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An Efficacy Study Comparing Oral Ixazomib/Dexamethasone and Oral Pomalidomide/Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT03170882
Recruitment Status : Recruiting
First Posted : May 31, 2017
Last Update Posted : August 17, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
The purpose of this study is to compare the effect of ixazomib+dexamethasone (ixa+dex) versus pomalidomide+dexamethasone (pom+dex) on progression-free survival (PFS) in participants with relapsed and/or refractory multiple myeloma (RRMM) who have received at least 2 prior lines of therapy, including lenalidomide and a proteasome inhibitor, and are refractory to lenalidomide but not refractory to proteasome inhibitors.

Condition or disease Intervention/treatment Phase
Relapsed and/or Refractory Multiple Myeloma Drug: Ixazomib Drug: Pomalidomide Drug: Dexamethasone Phase 2 Phase 3

Detailed Description:

The drug being tested in this study is called Ixazomib. Ixazomib is being tested to treat people who have relapsed and/or refractory multiple myeloma (RRMM). This study will compare the efficacy and safety in participants who take ixazomib and dexamethasone to pomalidomide and dexamethasone. It is an open-label, phase 2 study that, on the basis of a prespecified go/no-go decision rule, will progress to a phase 3 registrational study.

The study will enroll approximately 300 patients. Participants will receive:

  • Ixazomib 4 mg + dexamethasone 20 mg (or 10 mg if participant is aged ≥75 years) OR
  • pomalidomide 4 mg + dexamethasone 40 mg (or 20 mg if participant is aged ≥75 years)

All participants will be asked to take either ixazomib plus dexamethasone (in cases where only 4 mg tablets for dexamethasone are available, the following dexamethasone schedule is recommended for participants aged ≥75 years: 12 mg dexamethasone will be given on Days 1, 8, 15, and 22 of every 28-day cycle; and 8 mg dexamethasone will be given on Days 2, 9, 16, and 23 of every 28-day cycle) or pomalidomide 4 mg + dexamethasone 40 mg at recommended doses.

This multi-center trial will be conducted world wide. The overall time to participate in this study is approximately 63 months if the phase 3 portion of the study is completed. Alternatively, if the no-go criteria are met during the phase 2 portion, the study will be completed approximately 22 to 29 months after the first participant enters the study.

Participants will make multiple visits to the clinic, and will be contacted for progression free survival follow-up, in case of study drug discontinuation for up to 7 years from first dose administration. After disease progression, participants will be followed-up for overall survival every 12 weeks until death or up to 10 years.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2/3, Randomized, Open-Label Study Comparing Oral Ixazomib/Dexamethasone and Oral Pomalidomide/Dexamethasone in Relapsed and/or Refractory Multiple Myeloma
Actual Study Start Date : July 25, 2017
Estimated Primary Completion Date : November 30, 2021
Estimated Study Completion Date : March 31, 2023


Arm Intervention/treatment
Experimental: Ixazomib plus dexamethasone
Ixazomib 4 mg as starting dose, capsules, orally on Days 1, 8, and 15 of each 28-day cycle, with escalation to 5.5 mg at Cycle 2 for participants who tolerate the 4 mg dose in Cycle 1, plus dexamethasone 20 mg (or 10 mg if participant is aged ≥75 years) tablets, orally, on Days 1, 2, 8, 9, 15, 16, 22, and 23 of every 28-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or sponsor termination of study (up to 63 months).
Drug: Ixazomib
Ixazomib capsules
Other Names:
  • NINLARO
  • MLN9708

Drug: Dexamethasone
Dexamethasone tablets

Active Comparator: Pomalidomide plus dexamethasone
Pomalidomide 4 mg, capsules, orally on Days 1 to 21 of each 28-day cycle plus dexamethasone 40 mg, (or 20 mg if participant is aged ≥75 years), tablets, orally on Days 1, 8, 15, and 22 of each 28-day cycle until disease progression, unacceptable toxicity, withdrawal of consent, or sponsor termination of study (up to 63 months).
Drug: Pomalidomide
Pomalidomide capsules

Drug: Dexamethasone
Dexamethasone tablets




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: From date of randomization until disease progression or death due to any cause, whichever occurs first (Up to 7 years) ]
    PFS is defined as time from randomization to first documentation of progressive disease (PD) based on central laboratory results and assessment by an independent review committee (IRC) using modified International Myeloma Working Group (IMWG) response criteria or death due to any cause, whichever occurs first. PD requires following:Increase of ≥25% from nadir in:Serum M-component (increase must be ≥0.5 g/dl);Urine M-component (increase must be ≥200 mg/24-hour);In participants without measurable serum and urine M-protein levels difference between involved and uninvolved free light chain (FLC) levels increase of >10 mg/dl;In participants without measurable serum and urine M protein levels and without measurable disease by FLC level:bone marrow plasma cell percentage must be ≥10%;Development of new/ increase in size of existing bone lesions/ soft tissue plasmacytomas;development of hypercalcemia (>11.5 mg/dL corrected serum calcium) attributed solely to plasma cell proliferative disease.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: From randomization up to 10 years ]
    OS is defined as the time from randomization to death from any cause.

