Clinical Trials /

Phase I Study of the Combination of MLN9708 and Fulvestrant

NCT02384746

Description:

Participants in this study will have been diagnosed with advanced breast cancer that has become worse while being treated with fulvestrant. Participants will have estrogen-receptor positive disease, and have completed menopause. There is information from research labs which suggests that drugs that work like MLN9708 help kill breast cancer cells that have been treated with fulvestrant. The purpose of the study is to determine the proper dose as well as the good and bad effects of MLN9708 when it is given in combination with fulvestrant. The Investigators also want to learn more about how the drug combination affects tumor cells. The amount of MLN9708 participants receive will be determined by when they enter this study. Three different doses will be given to different participants. The Investigators expect to enroll a total of 12-18 people.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Phase I Study of the Combination of <span class="go-doc-concept go-doc-intervention">MLN9708</span> and <span class="go-doc-concept go-doc-intervention">Fulvestrant</span>

Title

  • Brief Title: Phase I Study of the Combination of MLN9708 and Fulvestrant
  • Official Title: Phase I Study of the Combination of MLN9708 and Fulvestrant in Patients With Advanced Estrogen Receptor Positive Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02384746

    ORG ID: D13036

    Trial Conditions

    Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Fulvestrant Faslodex Combination Treatment
    MLN9708 Ixazomib Combination Treatment

    Trial Purpose

    Participants in this study will have been diagnosed with advanced breast cancer that has
    become worse while being treated with fulvestrant. Participants will have estrogen-receptor
    positive disease, and have completed menopause.

    There is information from research labs which suggests that drugs that work like MLN9708
    help kill breast cancer cells that have been treated with fulvestrant. The purpose of the
    study is to determine the proper dose as well as the good and bad effects of MLN9708 when it
    is given in combination with fulvestrant. The Investigators also want to learn more about
    how the drug combination affects tumor cells.

    The amount of MLN9708 participants receive will be determined by when they enter this study.
    Three different doses will be given to different participants. The Investigators expect to
    enroll a total of 12-18 people.

    Detailed Description

    Subjects with metastatic ER+/HER2- breast cancer with disease progression on Fulvestrant,
    for whom continuation of endocrine therapy would be an appropriate treatment, will be
    treated with the combination of MLN9708 (proteasome inhibitor) and Fulvestrant
    (anti-estrogen). Subjects with visceral or soft tissue disease will have a tumor biopsy
    while on treatment with Fulvestrant but prior to initiation of MLN9708 to confirm ER/PR/HER2
    status, and to provide a baseline specimen for molecular analysis. A biopsy of the same
    tumor will be obtained after 2 days of treatment with MLN9708 plus Fulvestrant (i.e. on day
    3). Patients with bone-only disease will be eligible for the study, but will not be
    biopsied.

    The Investigators propose a 3x3 dose-escalation trial to assess the safety and efficacy of
    Fulvestrant and three dose levels of MLN9708 (2.3, 3, and 4mg) Subjects will be treated with
    Fulvestrant (500mg) once every four weeks on day 1. The dose of MLN9708 will start at 2.3mg,
    which is about 50% of the phase 3 dose in another ongoing study. If 2.3mg MLN9708 does not
    induce any grade 3 non-hematologic toxicity, or any grade 4 hematologic toxicity by CTCAE
    v4.0 (Common Terminology Criteria for Adverse Events, version 4.0) in any of the 3 subjects
    treated for 1 cycle, the Investigators will treat another 3 subjects with the combination of
    Fulvestrant and MLN9708 (3mg); and if no grade 3 non-hematologic toxicity, or any grade 4
    hematologic toxicity by CTCAE v4.0 is seen over the first cycle, the Investigators will
    treat another 3 subjects with Fulvestrant and MLN9708 (4mg, which is the phase 3 dose). If
    dose-limiting toxicity is observed in 1/3 subjects, the Investigators will treat an
    additional 3 subjects at that same dose. If dose-limiting toxicity is seen in 2 of 6
    subjects at any dose level, that dose level will be considered the maximum tolerated dose,
    and a total of 6 subjects will be treated at the prior dose. Plasma pharmacokinetic profiles
    of MLN9708 will be determined over 21 days after the first dose of the combination.

