Multiple Myeloma
Conditions
Keywords
Multiple Myeloma
Brief summary
This Phase I/II study is designed to first identify doses of MLN9708 and bendamustine that are associated with an acceptable adverse event profile when delivered together in 28-day cycles. Additionally, the study aims to assess the efficacy of the combination in patients with relapsed/refractory multiple myeloma. Responders (stable disease or more), will continue to receive up to eight cycles total in the absence of further progressive disease.
Detailed description
OVERVIEW: This Phase I/II study is designed to first identify doses of MLN9708 and bendamustine that are associated with an acceptable adverse event profile when delivered together in 28-day cycles. Additionally, the study aims to assess the efficacy of the combination in patients with relapsed/refractory multiple myeloma. Responders (stable disease or more),will continue to receive up to eight cycles total in the absence of further progressive disease. OVERVIEW OF THE DOSE ESCALATION/DE-ESCALATION: This study aims to assess the combination's efficacy in patients with relapsed/refractory multiple myeloma. Responders (stable disease or more) will continue to receive up to eight cycles total in the absence of further progressive disease. The dose of MLN9708 will be fixed at 4 mg given on days 1, 8 and 15. Dexamethasone will be administered at 40 mg (oral) on Days 1, 8, 15 of each 28 day cycle. Dexamethasone administered as 40 mg oral on Days 1, 8, 15 of each 28 day cycle. Three doses of bendamustine will be evaluated (Dose 1: 70 mg/m\^2, days 1 and 2; Dose 2: 80 mg/m\^2. days 1 and 2; and Dose 3: 90 mg/m\^2, days 1 and 2). PHASE 1 DESIGN: A 3+3 design was employed. At each dose, three patients were initially evaluated. When no dose limiting toxicities were observed, the bendamustine dose will be increased. PHASE 2 DESIGN: Design for Phase II portion of study: The MTD or a recommended phase 2 dose (RP2D) for the combination. The plan is to treat additional patients at that dose to assess efficacy and response to treatment. The investigators plan to enroll 19 patients (including those treated at the MTD in Phase I).
Interventions
DRUGMLN9708
4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.
DRUGDexamethasone
40 mg oral on Days 1, 8, 15 of each 28 day cycle.
DRUGBendamustine (multiple dose levels)
70 mg/m\^2, 80 mg/m\^2, or 90 mg/m\^2 on days 1 and 2
DRUGBendamustine (MTD)
80 mg/m\^2 on days 1 and 2
Sponsors
Parameswaran Hari
Study design
Allocation
NON_RANDOMIZED
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. Male or female patients 18 years or older. 2. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. 3. Female patients who: * Are postmenopausal for at least one year before the screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential, agree to practice two effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.) Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following: * Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.) 4. Patients must have have histologically or cytologically confirmed symptomatic Multiple Myeloma, who are non-responsive to or ineligible for autologous stem cell transplant, and who progress after prior exposure to proteasome inhibitor (bortezomib, carfilzomib) and lenalidomide or pomalidomide or thalidomide (IMID); and refractory/progressing to at least one of these agents and must meet at least one of the following parameters of measurable disease: * Measurable levels of monoclonal protein (M protein): \> 1 g/dL of immunoglobin G (IgG) or immunoglobin M (IgM) M-protein or \> 0.5 g/dL immunoglobin A (IgA) or immunoglobin D (IgD) M protein on serum protein electrophoresis OR \> 200 mg/24h of free light chain proteinuria on a 24 hour urine protein electrophoresis which must be obtained within 4 weeks prior to registration OR \> 10 mg/dL involved free light chain on serum free light chain testing with an abnormal kappa:lambda light chain ratio. * Patients with lytic bone disease, defined as at least one lytic lesion that can be accurately measured in at least one dimension. 5. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2. 6. Patients are eligible after autologous or allogeneic stem cell transplantation. Allogeneic transplantation can be enrolled only if they have no ongoing transplant related side effects. 7. Patients must be at least 2 weeks from major surgery, radiation therapy, participation in other investigational trials and have recovered from clinically significant toxicities of these prior treatments 8. Patients must meet the following clinical laboratory criteria: * Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3. Platelet transfusions or granulocyte-colony stimulating factor (G-CSF) can be used to help patients meet eligibility criteria but are not allowed within 3 days before study enrollment. * Total bilirubin \< 1.5 x the upper limit of the normal range (ULN), , OR, direct bilirubin within normal limits (WNL), when total bilirubin is \>\>\< 1.5 x the ULN. * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3 x ULN. * Calculated creatinine clearance ≥ 30 mL/min.
