Multiple Myeloma
Conditions
Keywords
MLN9708, allogeneic stem cell transplant, multiple myeloma, ixazomib, autologous stem cell transplant
Brief summary
The purpose of the study is to determine the safety of MLN9708 as maintenance therapy following allogeneic stem cell transplant in patients with multiple myeloma.
Detailed description
Although multiple myeloma is considered fatal, survival has dramatically improved over the last two decades with the introduction of more effective treatment options. Proteasome inhibitors have an anti-myeloma effect and are often used as either initial treatment or at relapse in patients with multiple myeloma. MLN9708 is an orally bioavailable, potent, reversible inhibitor of the 20S proteasome. Phase I studies have shown MLN9708 to be very well tolerated with minimal peripheral neuropathy. It has also shown impressive anti-myeloma activity in both the relapsed/refractory setting and the upfront setting (Kumar et al. 2011, Berdeja et al. 2011, Richardson et al. 2011). These characteristics make MLN9708 an ideal proteasome inhibitor to use after allogeneic stem cell transplant. In this Phase II, open-label, multicenter, non-randomized study the investigators will investigate the role of MLN9708 as maintenance after allogeneic stem cell transplant in patients with high-risk multiple myeloma, and in patients with multiple myeloma who have relapsed after an autologous stem cell transplant.
Interventions
DRUGMLN9708
Patients will be enrolled between Days 45 and 120 after allogeneic transplant and will receive MLN9708 orally (PO) as monotherapy on Days 1, 8, and 15 of each 28-day cycle for 6 cycles. Up to 18 patients will be enrolled in a dose-escalation phase to determine the maximum tolerated dose (MTD). Dose-Escalation Phase: MLN9708 will be administered orally (PO) as monotherapy. Dosing will start at 2.3 mg. If acceptable tolerability is demonstrated, escalations will be made to 3 mg and to a maximum-planned dose (MPD) of 4 mg.
Sponsors
Millennium Pharmaceuticals, Inc.
SCRI Development Innovations, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
KEY POINTS: 1. Symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ damage diagnosed according to standard criteria in patients who received allogeneic transplant due to high-risk prognostic features, such as, but not limited to: * Chromosome 17p, partial deletion \[del(17p)\], t(4;14), t(14;16), t(14;20) * Plasma cell leukemia * PFS of less than 2 years after autologous stem cell transplant 2. Evidence of engraftment of neutrophils (absolute neutrophil count \[ANC\] \>1000 cells/mm3) and platelets (platelets \>60,000 cells/mm3) \[dose escalation phase\] and \>50,000 cells/mm3 \[dose expansion phase\]). 3. Achievement of at least a PR prior to allogeneic stem cell transplant 4. Adequate liver and kidney function 5. Ability to swallow oral medication 6. Absence of gastrointestinal symptoms that precludes oral intake and absorption of MLN9708 7. Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungal therapy for the treatment of proven, probable or possible infections 8. ECOG of ≤ 2 9. Life expectancy ≥3 months 10. Ability to understand the nature of this study and give written informed consent
Exclusion criteria
1. Patients with progressive disease when compared to pre-transplant staging as defined by IMWG Uniform Response criteria for Multiple Myeloma. 2. Umbilical cord blood transplant 3. Patients with \> Grade 2 peripheral neuropathy with pain, or ≥ Grade 3 peripheral neuropathy per NCI CTCAE Version 4.0 4. Patients with uncontrolled bacterial, viral, or fungal infections 5. 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. 6. Patients who are pregnant or breastfeeding 7. Most recent chemotherapy ≤21 days and ≤ Grade 1 chemotherapy-related side effects, with the exception of alopecia 8. Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of MLN9708. For study drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the study drug and administration of MLN9708 is required. 9. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤14 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy 10. Major surgical procedures ≤14 days of beginning study drug, or minor surgical procedures ≤7 days. No waiting is required following port-a-cath placement. 11. Ongoing or active systemic infection. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C 12. Central Nervous System involvement 13. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. 14. Systemic treatment with moderate and strong inhibitors of cytochrome P450 (CYP) 1A2, CYP3A, or clinically significant CYP3A inducers, or use of Ginkgo biloba or St. John's wort within 14 days before study drug administration in the study. 15. Presence of other active cancers, or history of treatment for invasive cancer ≤5 years. Patients with Stage I cancer who have received definitive local treatment and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of non-melanoma skin cancer. 16. Graft versus host disease \> Grade 2; or GVHD grade 1 or Grade 2 which requires \> 0.5 mg/kg methylprednisolone, or equivalent. There are additional Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Phase I Patients Receiving 2.3mg, 3mg, or 4mg MLN9708 Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Maximum Tolerated Dose | Collected from day of first dose to the end of the first treatment cycle, up to 28 days | The maximum tolerated dose (MTD) of MLN9708 will be determined as the dose at which ≤1 of 6 patients experiences a DLT during one cycle (28 days) of therapy utilizing the National Cancer Institute Common Technology Criteria for Adverse Events (NCI CTCAE) v4.0 |
