Phase I Study of the Combination of MLN9708 and Fulvestrant (Millennium)
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|ClinicalTrials.gov Identifier: NCT02384746|
Recruitment Status : Recruiting
First Posted : March 10, 2015
Last Update Posted : September 20, 2018
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.
|Condition or disease||Intervention/treatment||Phase|
|Breast Cancer||Drug: Fulvestrant Drug: MLN9708||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||18 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Study of the Combination of MLN9708 and Fulvestrant in Patients With Advanced Estrogen Receptor Positive Breast Cancer|
|Study Start Date :||March 2015|
|Estimated Primary Completion Date :||August 2019|
|Estimated Study Completion Date :||August 2020|
Experimental: Combination Treatment
Fulvestrant (500mg) + MLN9708 (2.3, 3, and 4mg)
500 mg intramuscular every 28 days
Other Name: Faslodex
Subjects will be treated in 3 dose cohorts of MLN9708, at 2.3, 3, and 4 mg orally on days 1, 4, 8, and 11 every 21 days.
Other Name: Ixazomib
- 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 ]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)
- 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 ]The length of time on study until there is evidence of disease progression by Response Evaluation Criteria in Solid Tumors (Recist) criteria
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02384746
|Contact: Gary N Schwartz, MD||603-653-6181||Gary.N.Schwartz@Hitchcock.org|
|Contact: Research Nurse||(800) firstname.lastname@example.org|
|United States, New Hampshire|
|Dartmouth-Hitchcock Medical Center||Recruiting|
|Lebanon, New Hampshire, United States, 03756|
|Contact: Research Nurse, RN 800-639-6918 Cancer.Research.Nurse@Dartmouth.edu|
|Principal Investigator: Gary N Schwartz, MD|
|Principal Investigator:||Gary N Schwartz, MD||Dartmouth-Hitchcock Medical Center|