Clinical Trials /

A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Participants With Advanced Nonhematologic Malignancies

NCT02327169

Description:

The primary purpose of this study is to determine the safety profile and the maximum tolerated doses (MTDs)/ potential recommended phase 2 doses (RP2Ds) of the combination treatments of MLN2480 + MLN0128, MLN2480 + alisertib, MLN2480 + paclitaxel, MLN2480 + cetuximab, and MLN2480 + irinotecan in participants with advanced nonhematologic malignancies.

Related Conditions:
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

A <span class="go-doc-concept go-doc-intervention">Phase 1B</span> Study of <span class="go-doc-concept go-doc-intervention">MLN2480</span> in Combination With <span class="go-doc-concept go-doc-intervention">MLN0128</span> or <span class="go-doc-concept go-doc-intervention">Alisertib</span>, or <span class="go-doc-concept go-doc-intervention">Paclitaxel,</span> or <span class="go-doc-concept go-doc-intervention">Cetuximab</span>, or <span class="go-doc-concept go-doc-intervention">Irinotecan</span> in Adult Patients With Advanced Nonhematologic Malignancies

Title

  • Brief Title: A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Patients With Advanced Nonhematologic Malignancies
  • Official Title: A Multiarm, Open-label, Phase 1b Study of MLN2480 (an Oral A-, B-, and CRAF Inhibitor) in Combination With MLN0128 (an Oral mTORC 1/2 Inhibitor), or Alisertib (an Oral Aurora A Kinase Inhibitor), or Paclitaxel, or Cetuximab, or Irinotecan, in Adult Patients With Advanced Nonhematologic Malignancies
  • Clinical Trial IDs

    NCT ID: NCT02327169

    ORG ID: C28002

    NCI ID: 2014-003340-12

    Trial Conditions

    Advanced Nonhematologic Malignancies

    Trial Interventions

    Drug Synonyms Arms
    MLN2480 TAK-580 MLN2480 + MLN0128, MLN2480 + Alisertib, MLN2480 + Paclitaxel, MLN2480 + Cetuximab, ML2480 + Irinotecan
    MLN0128 MLN2480 + MLN0128
    Alisertib MLN2480 + Alisertib
    Paclitaxel MLN2480 + Paclitaxel
    Cetuximab MLN2480 + Cetuximab
    Irinotecan ML2480 + Irinotecan

    Trial Purpose

    The primary purpose of this study is to determine the safety profile and the maximum
    tolerated doses (MTDs/potential recommended phase 2 doses (RP2Ds) of the combination
    treatments of MLN2480 + MLN0128, MLN2480 + alisertib, MLN2480 + paclitaxel, MLN2480 +
    cetuximab, and MLN2480 + irinotecan in patients with advanced nonhematologic malignancies.

    Detailed Description

    The drug being tested in this study is called MLN2480. MLN2480 is being tested to evaluate
    side effects and determine the maximum tolerated dose (MTD) and recommended dose for future
    studies when administered in combination with three other medications. This study will
    assess the safety of MLN2480 as well as how it is processed by the body in participants with
    solid nonhematologic malignancies who have failed standard therapies.

    The study will be conducted in two phases, the Dose Escalation Phase and the Dose Expansion
    Phase. Approximately 49 participatns will be enrolled in the Escalation phase. Participants
    in this phase will be assigned to one of the five treatment groups:

    - MLN2480 + MLN0128

    - MLN2480 + Alisertib

    - MLN2480 + Paclitaxel

    - MLN2480 + Cetuximab

    - MLN2480 + Irinotecan

    Once the MTD for each combination treatment arm has been established in the Escalation
    Phase, one or more of the combination treatments will be selected for the Expansion Phase.
    Approximately 76 participants will be enrolled in the Expansion Phase.

    This multi-centre trial will be conducted worldwide. The overall time to participate in this
    study is approximately 14 months. Participants will make approximately 43 visits to the
    clinic including an end of study visit 30 days after last dose of study drug for a follow-up
    assessment.

