered at 5 µg/kg/day SC, starting day 6 until neutrophil recovery to ANC \>1000.
Doxorubicin:
Pegylated liposomal doxorubicin at phase I will be administered at 30 mg/m2 by IV over 1 hour, at day 4 of the 28 day treatment cycle.
Bortezomib:
Bortezomib at Phase I will be administered at 1.3 mg/m2 by IV bolus on days 1, 4, 8, and 11 of the 28 day cycle. | 3 |
| Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. Bendamustine:
At phase II, Bendamustine will be administered at 90mg/m\^2 by IV over 1 hour at days 1 and 4 of the 28 day treatment cycle.
Doxorubicin:
Pegylated liposomal doxorubicin at phase II will be administered at 30 mg/m2 by IV over 1 hour,at day 4 of the 28 day treatment cycle.
Bortezomib:
Bortezomib at Phase II will be administered at 1.3 mg/m2 by IV bolus or SQ injection on days 1, 4, 8, and 11 of the 28 day cycle. | 26 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Follow up | Death | 2 | 1 | 7 |
| Follow up | Patient lost to follow up | 0 | 0 | 2 |
| Follow up | Study closed by Sponsor due slow enrollment. | 1 | 2 | 15 |
| Study Treatment | Adverse Event | 0 | 1 | 12 |
| Study Treatment | Alternative therapy | 0 | 0 | 4 |
| Study Treatment | Disease Progressions during treatment | 2 | 0 | 3 |
| Study Treatment | Patient Withdrawal After Therapy Start | 0 | 2 | 1 |
| Study Treatment | Patient withdrawal before therapy start | 0 | 0 | 1 |
| Study Treatment | Physician Decision | 1 | 0 | 1 |
| Study Treatment | Subject came off study without receiving any treatment. | 0 | 0 | 1 |
| Study Treatment | Symptomatic Deterioration | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase I Level 2 : Bendamustine at 120mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase I Level 1 : Bendamustine at 90mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. |
|---|---|---|---|---|
| Age, Continuous | 61.63 years | 62.58 years | 53.33 years | 61.67 years |
| ECOG Performance Status (Baseline 0 | 16 Participants | 13 Participants | 2 Participants | 1 Participants |
| ECOG Performance Status (Baseline 1 | 14 Participants | 11 Participants | 1 Participants | 2 Participants |
| ECOG Performance Status (Baseline 2 | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 25 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 23 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 15 Participants | 11 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 17 Participants | 15 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 1 / 3 | 7 / 26 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 24 / 26 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 8 / 26 |
Outcome results
Primary
Phase II : Overall Response Rate
Overall response rate (CR+PR) of bendamustine in association with bortezomib and pegylated liposomal doxorubicin was assessed in patients with relapsed or refractory Multiple Myeloma. Per modified International Myeloma Working Group criteria: Complete Response (CR) : Negative for monoclonal protein by immunofixation on the serum and urine, and Disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow ; PR : 50% or more reduction in serum M-protein and 90% or more reduction in urine M-protein or to \<200 mg/24hours or a 50% or more reduction in free light chain level ; Overall Response (OR) = CR +PR.
Time frame: From C1D1 up to a maximum of 52 months or until death
Population: Two subjects never received treatment. Therefore, they were not included in any assessment of objectives.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase II : Overall Response Rate | CR+PR | 14 Participants |
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase II : Overall Response Rate | Non-CR+PR | 9 Participants |
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase II : Overall Response Rate | Missing | 1 Participants |
Primary
Phase I: MTD of Bendamustine When Combined With Bortezomib and Pegylated Liposomal Doxorubicin.
In the first phase, MTD of bendamustine was determined in combination with bortezomib and pegylated liposomal doxorubicin to gain a better idea of safe dosing before proceeding with the second phase to assess efficacy. Assuming myelosuppression being a dose-limiting effect that could have been overcome with growth factor support, MTD of the combination with myeloid growth factor support was also tested.