  2. Percentage of Participants with Objective Response Rate (ORR - Partial Response [PR], Very Good Partial Response [VGPR] and Complete Response [CR]) [ Time Frame: Day 1 of Cycle 1 (28 day cycle) then every cycle until disease progression for up to 7 years ]
    ORR is based on laboratory results and independent review committee (IRC) assessment using modified IMWG criteria. PR: ≥50% reduction of serum M protein + reduction in 24-hour urinary M protein by ≥90% or to <200 mg/24-hour; if M protein is not measurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required; if not measurable by FLC, ≥50% reduction in bone marrow plasma cells, when baseline value = ≥30% and; if present at baseline, ≥50% reduction in size of soft tissue plasmacytomas is required; VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein + urine M-protein level <100 mg/24-hour. CR: negative immunofixation on serum + urine; disappearance of soft tissue plasmacytomas; <5% plasma cells in bone marrow.

  3. Duration of Response (DOR) [ Time Frame: Day 1 of Cycle 1 (28 day cycle) then every cycle until disease progression for up to 7 years ]
    DOR is defined as time from first documentation of CR/PR/VGPR to first documentation of PD. Per IMWG criteria, PR:≥50% reduction of serum M protein+reduction in 24-hour urinary M protein by ≥90%/ to <200 mg/24-hour or ≥50% decrease in difference between involved and uninvolved FLC levels/ ≥50% reduction in bone marrow plasma cells, if ≥30% at baseline/ ≥50% reduction in size of soft tissue plasmacytomas. VGPR:serum+urine M-protein detectable by immunofixation but not on electrophoresis/ ≥90% reduction in serum M-protein+urine M-protein level <100 mg/24-hour. CR:negative immunofixation on serum+urine+disappearance of soft tissue plasmacytomas+<5% plasma cells in bone marrow. PD:serum M-component increase ≥0.5 g/dl or urine M-component increase ≥200 mg/24-hour/ difference between involved and uninvolved FLC levels increase >10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.

  4. Time to Response [ Time Frame: Day 1 of Cycle 1 (28 day cycle) then every cycle until the first documentation of PR or PR/VGPR/CR for up to 7 years ]
    Time to response is defined as the time from randomization to the first documentation of PR/VGPR/CR. Per IMWG criteria PR is defined as ≥50% reduction of serum M protein + reduction in 24-hour urinary M protein by ≥90% or to <200 mg/24-hour; if M-protein is not measurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required; if not measurable by FLC, ≥50% reduction in bone marrow plasma cells, when baseline value = ≥30% and; if present at baseline, ≥50% reduction in size of soft tissue plasmacytomas is required; VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein + urine M-protein level <100 mg/24-hour. CR: negative immunofixation on serum + urine; disappearance of soft tissue plasmacytomas; <5% plasma cells in bone marrow.

  5. Time to Progression (TTP) [ Time Frame: Day 1 of Cycle 1 (28 day cycle) then every cycle until disease progression for up to 7 years ]
    TTP is defined as the time from randomization to first documentation of PD. Per IMWG criteria, PD requires 1 of the following: Increase of ≥25% from nadir in: Serum M-component (increase must be ≥0.5 g/dl; Urine M-component (increase must be ≥200 mg/24-hour); In participants without measurable serum and urine M-protein levels difference between involved and uninvolved FLC levels increase of >10 mg/dl; In participants without measurable serum and urine M protein levels and without measurable disease by FLC level: Bone marrow plasma cell percentage must be ≥10%; Development of new or increase in size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (>11.5 mg/dL corrected serum calcium) attributed solely to plasma cell proliferative disease.

  6. Health-Related Quality of Life (HRQOL) based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 (EORTC QLQ-C30) Physical Domain Score [ Time Frame: Baseline up to 7 years ]
    The EORTC QLQ-C30 physical domain consists of 5 items covering participant's daily physical activities. The total score reported is between 0 and 100, with a high score indicating better functioning.

  7. HRQOL based on EORTC QLQ-C30 Total Score [ Time Frame: Baseline up to 7 years ]
    The EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and a global health status/QOL scale. Most of the 30 items have 4 response levels (not at all, a little, quite a bit, and very much), with 2 questions relying on a 7-point numeric rating scale. Raw scores are converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QOL scale, higher scores represent better QOL; for the symptom scales, lower scores represent better QOL.

  8. HRQOL based on EORTC Multiple Myeloma Module (EORTC QLQ-MY20) Score [ Time Frame: Baseline up to 7 years ]
    The EORTC QLQ-MY20 has 20 items across 4 independent subscales, 2 functional subscales (body image, future perspective), and 2 symptoms scales (disease symptoms, and side effects of treatment). Scores are averaged, and transformed to 0-100 scale. For the future perspective scale, higher score = better perspective of the future. For the body image scale, higher scores = better body image. Higher score for the disease symptoms scale = higher level of symptomatology.

