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A Phase 3 Study Comparing Oral Ixazomib Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by Millennium Pharmaceuticals, Inc.
Sponsor:
Information provided by (Responsible Party):
Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT01564537
First received: March 22, 2012
Last updated: November 18, 2014
Last verified: November 2014
  Purpose

The purpose of this phase 3, randomized, double-blind, multicenter study is to compare Oral Ixazomib (MLN9708) plus Lenalidomide and Dexamethasone versus Placebo plus Lenalidomide and Dexamethasone in adult patients with relapsed and/or refractory multiple myeloma.


Condition Intervention Phase
Relapsed Multiple Myeloma
Refractory Multiple Myeloma
Drug: ixazomib + Lenalidomide + Dexamethasone
Drug: Placebo + Lenalidomide + Dexamethasone
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral Ixazomib (MLN9708) Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Millennium Pharmaceuticals, Inc.:

Primary Outcome Measures:
  • Progression free survival (PFS) [ Time Frame: Change from the time of screening; Day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
    To determine whether the addition of oral ixazomib to the background therapy of lenalidomide and dexamethasone improves PFS in patients with relapsed and/or refractory multiple myeloma


Secondary Outcome Measures:
  • Overall Survival [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination ] [ Designated as safety issue: No ]
    To determine whether the addition of oral ixazomib to lenalidomide and dexamethasone improves OS

  • Overall Survival in high-risk patients carrying del(17) [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination ] [ Designated as safety issue: No ]
    To determine whether the addition of oral ixazomib to lenalidomide and dexamethasone improves the OS in high-risk patients carrying deletion del(17)

  • Overall Response Rate (ORR), including Partial Response (PR), Very Good Partial Response (VGPR), and Complete Response (CR) [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
    Standard multiple myeloma disease assessments

  • CR + VGPR [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
    Standard multiple myeloma disease assessments

  • Duration of Response (DOR) [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
  • Time to Progression (TTP) [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
  • Number of AEs, SAEs, assessment of clinical laboratory values and evaluate Eastern Cooperative Group (ECOG) performance scores [ Time Frame: From the date of signing of the informed consent form through 30 days after the last dose of study drug ] [ Designated as safety issue: Yes ]
    To determine the safety of addition of ixazomib to lenalidomide and dexamethasone

  • Pain response rate as assessed by the BFI-SF and analgesic use [ Time Frame: BPI-SF will be assessed at screening; Day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
  • Change in global health status, as measured by the patient reported outcome questionnaires, EORTC QLQ-C30 and MY-20 [ Time Frame: At the time of screening, Day 1 of Cycle 1 and Cycle 2; every other cycle until EOT; every 4 weeks after EOT until disease progression and thereafter every 12 weeks until OS ] [ Designated as safety issue: No ]
  • OS and PFS in high-risk population such as those carrying del(13), del(17), +1q21, t(4;14), or t(14;16) [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination ] [ Designated as safety issue: Yes ]
  • To collect PK data including Cmax, AUC and Tmax to contribute to population PK analyses [ Time Frame: Days 1 & 14 of cycles 1&2. Day 1 of cycles 3-10 ] [ Designated as safety issue: No ]
  • Association between response or resistance to MLN9708 treatment and proteasome and NFKB-related genes [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination ] [ Designated as safety issue: No ]

Estimated Enrollment: 703
Study Start Date: August 2012
Estimated Study Completion Date: May 2019
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: ixazomib
ixazomib+ Lenalidomide + Dexamethasone
Drug: ixazomib + Lenalidomide + Dexamethasone
Patients will receive single oral dose of ixazomib (4.0mg) on days 1,8,15 and single oral dose of Lenalidomide (25mg) on days 1-21 and single oral dose of Dexamethasone (40mg) on days 1,8, 15 and 22 every 28 days until disease progression
Placebo Comparator: Placebo
Placebo + Lenalidomide + Dexamethasone
Drug: Placebo + Lenalidomide + Dexamethasone
Patients will receive single oral dose of Placebo on days 1,8,15 and single oral dose of Lenalidomide (25mg) on days 1-21 and single oral dose of Dexamethasone (40mg) on days 1,8, 15 and 22 every 28 days until disease progression

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female patients 18 years of age or older.
  2. Multiple myeloma diagnosed according to standard criteria either currently or at the time of initial diagnosis NOTE: The initial diagnosis must be symptomatic MM, although the relapsed disease does not need to be symptomatic.
  3. Patients must have measurable disease defined by at least 1 of the following 3 measurements:

    • Serum M-protein ≥ 1 g/dL ( ≥10 g/L).

    • Urine M-protein ≥ 200 mg/24 hours.

    • Serum free light chain assay: involved free light chain level ≥ 10 mg/dL ( ≥ 100 mg/L), provided that the serum free light chain ratio is abnormal.

  4. Patients with relapsed and/or refractory MM who have received 1 to 3 prior therapies.

    NOTE: This patient population includes the following 3 categories of patients:

    • Patients who relapsed from their previous treatment(s) but were not refractory to any previous treatment.

    • Patients who were refractory to all lines of previous treatment(s) (ie, patients who have never responded to any therapies received).

    • Patients who were relapsed from at least 1 previous treatment AND additionally were refractory to at least 1 previous treatment. For the purposes of this study, refractory disease is defined as disease progression on treatment or progression within 60 days after the last dose of a given therapy.

    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, followed by maintenance is considered 1 line of therapy. Autologous and allogenic transplants are permitted.