Exclusion criteria
Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Bendamustine | Six months for each dosing cohort | Maximum tolerated dose of bendamustine in combination with fixed doses of ixazomib (MLN9708) and dexamethasone will be determined from the incidence of dose limiting toxicities at each dosage. |
| Objective Response Rate | 18 months | Objective response rate was defined as the number of subjects achieving a complete response (CR) or partial response (PR) after at least four cycles of ixazomib (MLN9708) and bendamustine plus dexamethasone. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Response Rates in Patients After Eight Cycles. | 18 months | Percentage of subject response rates at any point during the eight cycles. |
| Overall Survival (OS) | 36 months | Overall survival was determined as the average number of months subjects survived following enrollment. |
| Number of Participants Experiencing Dose-Limiting Toxicity (DLT) | Six months | A 3+3 design was employed. At each dose, three patients were initially evaluated. If no dose limiting toxicities were observed, the bendamustine dose was increased; if one dose limiting toxicity is observed, three additional patients were treated at that dose. A dose at which 2 DLTs were observed in 3 or 6 patients were judged to be too toxic and the lower dose was defined as the maximally tolerated dose (MTD). |
| Duration of Response (DoR) | 36 months | Median time in months participants maintain CR, PR or stable disease. |
| Progression Free Survival (PFS) | 18 months | This measure is the number of months participants remain free from evidence of disease. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Phase: Bendamustine (70 mg/m^2), MLN9708, Dex. MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.
Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.
Bendamustine: 70 mg/m\^2 days 1 and 2 | 4 |
| Dose Escalation Phase: Bendamustine (80 mg/m^2), MLN9708, Dex. MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.
Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.
Bendamustine: 80 mg/m\^2 days 1 and 2 | 8 |
| Dose Escalation Phase: Bendamustine (90 mg/m^2), MLN9708, Dex. MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.
Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.
Bendamustine: 90 mg/m\^2 days 1 and 2 | 6 |
| Fixed Dose Phase MLN9708: 4 mg of MLN9708 delivered on days 1, 8 and 15 of a 28 day cycle.
Dexamethasone: 40 mg oral on Days 1, 8, 15 of each 28 day cycle.
Bendamustine: 80 mg/m\^2 days 1 and 2 | 20 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Dose Escalation Phase | Physician Decision | 1 | 2 | 0 |
| Fixed Dose Phase | Physician Decision | 0 | 7 | 0 |
Baseline characteristics
| Characteristic | Dose Escalation Phase: Bendamustine (70 mg/m^2), MLN9708, Dex. | Dose Escalation Phase: Bendamustine (80 mg/m^2), MLN9708, Dex. | Dose Escalation Phase: Bendamustine (90 mg/m^2), MLN9708, Dex. | Fixed Dose Phase | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 6 Participants | 5 Participants | 10 Participants | 24 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 1 Participants | 10 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 8 Participants | 6 Participants | 19 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 7 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 7 Participants | 5 Participants | 13 Participants | 29 Participants |
| Region of Enrollment United States | 4 participants | 8 participants | 6 participants | 20 participants | 38 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 2 Participants | 13 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 8 / 19 | 2 / 6 |
| other Total, other adverse events | 0 / 3 | 0 / 19 | 0 / 6 |
| serious Total, serious adverse events | 2 / 3 | 8 / 19 | 0 / 6 |
Outcome results
Primary
Maximum Tolerated Dose of Bendamustine
Maximum tolerated dose of bendamustine in combination with fixed doses of ixazomib (MLN9708) and dexamethasone will be determined from the incidence of dose limiting toxicities at each dosage.