| Number of Participants With Grade 3/4/5 Serious Adverse Events and Adverse Events as a Measure of Safety of MLN9708 When Used as Maintenance After Allogeneic Stem Cell Transplant for Multiple Myeloma Multiple Myeloma | Defined as the time from Day 1 of study drug administration until 30 days after treatment completion for up to 2 years. | Defined as the number of participants with treatment-emergent grade 3/4/5 adverse events/serious adverse events utilizing the National Cancer Institute Common Technology Criteria for Adverse Events (NCI CTCAE) v4.0 determined to be related to MLN9708. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-Free Survival (PFS) at 2 Years Post-maintenance Therapy | every 8 weeks for approximately 24 weeks then every 3 months thereafter for 2 years | PFS is measured from the date of first protocol treatment until date of disease progression or death occurs, or date of last adequate tumor assessment using the International Myeloma Working Group Uniform Response Criteria. IMWG disease progression is defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: 1) serum M-protein, 2) urine M-protein, 3) only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels, 4) Bone marrow plasma cell percentage (absolute % must be ≥10%). OR Disease progression also could include development of new lytic bone lesions or increase from baseline in size of lytic bone lesion(s); development of new soft tissue plasmacytoma(s) or definite increase from nadir in existing soft tissue plasmacytomas; or development of hypercalcemia |
| Median Overall Survival (OS) at 2 Years Post-allogeneic Stem Cell Transplant (ASCT) | every 8 weeks for approximately 24 weeks after ASCT, then every 3 months thereafter for 2 years. | Overall survival is measured as the interval from first study treatment until date of death, or date last known alive. |
| Number of Participants With Incidence of Chronic Graft-versus-host Disease (cGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708 | from date of enrollment every 28 days, up to 2 years | Incidence of chronic Graft-versus-host disease GVHD was assessed based on the National Institutes of Health Consensus Development Project on Criteria for Clinical trials in Acute and Chronic Graft-versus-host-disease (Filipovich et al. 2005) from date of randomization until date of first documented progression, or date of death from any cause. |
| Number of Participants With Incidence of Acute Graft-versus-host Disease (aGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708 | from date of enrollment every 28 days, up to 2 years | Incidence of acute Graft-versus-host disease GVHD was assessed based on the National Institutes of Health Consensus Development Project on Criteria for Clinical trials in Acute and Chronic Graft-versus-host-disease (Przepiorka et al. 1995) from date of randomization until date of first documented progression, or date of death from any cause. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MLN9708 - 2.3 mg Patients will be enrolled between Days 45 and 120 after allogeneic transplant and will receive a weekly dose of 2.3 mg of MLN9708 orally (PO) on Days 1, 8, and 15 of each 28-day cycle for 6 cycles. | 3 |
| MLN9708 - 3 mg Patients will be enrolled between Days 45 and 120 after allogeneic transplant and will receive a weekly dose of 3 mg of MLN9708 on Days 1, 8, and 15 of each 28-day cycle for 6 cycles. | 3 |
| MLN9708 - 4 mg Patients will be enrolled between Days 45 and 120 after allogeneic transplant and will receive a weekly dose of 4 mg of MLN9708 on Days 1, 8, and 15 of each 28-day cycle for 6 cycles. | 3 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 2 | 2 | 1 |
Baseline characteristics
| Characteristic | MLN9708 - 2.3 mg | Total | MLN9708 - 4 mg | MLN9708 - 3 mg |
|---|---|---|---|---|
| Age, Continuous | 57 years | 47 years | 44 years | 47 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 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 | 3 Participants | 8 Participants | 2 Participants | 3 Participants |
| Region of Enrollment United States | 3 Participants | 9 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 6 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 2 / 3 | 1 / 3 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 2 / 3 | 2 / 3 |
Outcome results
Primary
Number of Participants With Grade 3/4/5 Serious Adverse Events and Adverse Events as a Measure of Safety of MLN9708 When Used as Maintenance After Allogeneic Stem Cell Transplant for Multiple Myeloma Multiple Myeloma
Defined as the number of participants with treatment-emergent grade 3/4/5 adverse events/serious adverse events utilizing the National Cancer Institute Common Technology Criteria for Adverse Events (NCI CTCAE) v4.0 determined to be related to MLN9708.
Time frame: Defined as the time from Day 1 of study drug administration until 30 days after treatment completion for up to 2 years.
