Breast CancerPhase 1MillenniumNCT02384746
Phase I Study of the Combination of MLN9708 and Fulvestrant
A Phase 1 study testing Fulvestrant and MLN9708 in people with Breast Cancer, run by Dartmouth-Hitchcock Medical Center at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Fulvestrant and MLN9708
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- 2 Jun 2015to 10 Jun 2018
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
- 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.
- 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.
- 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.
- Metastatic or locally advanced breast cancer for which endocrine therapy is an appropriate treatment option.
- 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.
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- Disease progression based on RECIST criteria while the subject has been taking Fulvestrant, and for which continuation of endocrine therapy would be appropriate.
- The subject must agree to undergo pre- and post- treatment research biopsies if a non-osseous metastatic site is available for biopsy.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Life expectancy 6 months or longer.
- 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
- Ability to give informed consent.
Who cannot join
- 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.
- Major surgery within 14 days before enrollment.
- 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.
- Central nervous system involvement.
- Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
- Evidence of current uncontrolled cardiovascular conditions.
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- Systemic treatment, within 14 days before the first dose of MLN9708, with strong inhibitors of CYP1A2 or CYP3A, or strong inducers of CYP3A.
- Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- Known allergy to any of the study medication, their analogues, or excipients in the various formulations of any agent.
- Known gastrointestinal (GI) disease or GI procedure that could interfere with oral absorption or tolerance of MLN9708 including difficulty swallowing.
- Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have evidence of residual disease.
- Patient has ≥ grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening period.
- Participation in other clinical trials within 21 days of the start of this trial or throughout the duration of this trial.
- Visceral crisis or rapidly progressive disease for which chemotherapy would be indicated.
Trial locations and contacts
1 site in 1 country.
United States1 site
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, 03756
About this study
Official title: Phase I Study of the Combination of MLN9708 and Fulvestrant in Patients With Advanced Estrogen Receptor Positive Breast Cancer
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.
Read the 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.
- Conditions
- Breast Cancer
- Being tested
- Fulvestrant, MLN9708
- Keywords
- metastatic breast cancer, ER-positive, HER2-negative, Fulvestrant, MLN9708
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FulvestrantDrug
Also called Faslodex
500 mg intramuscular every 28 days
MLN9708Drug
Also called Ixazomib
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.
| Study group | Role | What they receive |
|---|---|---|
| Combination Treatment | Experimental | Fulvestrant (500mg) + MLN9708 (2.3, 3, and 4mg) Receives: Drug: Fulvestrant; Drug: MLN9708 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants with adverse events prior to commencing a second cycle of treatment.
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)
Measured: End of cycle one - Day 21 of Cycle 1
Secondary outcomes (1)
Time to Disease Progression
The length of time on study until there is evidence of disease progression by Response Evaluation Criteria in Solid Tumors (Recist) criteria
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Mar 2015 (estimated)
- Study start2 Jun 2015
- Primary completion12 Apr 2018
- Study completion10 Jun 2018
Why it stopped: Low accrual
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by Dartmouth-Hitchcock Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Dartmouth-Hitchcock Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Gary Schwartz, Dartmouth-Hitchcock Medical Center
- Investigators
- Gary N Schwartz, MD, Principal investigator, Dartmouth-Hitchcock Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02384746
- Sponsor's protocol ID
- D13036
- Acronym
- Millennium
- Status last verified
- Apr 2019
- First submitted
- 20 Nov 2014
- Last updated
- 29 Apr 2019
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Schwartz G, Shee K, Romo B, Marotti J, Kisselev A, Lewis L, Miller T. Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib (MLN9708) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant. Oncologist. 2021 Jun;26(6):467-e924. doi: 10.1002/onco.13733. Epub 2021 Mar 18.
PubMed 33641211
Study at a glance
From the registry record, last updated by the sponsor on 29 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of the Combination of MLN9708 and Fulvestrant in Patients With Advanced Estrogen Receptor Positive Breast Cancer
- ClinicalTrials.gov ID
- NCT02384746
- Acronym / sponsor ID
- Millennium / D13036
- Conditions
- Breast Cancer
- Keywords
- metastatic breast cancer, ER-positive, HER2-negative, Fulvestrant, MLN9708
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Low accrual
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Dartmouth-Hitchcock Medical CenterUniversity, hospital or other
- Study start
- 2 Jun 2015 (actual)
- Primary completion
- 12 Apr 2018 (actual)
- Study completion
- 10 Jun 2018 (actual)
- First posted
- 10 Mar 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Combination Treatment | Experimental | Drug: Fulvestrant, Drug: MLN9708Fulvestrant (500mg) + MLN9708 (2.3, 3, and 4mg) |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- 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.
- 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.
- 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.
- 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.
- Metastatic or locally advanced breast cancer for which endocrine therapy is an appropriate treatment option.
Key exclusion criteria (15 listed)
- 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.
- Major surgery within 14 days before enrollment.
- 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.
- Central nervous system involvement.
- Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FulvestrantAlso: Faslodex500 mg intramuscular every 28 days | Drug | Combination Treatment |
| MLN9708Also: IxazomibSubjects 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. | Drug | Combination Treatment |
Primary outcome
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)
1 secondary outcome
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
Results and safety
The study was stopped early (reason given: Low accrual). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Apr 2019.
- Derived from this study: PubMed 33641211Schwartz G, Shee K, Romo B, Marotti J, Kisselev A, Lewis L, Miller T. Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib (MLN9708) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant. Oncologist. 2021 Jun;26(6):467-e924. doi: 10.1002/onco.13733. Epub 2021 Mar 18.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gary N Schwartz, MD principal investigator
Dartmouth-Hitchcock Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Fulvestrant and MLN9708 in people with Breast Cancer, run by Dartmouth-Hitchcock Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 29 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Low accrual). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02384746, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Apr 2019.