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Determining the Feasibility of MLN9708 as Maintenance After Allogeneic Stem Cell Transplant for Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT02168101
Recruitment Status : Active, not recruiting
First Posted : June 20, 2014
Last Update Posted : May 30, 2019
Sponsor:
Collaborator:
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
SCRI Development Innovations, LLC

Brief Summary:
The purpose of the study is to determine whether MLN9708 is effective as maintenance therapy following allogeneic stem cell transplant in patients with high-risk multiple myeloma.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: MLN9708 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-Label Study to Determine the Feasibility of MLN9708 as Maintenance After Allogeneic Stem Cell Transplant for Multiple Myeloma, Followed by an Expansion Phase at the Maximum-Tolerated Dose (MTD) - A Phase II Study
Study Start Date : September 2014
Estimated Primary Completion Date : January 31, 2020
Estimated Study Completion Date : January 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arm Intervention/treatment
Experimental: MLN9708

Patients will be enrolled between Days 45 and 120 after allogeneic transplant and will receive MLN9708 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). Once the MTD is determined, an additional 20 patients will be enrolled in an expansion phase at that dose.

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.

Expansion Phase: An additional 20 patients will be enrolled between Days 45 and 120 after allogeneic transplant and will receive MLN9708 orally on Days 1, 8, and 15 of each 28-day cycle for 6 cycles.

Drug: MLN9708

Dose-Escalation Phase: MLN9708 will be administered orally (PO) as monotherapy.

  • Cohort 1: 2.3mg single weekly dose
  • Cohort 2: 3mg single weekly dose
  • Cohort 3: 4mg single weekly dose

Expansion Phase: An additional 20 patients will receive MLN9708 at the MTD

Other Name: ixazomib




Primary Outcome Measures :
  1. Highest dose at which ≤1 of 6 patients experiences a dose-limiting toxicity (DLT) during one cycle (28 days) of therapy. [ Time Frame: Days 1, 4, 8 and 15 of Cycle 1 (28 days) ]
    The maximum tolerated dose (MTD) of study drug will be determined as the number of patients experiencing a Grade 3 or Grade 4 adverse event utilizing the National Cancer Institute Common Technology Criteria for Adverse Events (NCI CTCAE) v4.0


Secondary Outcome Measures :
  1. Progression-Free Survival at 2 years post-maintenance therapy [ Time Frame: every 8 weeks for approximately 24 weeks then every 3 months thereafter for 2 years ]
    Defined as the time from Day 1 of study drug administration to disease progression as defined by International Myeloma Working Group Uniform Response Criteria, or death on study. Patients who discontinue study treatment prior to progression will be followed every 3 months during years 1 and 2 for survival.

  2. Overall Survival 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. ]
    Defined as the time from Day 1 of study drug administration to death on study.

  3. Number of subjects with incidence of graft-versus-host disease (GVHD) [ Time Frame: every 28 days, up to 24 months ]
    Assessed from date of randomization until date of first documented progression, or date of death from any cause, up to 24 months



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02168101


Locations
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United States, Colorado
Colorado Blood Cancer Institute
Denver, Colorado, United States, 80218
United States, Ohio
Oncology Hematology Care
Cincinnati, Ohio, United States, 45242
United States, Tennessee
Tennessee Oncology PLLC
Nashville, Tennessee, United States, 37203
United States, Texas
Texas Transplant Institute
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
SCRI Development Innovations, LLC
Millennium Pharmaceuticals, Inc.
Investigators
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Study Chair: Carlos Bachier, MD Texas Transplant Institute

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Responsible Party: SCRI Development Innovations, LLC
ClinicalTrials.gov Identifier: NCT02168101     History of Changes
Other Study ID Numbers: SCRI MM 42
First Posted: June 20, 2014    Key Record Dates
Last Update Posted: May 30, 2019
Last Verified: May 2019
Keywords provided by SCRI Development Innovations, LLC:
MLN9708
allogeneic stem cell transplant
multiple myeloma
ixazomib
autologous stem cell transplant
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Ixazomib
Glycine
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Glycine Agents
Neurotransmitter Agents
Physiological Effects of Drugs