    Trial Arms

    Name Type Description Interventions
    MLN2480 + MLN0128 Experimental Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day Cycle for up to 12 Cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day Cycle for up to 12 Cycles. The doses of MLN2480 and MLN0128 may be increased during this phase based on tolerability during each 28-day cycle. Dose Expansion Phase: MLN2480 at a previously deemed maximum tolerated dose, tablets, orally, once, on protocol specified days of a 28-day Cycle for up to 12 Cycles, and MLN0128 capsules, orally, once on protocol specified days of a 28-day Cycle for up to 12 Cycles. MLN2480, MLN0128
    MLN2480 + Alisertib Experimental Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day Cycle for up to 12 Cycles, and alisertib 30 mg, tablets, orally, twice a day (BID) on protocol specified days of a 28-day Cycle for up to 12 Cycles. The doses of MLN2480 and alisertib may be increased during this phase based on tolerability during each 28-day cycle. Dose Expansion Phase: MLN2480 at a previously deemed maximum tolerated dose, tablets, orally, once, on protocol specified days of a 28-day Cycle for up to 12 Cycles, and alisertib, tablets, orally, BID on protocol specified days of a 28-day Cycle for up to 12 Cycles. MLN2480, Alisertib
    MLN2480 + Paclitaxel Experimental Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 Cycles, and paclitaxel 80 mg/m^2, intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day Cycle for up to 12 Cycles. The dose of MLN2480 may be increased during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose will be based on the standard of care. Dose Expansion Phase: MLN2480 at a previously deemed maximum tolerated dose, tablets, orally, once, on protocol specified days of a 28-day Cycle for up to 12 Cycles, and paclitaxel dose based on standard of care, intravenous (IV) infusion, QW for 3 weeks in each 28-day Cycle for up to 12 Cycles. MLN2480, Paclitaxel
    MLN2480 + Cetuximab Experimental Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 Cycles, and cetuximab will be administered IV at a loading dose of 400 mg/m2 (Cycle 1 Day 1), then at 250 mg/m2 QW on Days 8, 15, and 22 of Cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle. for up to 12 Cycles. The dose of MLN2480 may be increased during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose will be based on the standard of care. Dose Expansion Phase: MLN2480 at a previously deemed maximum tolerated dose, tablets, orally, once, on protocol specified days of a 28-day Cycle for up to 12 Cycles, and cetuximab dose based on standard of care, intravenous (IV) infusion, QW in each 28-day Cycle for up to 12 Cycles. MLN2480, Cetuximab
    ML2480 + Irinotecan Experimental Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 Cycles, and irinotecan 180 mg/m^2, intravenous (IV) infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day Cycle for up to 12 Cycles. The dose of MLN2480 may be increased during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose will be based on the standard of care. Dose Expansion Phase: MLN2480 at a previously deemed maximum tolerated dose, tablets, orally, once, on protocol specified days of a 28-day Cycle for up to 12 Cycles, and irinotecan dose based on standard of care, intravenous (IV) infusion, Q2W in each 28-day Cycle for up to 12 Cycles. MLN2480, Irinotecan

    Eligibility Criteria

    Inclusion Criteria:

    All Treatment Arms:

    1. Informed consent.

    2. Male or female participants 18 years or older.

    3. Participants who, in the opinion of the treating physician, have failed standard
    therapies and for whom a phase 1 trial is an appropriate option.

    4. Radiographically or clinically evaluable tumor. For Expansion phase: Tumors must be
    measurable and of the protocol specified genetic mutational status, where applicable.

    5. Recovered (ie, Grade 1 toxicity) from adverse effects (except alopecia) of prior
    therapy.

    6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

    7. Expected survival time of at least 3 months in the opinion of the investigator.

    8. Block of banked tumor tissue and/or 10 unstained slides. Participants who satisfy
    all other eligibility criteria but do not have banked tissue/slides may be asked to
    consent to baseline biopsy.

    9. Suitable vein access for the study-required blood sampling.

    10. Thyroid function tests consistent with stable thyroid function. Note: Participants on
    a stable dose of thyroid replacement therapy for a suggested minimum of 12 weeks
    before Cycle 1, Day 1 are eligible.