  5. Patients must meet the following clinical laboratory criteria:

    • Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days prior to randomization.

    • Total bilirubin ≤1.5 times the upper limit of the normal range (ULN).

    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 times ULN.
    • Calculated creatinine clearance ≥ 30 mL/min NOTE: Patients with a low creatinine clearance ≤ 60 mL/min (or ≤ 50 mL/min, according to local label/practice) will receive a reduced lenalidomide dose of 10 mg once daily on Days 1 through 21 of a 28-day cycle. The lenalidomide dose may be escalated to 15 mg once daily after 2 cycles if the patient is not responding to treatment and is tolerating the treatment. If renal function normalizes (ie, creatinine clearance > 60 mL/min or > 50 mL/min, according to local label/practice) and the patient continues to tolerate this treatment, lenalidomide may then be escalated to 25 mg once daily.
  6. ECOG performance status of 0, 1, or 2.
  7. Patients who received prior allogenic transplant must have no active graft-versus-host disease (GVHD).
  8. Female patients who:

    • Are postmenopausal for at least 24 months before the screening visit, OR
    • Are surgically sterile, OR
    • Females of childbearing potential must:

1. Have a negative pregnancy test with a sensitivity of at least 25 mIU/mL within 10 to 14 days and again within 24 hours prior to starting Cycle 1 of lenalidomide 2. Either agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) OR begin TWO reliable methods of birth control: 1 highly effective method and 1 additional effective method AT THE SAME TIME, at least 28 days before starting study drug through 90 days after the last dose of study treatment 3. Agree to ongoing pregnancy testing 4. Adhere to the guidelines of the RevAssist program (United States [US] participants), RevAid program (Canadian participants), iAccess program (Australian participants), RevMate program (Japanese participants) or The Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the Study Manual (all other participants who are not using commercial supplies)

Male patients, even if surgically sterilized (ie, status postvasectomy), must:

• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) OR

  • Agree to practice effective barrier contraception during the entire study treatment period and 90 days after the last dose of study treatment if their partner is of childbearing potential, even if they have had a successful vasectomy, AND
  • Adhere to the guidelines of the RevAssist program (US participants), RevAid program (Canadian participants), iAccess program (Australian participants), RevMate program (Japanese participants) or The Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the study Manual (all other participants who are not using commercial supplies)

    9. Must be able to take concurrent aspirin 81 to 325 mg daily (or enoxaparin 40 mg subcutaneously daily [or its equivalent] if allergic to aspirin), per published standard or institutional standard of care, as prophylactic anticoagulation.

NOTE: For patients with prior history of DVT, low molecular weight heparin (LMWH) is mandatory.

10. 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.

11. Patient is willing and able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

  1. Patient was refractory to lenalidomide or proteasome inhibitor-based therapy at any line.

    NOTE: Refractory disease defined as disease progression on treatment or progression within 60 days after the last dose of a given therapy. Patients who progress after 60 days from the last dose of a given therapy will be considered relapsed and are eligible for inclusion in the study.

    Patients who were refractory to thalidomide-based therapy are eligible.

  2. Female patients who are breast feeding or pregnant.
  3. Failure to have fully recovered (ie, ≤ Grade 1 toxicity) from the effects of prior chemotherapy (except for alopecia) regardless of the interval since last treatment.
  4. Major surgery within 14 days before randomization.
  5. Radiotherapy within 14 days before randomization.
  6. Central nervous system involvement.
  7. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before randomization.
  8. Diagnosis of Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
  9. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
  10. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before randomization in the study.
  11. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
  12. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens (eg, peripheral neuropathy that is Grade 1 with pain or Grade 2 or higher of any cause).
  13. Psychiatric illness/social situation that would limit compliance with study requirements.
  14. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
  15. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) condition that could interfere with the oral absorption or tolerance of treatment.
  16. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01564537

Contacts
Contact: For an updated listing of recruitment sites contact: Millennium Medical and Drug Information Center 1-877-674-3784 medical@mlnm.com

  Show 147 Study Locations
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Study Director: Medical Monitor Millennium Pharmaceuticals, Inc.
  More Information

No publications provided

Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01564537     History of Changes
Other Study ID Numbers: C16010, 2011-005496-17, CTR20130908
Study First Received: March 22, 2012
Last Updated: November 18, 2014
Health Authority: United States: Food and Drug Administration
European Union: European Medicines Agency
Australia: Department of Health and Ageing Therapeutic Goods Administration
Austria: Federal Office for Safety in Health Care
Belgium: Federal Agency for Medicinal Products and Health Products
Canada: Health Canada
China: Food and Drug Administration
Czech Republic: State Institute for Drug Control
Denmark: Danish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Hungary: National Institute for Quality and Organizational Development in Healthcare and Medicines
Israel: Ministry of Health
Italy: The Italian Medicines Agency
Japan: Pharmaceuticals and Medical Devices Agency
Korea: Food and Drug Administration
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
New Zealand: Ministry of Health
Norway: Norwegian Medicines Agency
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Portugal: National Pharmacy and Medicines Institute
Romania: National Agency for Medicines and Medical Devices
Russia: Ministry of Health of the Russian Federation
Singapore: Health Sciences Authority
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
Turkey: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Millennium Pharmaceuticals, Inc.:
Relapsed multiple myeloma
Refractory multiple myeloma
Ixazomib
MLN9708
Proteasome inhibitor
Tourmaline-MM1

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
BB 1101
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Lenalidomide
Thalidomide
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Anti-Inflammatory Agents
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Autonomic Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on November 24, 2014