Population: All patients who received at least one dose of MLN9708.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MLN9708 - 2.3 mg | Number of Participants With Grade 3/4/5 Serious Adverse Events and Adverse Events as a Measure of Safety of MLN9708 When Used as Maintenance After Allogeneic Stem Cell Transplant for Multiple Myeloma Multiple Myeloma | 1 Participants |
| MLN9708 - 3 mg | Number of Participants With Grade 3/4/5 Serious Adverse Events and Adverse Events as a Measure of Safety of MLN9708 When Used as Maintenance After Allogeneic Stem Cell Transplant for Multiple Myeloma Multiple Myeloma | 2 Participants |
| MLN9708 - 4 mg | Number of Participants With Grade 3/4/5 Serious Adverse Events and Adverse Events as a Measure of Safety of MLN9708 When Used as Maintenance After Allogeneic Stem Cell Transplant for Multiple Myeloma Multiple Myeloma | 2 Participants |
Primary
Number of Phase I Patients Receiving 2.3mg, 3mg, or 4mg MLN9708 Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Maximum Tolerated Dose
The maximum tolerated dose (MTD) of MLN9708 will be determined as the dose at which ≤1 of 6 patients experiences a DLT during one cycle (28 days) of therapy utilizing the National Cancer Institute Common Technology Criteria for Adverse Events (NCI CTCAE) v4.0
Time frame: Collected from day of first dose to the end of the first treatment cycle, up to 28 days
Population: All patients who received at least one dose of MLN9708.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MLN9708 - 2.3 mg | Number of Phase I Patients Receiving 2.3mg, 3mg, or 4mg MLN9708 Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Maximum Tolerated Dose | 0 Participants |
| MLN9708 - 3 mg | Number of Phase I Patients Receiving 2.3mg, 3mg, or 4mg MLN9708 Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Maximum Tolerated Dose | 0 Participants |
| MLN9708 - 4 mg | Number of Phase I Patients Receiving 2.3mg, 3mg, or 4mg MLN9708 Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Maximum Tolerated Dose | 0 Participants |
Secondary
Median Overall Survival (OS) at 2 Years Post-allogeneic Stem Cell Transplant (ASCT)
Overall survival is measured as the interval from first study treatment until date of death, or date last known alive.
Time frame: every 8 weeks for approximately 24 weeks after ASCT, then every 3 months thereafter for 2 years.
Population: All patients with measurable or evaluable disease at baseline who receive at least 1 dose of MLN9708 and undergo at least one post-baseline disease assessment. Pre-specified in Protocol to calculate PFS for all participants and for all patients receiving the MTD. Because the MTD was not reached, this analysis was only performed on all participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN9708 - 2.3 mg | Median Overall Survival (OS) at 2 Years Post-allogeneic Stem Cell Transplant (ASCT) | NA months |
Secondary
Median Progression-Free Survival (PFS) at 2 Years Post-maintenance Therapy
PFS is measured from the date of first protocol treatment until date of disease progression or death occurs, or date of last adequate tumor assessment using the International Myeloma Working Group Uniform Response Criteria. IMWG disease progression is defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: 1) serum M-protein, 2) urine M-protein, 3) only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels, 4) Bone marrow plasma cell percentage (absolute % must be ≥10%). OR Disease progression also could include development of new lytic bone lesions or increase from baseline in size of lytic bone lesion(s); development of new soft tissue plasmacytoma(s) or definite increase from nadir in existing soft tissue plasmacytomas; or development of hypercalcemia
Time frame: every 8 weeks for approximately 24 weeks then every 3 months thereafter for 2 years
Population: All patients with measurable or evaluable disease at baseline who receive at least 1 dose of MLN9708 and undergo at least one post-baseline disease assessment. Pre-specified in Protocol to calculate PFS for all participants and for all patients receiving the MTD. Because the MTD was not reached, this analysis was only performed on all participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN9708 - 2.3 mg | Median Progression-Free Survival (PFS) at 2 Years Post-maintenance Therapy | 6.5 months |
Secondary
Number of Participants With Incidence of Acute Graft-versus-host Disease (aGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708
Incidence of acute Graft-versus-host disease GVHD was assessed based on the National Institutes of Health Consensus Development Project on Criteria for Clinical trials in Acute and Chronic Graft-versus-host-disease (Przepiorka et al. 1995) from date of randomization until date of first documented progression, or date of death from any cause.
Time frame: from date of enrollment every 28 days, up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MLN9708 - 2.3 mg | Number of Participants With Incidence of Acute Graft-versus-host Disease (aGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708 | 2 Participants |
| MLN9708 - 3 mg | Number of Participants With Incidence of Acute Graft-versus-host Disease (aGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708 | 2 Participants |
| MLN9708 - 4 mg | Number of Participants With Incidence of Acute Graft-versus-host Disease (aGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708 | 2 Participants |
Secondary
Number of Participants With Incidence of Chronic Graft-versus-host Disease (cGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708
Incidence of chronic Graft-versus-host disease GVHD was assessed based on the National Institutes of Health Consensus Development Project on Criteria for Clinical trials in Acute and Chronic Graft-versus-host-disease (Filipovich et al. 2005) from date of randomization until date of first documented progression, or date of death from any cause.
Time frame: from date of enrollment every 28 days, up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MLN9708 - 2.3 mg | Number of Participants With Incidence of Chronic Graft-versus-host Disease (cGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708 | 2 Participants |
| MLN9708 - 3 mg | Number of Participants With Incidence of Chronic Graft-versus-host Disease (cGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708 | 2 Participants |
| MLN9708 - 4 mg | Number of Participants With Incidence of Chronic Graft-versus-host Disease (cGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708 | 2 Participants |