Time frame: Six months for each dosing cohort
Population: All participants received at least ne dose of Bendamustine at either 70 mg/m\^2, 80 mg\^2 or 90 mg/m\^2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN9708, Bendamustine and Dexamethasone | Maximum Tolerated Dose of Bendamustine | 80 mg/m^2 |
Primary
Objective Response Rate
Objective response rate was defined as the number of subjects achieving a complete response (CR) or partial response (PR) after at least four cycles of ixazomib (MLN9708) and bendamustine plus dexamethasone.
Time frame: 18 months
Population: Subjects receiving the fixed dose of 80 mg/m\^2 Bendamustine were included in this analysis. Results from five of the subjects in the Dose Escalation Phase of this study who also received 80 mg/m\^2 Bendamustine were included in the analysis. One of the Dose Expansion Phase subjects did not complete sufficient dosing cycles for inclusion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN9708, Bendamustine and Dexamethasone | Objective Response Rate | 11 participants |
Secondary
Cumulative Response Rates in Patients After Eight Cycles.
Percentage of subject response rates at any point during the eight cycles.
Time frame: 18 months
Population: Subjects receiving the fixed dose of 80 mg/m\^2 Bendamustine were included in this analysis. Results from five of the subjects in the Dose Escalation Phase of this study who also received 80 mg/m\^2 Bendamustine were included in the analysis. One of the Dose Expansion Phase subjects did not complete sufficient dosing cycles for inclusion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN9708, Bendamustine and Dexamethasone | Cumulative Response Rates in Patients After Eight Cycles. | 28 percentage of participants |
Secondary
Duration of Response (DoR)
Median time in months participants maintain CR, PR or stable disease.
Time frame: 36 months
Population: Subjects receiving the fixed dose of 80 mg/m\^2 Bendamustine were included in this analysis. Results from five of the subjects in the Dose Escalation Phase of this study who also received 80 mg/m\^2 Bendamustine were included in the analysis. One of the Dose Expansion Phase subjects did not complete sufficient dosing cycles for inclusion.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN9708, Bendamustine and Dexamethasone | Duration of Response (DoR) | 5.1 MONTHS |
Secondary
Number of Participants Experiencing Dose-Limiting Toxicity (DLT)
A 3+3 design was employed. At each dose, three patients were initially evaluated. If no dose limiting toxicities were observed, the bendamustine dose was increased; if one dose limiting toxicity is observed, three additional patients were treated at that dose. A dose at which 2 DLTs were observed in 3 or 6 patients were judged to be too toxic and the lower dose was defined as the maximally tolerated dose (MTD).
Time frame: Six months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MLN9708, Bendamustine and Dexamethasone | Number of Participants Experiencing Dose-Limiting Toxicity (DLT) | 0 Participants |
| Bendamustine (80 mg/m^2), MLN9708, Dexamethasone | Number of Participants Experiencing Dose-Limiting Toxicity (DLT) | 1 Participants |
| Bendamustine (90 mg/m^2), MLN9708, Dexamethasone | Number of Participants Experiencing Dose-Limiting Toxicity (DLT) | 2 Participants |
Secondary
Overall Survival (OS)
Overall survival was determined as the average number of months subjects survived following enrollment.
Time frame: 36 months
Population: Subjects receiving the fixed dose of 80 mg/m\^2 Bendamustine were included in this analysis. Results from five of the subjects in the Dose Escalation Phase of this study who also received 80 mg/m\^2 Bendamustine were included in the analysis. One of the Dose Expansion Phase subjects did not complete sufficient dosing cycles for inclusion.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN9708, Bendamustine and Dexamethasone | Overall Survival (OS) | 23.2 MONTHS |
Secondary
Progression Free Survival (PFS)
This measure is the number of months participants remain free from evidence of disease.
Time frame: 18 months
Population: For this analysis, all 20 participants who received the fixed dose of 80 mg/m\^2 Bendamustine and all 8 participants who received Bendamustine (80 mg/m\^2) in the Dose Escalation phase, were combined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN9708, Bendamustine and Dexamethasone | Progression Free Survival (PFS) | 5.2 MONTHS |