Phase I Study of the Combination of MLN9708 and Fulvestrant

NCT02384746 | Terminated Phase 1 DMC

• 1 other identifier: D13036
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Breast Cancer

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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)

  End of cycle one - Day 21 of Cycle 1

Secondary Outcomes (1)

• Time to Disease Progression

  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

Study Arms (1)

Combination Treatment

EXPERIMENTAL

Fulvestrant (500mg) + MLN9708 (2.3, 3, and 4mg)

Drug: Fulvestrant; Drug: MLN9708

Interventions

Fulvestrant DRUG

500 mg intramuscular every 28 days

Also known as: Faslodex

Combination Treatment

MLN9708 DRUG

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.

Also known as: Ixazomib

Combination Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Dartmouth-Hitchcock Medical Center: lead

Study Sites (1)

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

Related Publications (1)

• 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.

  PMID: 33641211 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Fulvestrant; ixazomib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Gary N Schwartz, MD

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: November 20, 2014
• First Posted: March 10, 2015
• Study Start: June 2, 2015
• Primary Completion: April 12, 2018
• Study Completion: June 10, 2018
• Last Updated: April 29, 2019

Record last verified: 2019-04

Locations

US (1)