    11. Left ventricular ejection fraction (LVEF) of 50% or greater, as measured by
    echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 28 days
    before the first dose of MLN2480

    12. Female participants who are post menopausal for at least 1 year, surgically sterile,
    or agree to practice 2 effective methods of contraception through 120 days (4 months)
    after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6
    months for participants in Arms 3 and 4, or agree to practice true abstinence.

    13. Male patients who, even if surgically sterilized, agree to practice effective barrier
    contraception through 120 days (4 months) after the last dose of study drug for
    participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3,
    and 4, or agree to practice true abstinence.

    14. Additional inclusion criteria for Arm 3 Expansion Only (MLN2480 + paclitaxel):

    a. Participants with KRAS exon 2 or BRAF non-V600 mutation-positive non small cell
    lung cancer (NSCLC) who have received a minimum of 1 but not more than 2 prior
    cytotoxic-approved regimens.

    15. Additional inclusion criteria for Arms 4 and 5 Expansion Only (MLN2480 + cetuximab;
    MLN2480 + irinotecan):

    1. Participants with CRC who have received a minimum of 1 but not more than 2 prior
    cytotoxic-approved regimens.

    Exclusion Criteria:

    All treatment arms:

    1. Female participants who are pregnant or currently breastfeeding.

    2. History of any serious medical or psychiatric illness that could, in the
    investigator's opinion, potentially interfere with safe protocol completion.

    3. History of uncontrolled brain metastasis unless: previously treated with surgery,
    whole-brain radiation, or stereotactic radiosurgery; stable disease for 60 days
    without steroid use (or stable steroid dose established for 28 days before the
    first dose of MLN2480).

    4. Ongoing seizure disorder or a requirement for antieplieptics.

    5. Recent prior therapies, including: chemotherapy and hormonal therapy 4 weeks or 4
    half lives, whichever occurs first, before administration of study drug;
    immunotherapy/monoclonal antibody use 4 weeks before administration of MLN2480; or
    radiation therapy 3 weeks before administration of study drug.

    6. Chronic therapeutic corticosteroid use with the exception of replacement therapy for
    adrenal insufficiency or corticosteroid inhalers.

    7. Known history of human immunodeficiency virus infection, hepatitis B, or hepatitis C;
    Prior allogeneic bone marrow or organ transplantation, or active condition of chronic
    immune suppression is not allowed.

    8. Concomitant use, or administration 14 days before first dose of study drug(s), of
    clinically significant enzyme inducers.

    9. Treatment with gemfibrozil (strong CYP2C8 inhibitor) within 14 days before the first
    dose of MLN2480. 14. History of or current illicit drug use, drug abuse, or alcohol
    abuse.

    10. Major surgery within 14 days before the first dose of study drug.

    11. Inability to comply with study requirements.

    12. Other unspecified reasons that, in the opinion of the investigator or Millennium,
    make the patient unsuitable for enrollment.

    13. Expansion phase only: Prior treatment with RAF, MEK, or other inhibitors of the MAPK
    pathway.

    14. Additional exclusion criteria for Arm 2 Only (MLN2480 + alisertib):

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

    15. Additional exclusion criteria for Arm 3 Only (MLN2480 + paclitaxel):

    a. Known hypersensitivity to paclitaxel or its components or other drugs formulated
    in Cremophor EL (polyoxyethylated castor oil).

    16. Additional exclusion criteria for Arm 5 Only (MLN2480 + irinotecan):

    1. Use of strong or moderate CYP3A inhibitors days of the first dose of
    irinotecan.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Number of Participants With Adverse Events (AEs)

    Secondary Outcome Measures

    Cmax: Maximum Observed Plasma Concentration for MLN2480, MLN0128, Alisertib, cetuximab, and irinotecan

    Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480, MLN0128, Alisertib, cetuximab, and irinotecan

    AUC(0-tau): Area Under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for MLN2480, MLN0128, Alisertib, cetuximab, and irinotecan

    Cmax: Maximum Observed Plasma Concentration for Paclitaxel

    AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel

    Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for Paclitaxel

    Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)

    Time to Response

    Duration of Response

    Progression Free Survival (PFS)

    AUC(0-tlast): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel

    Trial Keywords

    Drug therapy