Description:
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.
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.
Completed
Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| MLN9708 | ixazomib | MLN9708 - 2.3 mg |
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.
| Name | Type | Description | Interventions |
|---|---|---|---|
| MLN9708 - 2.3 mg | Experimental | Patients will be enrolled between Days 45 and 120 after allogeneic transplant and will receive a weekly dose of 2.3 mg of MLN9708 on Days 1, 8, and 15 of each 28-day cycle for 6 cycles. |
|
| MLN9708 - 3 mg | Experimental | 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. |
|
| MLN9708 - 4 mg | Experimental | 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. |
|
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/Exclusion criteria. The Study Center will determine if you
meet all criteria and will answer any questions you may have about the trial.
| Maximum Eligible Age: | 70 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Number of Phase I Patients Receiving 2.3mg, 3mg, or 4mg MLN9708 Experiencing a Dose-Limiting Toxicity (DLT) to Determine the Maximum Tolerated Dose |
| Time Frame: | Collected from day of first dose to the end of the first treatment cycle, up to 28 days |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Median Progression-Free Survival (PFS) at 2 Years Post-maintenance Therapy |
| Time Frame: | every 8 weeks for approximately 24 weeks then every 3 months thereafter for 2 years |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Median Overall Survival (OS) at 2 Years Post-allogeneic Stem Cell Transplant (ASCT) |
| Time Frame: | every 8 weeks for approximately 24 weeks after ASCT, then every 3 months thereafter for 2 years. |
| Safety Issue: | |
| Description: | Overall survival is measured as the interval from first study treatment until date of death, or date last known alive. |
| Measure: | Number of Participants With Incidence of Chronic Graft-versus-host Disease (cGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708 |
| Time Frame: | from date of enrollment every 28 days, up to 2 years |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Incidence of Acute Graft-versus-host Disease (aGVHD) After Receiving Allogeneic Stem Cell Transplant and Maintenance With MLN9708 |
| Time Frame: | from date of enrollment every 28 days, up to 2 years |
| Safety Issue: | |
| Description: | 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. |
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | SCRI Development Innovations, LLC |
February 27, 2020