    Pre- and post- treatment tumor biopsies will be formalin-fixed and paraffin-embedded. Tissue
    sections will be analyzed by H&E (Hematoxylin and eosin) staining and immunohistochemistry
    using antibodies against markers of proliferation, apoptosis, estrogen receptor alpha
    activation, endoplasmic reticulum stress, and polyubiquitin. Proteasome activity of whole
    blood will be determined using samples acquired prior to treatment initiation, and on day 3.
    Tumor-specific plasma DNA will also be measured prior to treatment initiation and after the
    first two doses of MLN9708.

    Trial Arms

    Name Type Description Interventions
    Combination Treatment Experimental Fulvestrant (500mg) + MLN9708 (2.3, 3, and 4mg) Fulvestrant, MLN9708

    Eligibility Criteria

    Inclusion Criteria:

    1. Female post-menopausal patients 18 years or older. 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.

    2. Patients must have either A) histologic documentation of metastatic or locally
    advanced breast cancer by needle or incisional biopsy, or B) history of breast cancer
    with radiologic evidence of bone-only metastatic disease.

    3. Patients must be post-menopausal based on either a history of an oophorectomy, or at
    lease one year of amenorrhea. An elevated serum gonadotropin level can be used to
    confirm menopausal status in a subject with one year or more of amenorrhea.

    4. The invasive cancer must be HER2-negative, defined as IHC0-1+, or with a FISH ratio
    of <1.8 if IHC is 2+ or if IHC has not been performed.

    5. Metastatic or locally advanced breast cancer for which endocrine therapy is an
    appropriate treatment option.

    6. Patients must have been treated with Fulvestrant for at least 56 days as their most
    recent anti-cancer treatment, and they must be tolerating Fulvestrant with at most
    grade I toxicity by CTCAE v4.0.

    7. Disease progression based on RECIST criteria while the subject has been taking
    Fulvestrant, and for which continuation of endocrine therapy would be appropriate.

    8. The subject must agree to undergo pre- and post- treatment research biopsies if a
    non-osseous metastatic site is available for biopsy.

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

    10. Life expectancy 6 months or longer.

    11. Patients must meet the following clinical laboratory data:

    - Absolute Neutrophil Count (ANC) 1,000/mm(3) and platelet count 75,000/mm(3)

    - Total bilirubin 1.5 x the upper limit of normal range (ULN).

    - Alanine aminotranserase (ALT) and aspartate aminotransferase (AST) 3 x ULN.

    - Calculated creatinine clearance 30 mL/min

    12. Ability to give informed consent.

    Exclusion Criteria:

    1. Failure to have fully recovered from the reversible effects of prior chemotherapy or
    endocrine therapy.

    2. Major surgery within 14 days before enrollment.

    3. Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days
    will be considered a sufficient interval between treatment and administration of the
    MLN9708.

    4. Central nervous system involvement.

    5. Infection requiring systemic antibiotic therapy or other serious infection within 14
    days before study enrollment.

    6. Evidence of current uncontrolled cardiovascular conditions.

    7. Systemic treatment, within 14 days before the first dose of MLN9708, with strong
    inhibitors of CYP1A2 or CYP3A, or strong inducers of CYP3A.

    8. Ongoing or active systemic infection, active hepatitis B or C virus infection, or
    known human immunodeficiency virus (HIV) positive.

    9. Any serious medical or psychiatric illness that could, in the investigator's opinion,
    potentially interfere with the completion of treatment according to this protocol.

    10. Known allergy to any of the study medication, their analogues, or excipients in the
    various formulations of any agent.

    11. Known gastrointestinal (GI) disease or GI procedure that could interfere with oral
    absorption or tolerance of MLN9708 including difficulty swallowing.

    12. Diagnosed or treated for another malignancy within 2 years before study enrollment or
    previously diagnosed with another malignancy and have evidence of residual disease.

    13. Patient has grade 3 peripheral neuropathy, or grade 2 with pain on clinical
    examination during the screening period.

    14. Participation in other clinical trials within 21 days of the start of this trial or
    throughout the duration of this trial.

    15. Visceral crisis or rapidly progressive disease for which chemotherapy would be
    indicated.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    Number of participants with adverse events prior to commencing a second cycle of treatment.

    Secondary Outcome Measures

    Time to Disease Progression

    Trial Keywords

    metastatic breast cancer

    ER-positive

    HER2-negative

    Fulvestrant

    MLN9708