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

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

  • ORG STUDY ID: D13036
  • NCT ID: NCT02384746

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
FulvestrantFaslodexCombination Treatment
MLN9708IxazomibCombination Treatment

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

NameTypeDescriptionInterventions
Combination TreatmentExperimentalFulvestrant (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 aminotransferase (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 (i.e., ≤ Grade 1 toxicity) from the reversible effects
             of prior chemotherapy or endocrine therapy, except for Grade 2 or greater anemia.

          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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with adverse events prior to commencing a second cycle of treatment.
Time Frame:End of cycle one - Day 21 of Cycle 1
Safety Issue:
Description:If the current dose of MLN9708 does not induce any grade 3 non-hematologic toxicity, or any grade 4 hematologic toxicity in any of 3 subjects treated for one cycle, another 3 participants will be treated at the next dose level of MLN9708 (up to 4mg, which is the current phase 3 dose)

Secondary Outcome Measures

Measure:Time to Disease Progression
Time Frame:First assessment on Day 1 Cycle 3 - After two cycles, or 42 days of treatment, and then reassessed every 2 cycles or 42 days thereafter
Safety Issue:
Description:The length of time on study until there is evidence of disease progression by Response Evaluation Criteria in Solid Tumors (Recist) criteria

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Terminated
Lead Sponsor:Dartmouth-Hitchcock Medical Center

Trial Keywords

  • metastatic breast cancer
  • ER-positive
  • HER2-negative
  • Fulvestrant
  • MLN9708

Last Updated

April 29, 2019