  9. HRQOL based on 5-level Classification System of the EuroQol 5-Dimensional Health Questionnaire (EQ-5D-5L) Score [ Time Frame: Baseline up to 7 years ]
    The EQ-5D-5L consists of 2 domains: the EQ-5D-5L descriptive system and the EuroQol visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each rated on 5 levels. 1 = no problems, 2 = slight problems, 3= moderate problems, 4= severe problems, 5 = extremely severe problems. The EQ VAS records the respondent's self-rated health on a 20 cm, vertical, visual analogue scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The scores from all dimensions are combined into a single index score that is reported.

  10. Health Care Utilization (HU): Number of Medical Encounters [ Time Frame: Baseline up to 7 years ]
    HU as measured by the number of medical encounters.

  11. HU: Duration of Medical Encounters [ Time Frame: Baseline up to 7 years ]
    HU as measured by the duration of medical encounters.



Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Must have a confirmed diagnosis of multiple myeloma (MM) requiring therapy according to International Myeloma Working Group (IMWG) criteria.
  2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
  3. Must have had a relapse or progressive disease (PD) after having received 2 or more prior lines of systemic therapy. Note: A line of therapy is defined as 1 or more cycles of a planned treatment program; this may consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem cell transplantation (SCT), followed by maintenance is considered 1 line of therapy. Typically each line of therapy is separated by PD.
  4. Must be refractory to lenalidomide, defined as having received at least 2 consecutive cycles of lenalidomide as a single agent or within a lenalidomide-containing regimen and having had PD during treatment with or within 60 days after the last dose of lenalidomide. The starting dose of lenalidomide should have been 25 mg (or as low as 10 mg in the case of renal function impairment or other safety concern), and the final dose should have been a minimum of 10 mg.
  5. Must have received at least 2 consecutive cycles of a bortezomib- or carfilzomib-containing regimen, and either:

    • Achieved at least a partial response (PR) and did not have PD during treatment with or within 60 days after the last dose of bortezomib or carfilzomib, OR
    • Had bortezomib and/or carfilzomib intolerance (defined as discontinuation because of drug-related adverse events (AEs) before completion of the planned treatment course) without PD before the start of the next regimen.
  6. Must have measurable disease defined by:

    • Serum M-protein ≥1 g/dL (≥10 g/L), OR
    • Urine M-protein ≥200 mg/24 hours and must have documented MM isotype by immunofixation (central laboratory).
  7. Suitable venous access for the study-required blood sampling, including pharmacokinetic (PK) sampling.
  8. Recovered (i.e., ≤Grade 1 nonhematologic toxicity) from the reversible effects of prior anticancer therapy.
  9. Must be willing and able to adhere to pomalidomide-related risk mitigation activities if randomized to the pomalidomide+dexamethasone (pom+dex) arm (e.g., Risk Evaluation and Mitigation Strategies [REMS], pregnancy prevention programs).

Exclusion Criteria:

  1. Prior allogenic bone marrow transplantation in any prior line of therapy or prior autologous SCT in the last prior line of therapy.
  2. Diagnosed with or treated for another malignancy within 2 years before randomization, or previously diagnosed with another malignancy and have any evidence of residual, persistent, or recurrent disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
  3. Diagnosis of smoldering MM, Waldenström's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
  4. Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy of any cause on clinical examination during the Screening period.
  5. Treatment with any investigational products or with chimeric or fully human monoclonal antibodies within 30 days before randomization, systemic anticancer therapy or radiotherapy within 14 days before randomization (Note: "spot" radiation for areas of pain is permitted), and major surgery within 14 days before randomization.
  6. Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral absorption or tolerance of study therapy, including difficulty swallowing.
  7. Serious infection requiring parenteral antibiotic therapy or any other serious infection within 14 days before randomization.
  8. Central nervous system involvement with MM (by clinical symptoms and signs).
  9. Ongoing or active systemic infection, known human immunodeficiency virus-ribonucleic acid (RNA) positive, known hepatitis B surface antigen seropositive, or known hepatitis C virus-RNA positive.
  10. Systemic treatment with strong cytochrome P-450 3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) or use of St. John's wort within 14 days before randomization.
  11. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.

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): NCT03170882


Contacts
Contact: Takeda Study Registration Call Center +1-844-622-6468 GlobalOncologyMedinfo@takeda.com

  Show 124 Study Locations
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.

Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03170882     History of Changes
Other Study ID Numbers: C16029
2016-004742-28 ( EudraCT Number )
U1111-1188-2677 ( Other Identifier: WHO [Universal Trial Number] )
2017/1235 ( Registry Identifier: Norwegian Medicines Agency )
N-20170083 ( Registry Identifier: Danish Medicines Agency )
17/NW/0546 ( Registry Identifier: NRES )
First Posted: May 31, 2017    Key Record Dates
Last Update Posted: August 17, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Drug therapy

Additional relevant MeSH terms:
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
Dexamethasone acetate
Dexamethasone
Pomalidomide
Ixazomib
Thalidomide
BB 1101
Glycine
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists