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    Summary
    EudraCT Number:2011-000609-32
    Sponsor's Protocol Code Number:C14011
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2012-05-03
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2011-000609-32
    A.3Full title of the trial
    A Multicenter, Phase 1-2 Study of MLN8237, an Oral Aurora A Kinase Inhibitor, in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab and Vincristine
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study on the effects of adding MLN8237 with Rituximab and Vincristine in patients with B-cell lymphoma treated who have failed previous treatments for the disease.
    A.4.1Sponsor's protocol code numberC14011
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01397825
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMillennium Pharmaceuticals, Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMillennium Pharmaceuticals Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMillennium Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointDrug Information Call Center
    B.5.3 Address:
    B.5.3.1Street Address40 Landsdowne St
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number001510740-2412
    B.5.5Fax number001800881-6092
    B.5.6E-mailmedical@mlnm.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAlisertib
    D.3.2Product code MLN8237
    D.3.4Pharmaceutical form Coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAlisertib
    D.3.9.1CAS number 1208255-63-3
    D.3.9.2Current sponsor codeMLN8237
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed or Refractory Aggressive B-Cell Lymphoma
    E.1.1.1Medical condition in easily understood language
    Cancer of the white blood cells that has not responded to previous treatment or which has come back.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10003902
    E.1.2Term B-cell lymphoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10003903
    E.1.2Term B-cell lymphoma refractory
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    PART 1:
    To evaluate safety and tolerability and determine the recommended phase 2 dose (RP2D) and schedule of MLN8237 in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), and other eligible aggressive B-cell lymphomas, treated with rituximab

    PART 2:
    To evaluate safety and tolerability of the MRV combination in patients with relapsed or refractory DLBCL, and other eligible aggressive B-cell lymphomas, and to determine the RP2D and schedule for phase 2

    PART 3:
    To determine ORR (complete response [CR] and partial response [PR]) of the MRV combination in patients with relapsed or refractory DLBCL or TFL
    E.2.2Secondary objectives of the trial
    PART 1:
    - To characterize the pharmacokinetics (PK) of MLN8237 co-administered with rituximab
    - To describe antitumor activity in terms of overall response rate (ORR)

    PART 2:
    - To characterize the PK of MLN8237 when co-administered with rituximab and vincristine
    - To characterize the effect of co-administered MLN8237 on the PK of vincristine in the setting of co-administration with rituximab
    - To describe any antitumor activity in terms of ORR with the MRV combination

    PART 3:
    - To assess additional measures of antitumor activity, including CR rate, duration of response (DOR), and progression free survival (PFS)
    - To evaluate safety and tolerability of the MRV combination
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must have histologically confirmed diagnosis of DLBCL/TFL (WHO criteria, with neoplastic cells expressing CD20). Transformed DLBCL/TFL from a previous indolent NHL or the concomitant presence of a component of low-grade lymphoma will not exclude participation. (Note: Patients with Mantle cell or Burkitt’s lymphoma) may be eligible for enrollment to the safety lead-in and dose escalation cohorts, parts 1 and 2 only.

    2. Relapsed or refractory after at least 1 prior systemic treatment for aggressive lymphoma (including anthracycline unless contra-indicated). Relapsed is defined as patients who initially responded and then progressed. Refractory is defined as patients who, in the judgment of the investigator, received adequate prior treatment and did not respond during treatment or progressed within 60 days of last treatment. Relapse following an autologous stem cell transplant is allowed.

    3. Patients must have relapsed after autologous stem cell transplantation or not be eligible for autologous stem cell transplantation, in the judgment of the investigator, or refuse autologous stem cell transplantation. Patients may have received up to 4 treatment regimens for aggressive lymphoma. Salvage chemotherapy and high-dose conditioning for autologous stem cell transplantation count as 2 separate regimens. Patients enrolled to the phase 2 part must have received prior rituximab.

    4. Measurable disease on cross-sectional imaging that is at least 2.0 cm in the longest diameter.

    5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

    6. Male or female patients 18 years or older.

    7. Female patients who:
    • Are postmenopausal for at least 1 year before the screening visit, or
    • Are surgically sterile, or
    • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing of the informed consent form (ICF) through 30 days after the last dose of MLN8237 or agree to completely abstain from heterosexual intercourse. Individuals of childbearing potential should also use effective contraception for 12 months following the last dose of rituximab.

    8. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
    • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of MLN8237, or
    • Agree to completely abstain from heterosexual intercourse.

    9. 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.
    E.4Principal exclusion criteria
    1. Received more than 4 prior systemic treatment regimens for lymphoma

    2. Known seropositive for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness; HBV, or hepatitis C virus (HCV); known history of Charcot-Marie-Tooth disease or polio

    3. Diagnosed or treated for a malignancy other than lymphoma within 2 years prior to first dose, or evidence of active malignancy other than lymphoma. Patients are not excluded if they have basal cell or squamous cell carcinoma of the skin that was completely resected or any in situ malignancy that was adequately treated.

    4. Clinical laboratory values as specified below:
    • Total serum bilirubin > 1.5 x the upper limit of normal (ULN).
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 3.0 x the ULN. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to documented liver involvement bylymphoma
    • Absolute neutrophil count (ANC) < 1,250/mm3 without growth factor support
    • Platelet count < 75,000/mm3 without growth factor or transfusion support
    • Calculated creatinine clearance < 30 mL/minute (see Cockcroft-Gault formula in protocol)

    5. Autologous stem cell transplant less than 3 months prior to enrollment

    6. Patients who have undergone allogeneic stem cell or organ transplantation any time

    7. Systemic antineoplastic therapy, including glucocorticoids (> 15 mg prednisone/day or equivalent) or treatment with an investigational agent within 14 days preceding the first dose of study drug treatment (see Section in protocol). No concurrent systemic corticosteroids are allowed except for treatment of anaphylactic-like reactions to study drugs. Steroids are permitted for administration with rituximab to prevent or treat infusion reaction

    8. Patients who have received treatment with nitrosoureas, mitomycin C, rituximab, alemtuzumab, or other unconjugated antibody treatment within 42 days (21 days if clear evidence of PD) prior to the first day of study drug treatment

    9. Patients who have received treatment with radioimmunoconjugates or toxin immunoconjugates, such as ibritumomab-tiuxetan, or tositumomab, within 12 weeks prior to the first day of study drug treatment

    10. Patients who have received radiotherapy within 21 days prior to the first day of study drug treatment

    11. Patients treated with enzyme-inducing antiepileptic drugs, such as phenytoin, carbamazepine, or phenobarbital, or with rifampin, rifabutin, rifapentine, or St. John’s wort, within 14 days prior to the first dose of MLN8237; co-administration of these drugs is also not permitted during participation in the study

    12. Myocardial infarction within 6 months of enrollment or current history of New York Heart Association (NYHA) Class III or IV heart failure (see Section in protocol), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or ECG evidence of acute ischemia (heart disease)

    13. Has an LVEF measured by MUGA or echocardiogram of < 40%

    14. Major surgery within 14 days prior to the first dose of study treatment

    15. Infection requiring systemic antibiotic therapy within 14 days prior to the first dose of study treatment, or other serious infection

    16. History of hemorrhagic or thrombotic cerebrovascular event in the past 12 months

    17. Clinically uncontrolled CNS involvement. Patients who have a history of CNS involvement but no evidence of active CNS disease are not excluded. Patients diagnosed with primary CNS malignancy or carcinomatous meningitis are excluded

    18. Inability to receive IV rituximab or vincristine, or to swallow tablets or inability or unwillingness to avoid taking anything by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose of MLN8237

    19. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease

    20. Female patients who are lactating or have a positive serum pregnancy test during the Screening period

    21. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this trial

    22. Clinically apparent ≥ Grade 2 neuropathy due to any cause in the 3 months prior to enrollment, or history of ≥ Grade 3 neuropathy related to vincristine at any time

    23. Prior treatment with Aurora A-targeted agents, including MLN8237

    24. Patients who have received myeloid growth factors or platelet transfusion within 14 days prior to the first dose of study treatment

    25. Patients with a known hypersensitivity to rituximab, vincristine (or vinca alkaloids), or their diluents
    E.5 End points
    E.5.1Primary end point(s)
    PART 1:
    Safety and tolerability of MLN8237 when given in combination with standard doses of rituximab, based on vital signs, ECGs, MUGA/ECHO, physical examination, laboratory tests, and AEs

    PART 2:
    Safety and tolerability of MLN8237 when given in combination with standard doses of rituximab, based on vital signs, ECGs, MUGA/ECHO, physical examination, laboratory tests, and AEs

    PART 3:
    • ORR: CR + PR
    E.5.1.1Timepoint(s) of evaluation of this end point
    PART 1 & 2:
    Continuously

    PART 3:
    End of cycle 2 and end of every second treatment cycle thereafter and at end of treatment
    E.5.2Secondary end point(s)
    PART 1:
    • PK parameters of MLN8237, including, but not limited to Cmax, Tmax, and AUC 0-τ (area under the plasma concentration versus time curve over the dosing interval) on Day 1 and on the last day of dosing (Day 7 in a 7-day schedule)
    • ORR: CR + PR, assessed according to the International Working Group (IWG) Criteria

    PART 2:
    • PK parameters of MLN8237, including, but not limited to Cmax, Tmax, and AUC 0-τ (area under the plasma concentration versus time curve over the dosing interval) on Day 1 and on the last day of dosing (Day 7 in a 7-day schedule)
    • PK parameters of vincristine including, but not limited to, Cmax, AUC 0-tlast (area under the plasma concentration versus time curve from time zero to the time of the last quantifiable concentration), AUC 0-inf (area under the plasma concentration versus time curve from time zero to infinity), and t1/2, when administered with rituximab and when co-administered with MR.
    • ORR: CR + PR, assessed according to the International Working Group (IWG) Criteria

    PART 3:
    • CR, DOR, and PFS
    • Safety and tolerability of MLN8237 treatment based on vital signs, ECGs, physical examination, laboratory tests, and AEs
    E.5.2.1Timepoint(s) of evaluation of this end point
    PART 1:
    • PK on Day 1 and on the last day of dosing (Day 7 in a 7-day schedule)

    PART 2:
    • PK Day 1 and on the last day of dosing (Day 7 in a 7-day schedule)

    PART 3:
    Safety: Continuously
    CR, DOR, and PFS: End of cycle 2 and end of every second treatment cycle thereafter and at end of treatment

    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Italy
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last patient, last visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-05-03. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 36
    F.4.2.2In the whole clinical trial 100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Not applicable.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-06-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-09-06
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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