Clinical Trials /

S1211 Bortezomib, Dexamethasone, and Lenalidomide With or Without Elotuzumab in Treating Patients With Newly Diagnosed High-Risk Multiple Myeloma

NCT01668719

Description:

This partially randomized phase I/II trial studies the side effects and best dose of elotuzumab and to see how well it works when given together with lenalidomide, bortezomib, and dexamethasone in treating patients with newly diagnosed multiple myeloma that is likely to recur (come back), or spread (high-risk). Lenalidomide and bortezomib may stop the growth of multiple myeloma by blocking blood flow to the tumor. Also, bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as lenalidomide and dexamethasone, also work in different ways to kill cancer cells, by stopping them from dividing, or by stopping them from spreading. Giving elotuzumab together with lenalidomide, bortezomib, and dexamethasone may be a better way to block cancer growth.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: S1211 Bortezomib, Dexamethasone, and Lenalidomide With or Without Elotuzumab in Treating Patients With Newly Diagnosed High-Risk Multiple Myeloma
  • Official Title: A Randomized Phase I/II Study of Optimal Induction Therapy of Bortezomib, Dexamethasone and Lenalidomide With or Without Elotuzumab (NSC-764479) for Newly Diagnosed High Risk Multiple Myeloma (HRMM)

Clinical Trial IDs

  • ORG STUDY ID: S1211
  • SECONDARY ID: NCI-2012-01998
  • SECONDARY ID: PS1211_A12PAMDREVW01
  • SECONDARY ID: CDR0000738512
  • SECONDARY ID: S1211
  • SECONDARY ID: S1211
  • SECONDARY ID: U10CA180888
  • SECONDARY ID: U10CA032102
  • NCT ID: NCT01668719

Conditions

  • DS Stage I Plasma Cell Myeloma
  • DS Stage II Plasma Cell Myeloma
  • DS Stage III Plasma Cell Myeloma

Interventions

DrugSynonymsArms
Bortezomib[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, VelcadeArm I (bortezomib, lenalidomide, dexamethasone)
DexamethasoneAacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, VisumetazoneArm I (bortezomib, lenalidomide, dexamethasone)
ElotuzumabBMS-901608, HuLuc63, PDL-063, PDL063Arm II (bortezomib, lenalidomide, dexamethasone, elotuzumab)
LenalidomideCC-5013, CC5013, CDC 501, RevlimidArm I (bortezomib, lenalidomide, dexamethasone)

Purpose

This partially randomized phase I/II trial studies the side effects and best dose of elotuzumab and to see how well it works when given together with lenalidomide, bortezomib, and dexamethasone in treating patients with newly diagnosed multiple myeloma that is likely to recur (come back), or spread (high-risk). Lenalidomide and bortezomib may stop the growth of multiple myeloma by blocking blood flow to the tumor. Also, bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as lenalidomide and dexamethasone, also work in different ways to kill cancer cells, by stopping them from dividing, or by stopping them from spreading. Giving elotuzumab together with lenalidomide, bortezomib, and dexamethasone may be a better way to block cancer growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the appropriate Phase II dose of elotuzumab to use in combination with
      lenalidomide, bortezomib, and dexamethasone for patients with multiple myeloma. (Phase I) II.
      To assess whether incorporation of the novel agent elotuzumab into the treatment algorithm of
      high-risk multiple myeloma (HRMM) will improve progression-free survival (PFS). (Phase II)
      III. To estimate the frequency and severity of toxicities of this treatment strategy in this
      patient population. (Phase II)

      OUTLINE: This is a phase I, dose-escalation study of elotuzumab, followed by a phase II,
      randomized study.

      PHASE I:

      INDUCTION: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) on days 1,
      4, 8, and 11; lenalidomide orally (PO) once daily (QD) on days 1-14; and dexamethasone PO or
      IV on days 1, 2, 4, 5, 8, 9, 11, and 12 (and on day 15 of courses 1 and 2 only). Patients
      also receive elotuzumab IV on days 1, 8, and 15 of courses 1 and 2 and on days 1 and 11 of
      courses 3-8. Treatment repeats every 21 days for 8 courses in the absence of disease
      progression or unacceptable toxicity.

      MAINTENANCE: Patients receive bortezomib SC or IV on days 1, 8, and 15; lenalidomide PO QD on
      days 1-21; dexamethasone PO on days 1, 8, and 15; and elotuzumab IV on days 1 and 15.
      Treatment repeats every 28 days in the absence of disease progression or unacceptable
      toxicity.

      PHASE II: Patients are randomized to 1 of 2 treatment arms.

      ARM I:

      INDUCTION: Patients receive bortezomib SC or IV on days 1, 4, 8, and 11; lenalidomide PO QD
      on days 1-14; and dexamethasone PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12. Treatment
      repeats every 21 days for 8 courses in the absence of disease progression or unacceptable
      toxicity (patients who received a course of chemotherapy prior to registration will begin
      protocol treatment with course 2 and receive a total of 7 courses of protocol therapy).

      MAINTENANCE: Patients receive bortezomib SC or IV on days 1, 8, and 15; lenalidomide PO QD on
      days 1-21; and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      ARM II:

      INDUCTION: Patients receive bortezomib, lenalidomide, and dexamethasone as in Arm I. Patients
      also receive elotuzumab IV on days 1, 8, and 15 of courses 1 and 2 and on days 1 and 11 of
      courses 3-8. Treatment repeats every 21 days for 8 courses in the absence of disease
      progression or unacceptable toxicity.

      MAINTENANCE: Patients receive bortezomib, lenalidomide, and dexamethasone as in Arm I.
      Patients also receive elotuzumab IV on days 1 and 15. Courses repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for up to 6
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (bortezomib, lenalidomide, dexamethasone)Active ComparatorINDUCTION: Patients receive bortezomib SC or IV on days 1, 4, 8, and 11; lenalidomide PO QD on days 1-14; and dexamethasone PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity (patients who received a course of chemotherapy prior to registration will begin protocol treatment with course 2 and receive a total of 7 courses of protocol therapy). MAINTENANCE: Patients receive bortezomib SC or IV on days 1, 8, and 15; lenalidomide PO QD on days 1-21; and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Bortezomib
  • Dexamethasone
  • Lenalidomide
Arm II (bortezomib, lenalidomide, dexamethasone, elotuzumab)ExperimentalINDUCTION: Patients receive bortezomib, lenalidomide, and dexamethasone as in Arm I. Patients also receive elotuzumab IV on days 1, 8, and 15 of courses 1 and 2 and on days 1 and 11 of courses 3-8. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive bortezomib, lenalidomide, and dexamethasone as in Arm I. Patients also receive elotuzumab IV on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Bortezomib
  • Dexamethasone
  • Elotuzumab
  • Lenalidomide

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have newly diagnosed active multiple myeloma (MM)

          -  For the Phase II portion only, patients must have high-risk MM based on one or more of
             the following criteria at the time of initial diagnosis (prior to any chemotherapy):

               -  Poor-risk genomic signature according to the University of Arkansas 70-gene model
                  (available clinically as myeloma prognostic risk score [MyPRS] score, Signal
                  Genetics, Inc) AND/OR

               -  Translocation (14;16), and/or translocation (14;20), and/or deletion (17p) by
                  fluorescence in-situ hybridization (FISH) or cytogenetics AND/OR

               -  Primary plasma cell leukemia (defined by either >= 2,000 plasma cells/mL of
                  peripheral blood, or 20% on a manual differential count) AND/OR

               -  Serum lactate dehydrogenase (LDH) >= 2 x institutional upper limit of normal
                  (IULN) AND/OR

               -  1q21 amplification by FISH analysis AND/OR

               -  High risk by the SKY92 signature

          -  Patients with non-secretory MM or known amyloidosis are not eligible

          -  Patients must have measurable disease within 28 days prior to registration (or prior
             to initiation of first induction course for patients with prior therapy)

          -  Patients on the Phase I portion may not have received ANY prior chemotherapy; patients
             on the Phase II portion may have received one prior cycle of any non-investigational
             chemotherapy; prior chemotherapy must have been completed within 56 days prior to
             registration and all toxicities must have resolved to =< grade 1; patients on either
             portion may have received prior treatment with dexamethasone, providing total number
             of days of treatment was =< 14 days and total treatment dose was =< 360 mg

          -  Patients may have received prior radiotherapy for symptomatic localized bone lesions
             or impending spinal cord compression only; radiotherapy must be completed at least 14
             days prior to registration and all toxicities must have resolved to =< grade 1

          -  Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 without growth factor support

          -  Platelet count >= 70,000 cells/mm^3 for patients who have bone marrow plasmacytosis <
             50%; or >= 50,000 cells/mm^3 for patients who have bone marrow plasmacytosis of >= 50%

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)

          -  Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) and
             serum glutamate pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) =< 2.5 x
             IULN

          -  Creatinine clearance (CrCL) >= 30 mL/min, measured by a 24-hour urine collection or
             estimated by the Cockcroft and Gault formula within 14 days prior to registration

          -  Patients must not have active involvement of the central nervous system (CNS) with MM
             (by clinical evaluation); patients with documentation of, or clinical signs or
             symptoms consistent with, CNS involvement of MM must have a lumbar puncture that is
             negative for CNS involvement of MM; the lumbar puncture must be completed within 14
             days prior to registration; patients with no previous history of documented CNS
             involvement and with no clinical signs or symptoms consistent with CNS involvement are
             not required to have completed a lumbar puncture prior to registration; note that
             monitoring of CNS involvement and treatment with intrathecal therapy is recommended
             during protocol treatment

          -  Patients who are known to be human immunodeficiency virus positive (HIV+) are eligible
             providing they meet all of the following additional criteria within 28 days prior to
             registration:

               -  Cluster of differentiation (CD)4 cells >= 500/mm^3

               -  Viral load of < 50 copies HIV messenger ribonucleic acid (mRNA)/mm^3 if on
                  combination antiretroviral therapy (cART) or < 25,000 copies HIV mRNA if not on
                  cART

               -  No zidovudine or stavudine as part of cART

               -  Patients who are HIV+ and do not meet all of these criteria are not eligible for
                  this study

          -  Patients must have baseline skeletal survey (whole body x-ray) to document lytic
             lesions, osteopenia or compression fracture

          -  Patients must have Zubrod performance status =< 2

          -  Patients with known hepatitis B or hepatitis C infection may be eligible providing
             they have viral load < 800,000 IU/L within 28 days prior to registration

          -  Patients must not have POEMS syndrome (plasma cell dyscrasia with polyneuropathy,
             organomegaly, endocrinopathy, monoclonal protein, and skin changes)

          -  Patients must not have clinically significant illness including uncontrolled, active
             infection requiring intravenous antibiotics, New York Heart Association (NYHA) class
             III or class IV heart failure, unstable angina pectoris, myocardial infarction within
             the past 6 months, uncontrolled >= grade 3 cardiac arrhythmias, uncontrolled
             hypertension, or uncontrolled diabetes mellitus; patients must have undergone an
             electrocardiogram (EKG) within 28 days prior to registration

          -  Uncontrolled diabetes: a glycated hemoglobin (Hg A1C) > 7% within 14 days prior to
             registration; the same criterion will be used in patients with confirmed diagnosis of
             diabetes mellitus who have been on a stable dietary or therapeutic regimen for this
             condition in the last three months

          -  Uncontrolled blood pressure and hypertension: systolic blood pressure (SBP) > 140 mm
             Hg or diastolic blood pressure (DBP) > 90 mm Hg within 14 days prior to registration;
             patients are permitted to be receiving multiple anti-hypertensive medications (unless
             otherwise indicated in the study); all blood pressure measurements within the 14 days
             prior to registration and on day 1 of cycle 1 must be SBP =< 140 and DBP =< 90; an
             exception can be made by a healthcare provider for a patient with a single blood
             pressure elevation who upon rechecking has a normal blood pressure

          -  Patients must have history and physical examination within 28 days prior to
             registration

          -  Patients must not have any psychiatric illness that could potentially interfere with
             the completion of treatment according to this protocol

          -  Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
             test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to
             registration; (Note: that pregnancy testing is also required within 24 hours prior to
             treatment on cycle 1, day 1); furthermore, they must either commit to continued
             abstinence from heterosexual intercourse or begin TWO acceptable methods of birth
             control: one highly effective method and one additional effective method AT THE SAME
             TIME, at least 28 days before starting lenalidomide; FCBP must also agree to ongoing
             pregnancy testing; men must agree to use a latex condom during sexual contact with a
             FCBP, even if they have had a successful vasectomy; a FCBP is a sexually mature woman
             who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
             naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at
             any time in the preceding 24 consecutive months)

          -  No other prior malignancy is allowed except for the following: adequately treated
             basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
             stage I or II cancer from which the patient is currently in complete remission, or any
             other cancer from which the patient has been disease free for five years

          -  Patients must be offered participation in banking of specimens for future research;
             with the patient's consent, specimens (serum and bone marrow biopsy core) must be
             submitted to the repository; patient consent must be obtained before specimens are
             submitted

          -  Patients must be registered to the mandatory Revlimid Risk Evaluation and Mitigation
             Strategy (REMS)™ program and must be willing and able to comply with the requirements
             of the Revlimid REMS™ program

          -  Patients or their legally authorized representative must be informed of the
             investigational nature of this study and must sign and give written informed consent
             in accordance with institutional and federal guidelines

          -  As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
             treating institution's identity is provided in order to ensure that the current
             (within 365 days) date of institutional review board approval for this study has been
             entered in the system
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:PFS
Time Frame:From date of registration to date of first documentation of progression or death due to any cause assessed up to 6 years
Safety Issue:
Description:A stratified log-rank test will be used to compare PFS in the two treatment arms. In addition, the distribution of PFS in each arm will be estimated using the method of Kaplan-Meier by treatment group. Exploratory multivariate analyses will be performed to assess the treatment effect adjusting for key prognostic factors using the Cox proportional hazard regression model.

Secondary Outcome Measures

Measure:Incidence of toxicity assessed by the NCI CTCAE version 4.0
Time Frame:Up to 6 years
Safety Issue:
Description:The maximum grade for each toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Measure:Overall survival
Time Frame:Up to 6 years
Safety Issue:
Description:Evaluated using a stratified long-rank test to compare the experimental arm to the control arm. In addition, the method of Kaplan-Meier will be used to estimate and display the distribution of the endpoints over time.
Measure:Response (partial response [PR] or better) rate
Time Frame:Up to 6 years
Safety Issue:
Description:The number of patients who achieve a PR or better will be divided by the number of patients in the intent to treat population. Comparisons between arms will be made using Fisher's Exact Test.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Southwest Oncology Group

Last Updated