Time frame: From C1D1 up to a maximum of 7 months or until death
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase I: MTD of Bendamustine When Combined With Bortezomib and Pegylated Liposomal Doxorubicin. | 120 mg/m^2 |
| Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal | Phase I: MTD of Bendamustine When Combined With Bortezomib and Pegylated Liposomal Doxorubicin. | 120 mg/m^2 |
Secondary
Phase II: Duration of Survival
Duration of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin. from first date of at least partial response to the time of progression or death due to disease progression as events, with disease progression and death due to disease progression as events and deaths due to causes other than progression as censored. Censoring date will be the last disease evaluation date or date of death due to other causes as appropriate.
Time frame: From C1D1 up to a maximum of 52 months
Population: Two subjects never received treatment. Therefore, they were not included in any assessment of objectives.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase II: Duration of Survival | 13.80 months |
Secondary
Phase II: Overall Survival
The time from the start of treatment to death from any cause with last date known alive as censoring date.
Time frame: From C1D1 up to a maximum of 54 months or until death
Population: Two subjects never received treatment. Therefore, they were not included in any assessment of objectives.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase II: Overall Survival | 30.13 months |
Secondary
Phase II: Progression-free Survival (PFS)
The time from the start of treatment of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin. to disease progression or death (regardless of cause of death), whichever comes first. Censoring date will be the last disease evaluation date.Per modified International Myeloma Working Group criteria: Progressive disease (PD) is reported if any one of the following criteria is met: Increase of 25% or more in serum or urine M-protein from baseline;Serum M-protein and/or the absolute increase must be ≥0.5 g/dL;Urine M-protein and/or absolute increase must be ≥200 mg/24 hours ; Development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas;Development of hyperc.
Time frame: From C1D1 up to a maximum of 54 months until death
Population: Two subjects never received treatment. Therefore, they were not included in any assessment of objectives.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase II: Progression-free Survival (PFS) | 18.96 months |
Secondary
Phase II : Time to Progression
The time from the start of treatment (i.e., first dose) of MM patients treated with bendamustine, bortezomib and pegylated liposomal doxorubicin to disease progression, with disease progression and death due to disease progression as events and deaths due to causes other than progression as censored. Censoring date will be the last disease evaluation date for patient without progression/death or date of death due to other diseases for patients' deaths due to other causes.Per modified International Myeloma Working Group criteria: Progressive disease (PD) is reported if any one of the following criteria is met: Increase of 25% or more in serum or urine M-protein from baseline;Serum M-protein and/or the absolute increase must be ≥0.5 g/dL;Urine M-protein and/or absolute increase must be ≥200 mg/24 hours ; Development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas;Development of hyperc.
Time frame: From C1D1 up to a maximum of 54 months or until death
Population: Two subjects never received treatment. Therefore, they were not included in any assessment of objectives.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase II : Time to Progression | 20.53 months |
Secondary
Phase I & Phase II : Toxicity of Treatment Regimen
Toxicity profile (for all patients) were presented by rate of overall toxicity and rates of grade 3 or 4 toxicities analyzed separately and combined.
Time frame: From C1D1 until death or up to a maximum of 54 months
Population: Two subjects in phase II never received treatment. Therefore, they were not included in any assessment of objectives.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients had at least one adverse event of any grade | 3 Participants |
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients had at least one grade 3 or greater adverse event | 2 Participants |
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients had at least one grade 3 or greater treatment related adverse event | 2 Participants |
| Phase I Level 1:Bendamustine at 90 mg/m^2 With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients having serious adverse event | 1 Participants |
| Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients having serious adverse event | 1 Participants |
| Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients had at least one adverse event of any grade | 3 Participants |
| Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients had at least one grade 3 or greater treatment related adverse event | 3 Participants |
| Phase I Level 2:Bendamustine at 120 mg/m^2 With Bortezomib and Pegylated Liposomal | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients had at least one grade 3 or greater adverse event | 3 Participants |
| Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients having serious adverse event | 8 Participants |
| Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients had at least one grade 3 or greater adverse event | 19 Participants |
| Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients had at least one grade 3 or greater treatment related adverse event | 14 Participants |
| Phase II : Bendamustine in Combination With Bortezomib and Pegylated Liposomal Doxorubicin. | Phase I & Phase II : Toxicity of Treatment Regimen | Number of patients had at least one adverse event of any grade | 24 Participants |