Onapristone and Fulvestrant for ER+ HER2- Metastatic Breast Cancer After Endocrine Therapy and CDK4/6 Inhibitors (The SMILE Study)

NCT04738292 | Terminated Phase 2 Results DMC FDA Drug

• 6 other identifiers: UW20037A534260SMPH/MEDICINE/HEM-ONC2020-0877NCI-2021-00371Protocol Version 8/26/2021
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

Brief Summary

A phase II single-arm trial of onapristone in combination with fulvestrant for women and men with ER-positive, PgR-positive or negative and HER2-negative locally advanced or metastatic breast cancer after progression on aromatase and CDK4/6 inhibitors. The study will enroll up to 39 participants.

Conditions

ER-positive Breast Cancer; HER2-negative Breast Cancer; Metastatic Cancer

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Objective Response (ORR)

  Best overall response of complete response (CR) or partial response (PR), as per RECIST 1.1. Point and 95% interval estimate of ORR will be evaluated accounting for possibility of early futility stopping.

  up to 17 months

Secondary Outcomes (5)

• Number of Participants Experiencing Progression Free Survival (PFS)

  up to 17 months

• Number of Participants With Disease Control (DCR)

  up to 17 months

• Time to Response

  up to 17 months

• Duration of Response

  up to 17 months

• Incidence of Treatment-Related Adverse Events

  up to 17 months

Study Arms (1)

Onapristone In Combination with Fulvestrant

EXPERIMENTAL

All participants will receive onapristone 50 mg p.o. BID (twice) daily and fulvestrant (500 mg) intramuscular injection on days 1, 15 (cycle 1), then two weeks later (cycle 2, day1), then once every 28 days thereafter. A cycle is defined as 28 days. There will be no breaks between dosing cycles.

Drug: Onapristone; Drug: Fulvestrant

Interventions

Onapristone DRUG

Onapristone is a type I antiprogestin which prevents the PgR from dimerizing and blocks ligand induced protein kinase-mediated phosphorylation of the PgR.

Onapristone In Combination with Fulvestrant

Fulvestrant DRUG

Fulvestrant binds, blocks and degrades the ER, completely inhibiting ER signaling.

Also known as: Fulvestrant Injection

Onapristone In Combination with Fulvestrant

Eligibility Criteria

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

You may qualify if:

• Advanced ER+, (PgR positive or negative), and HER2 negative breast cancer. Advanced is defined as locally advanced or locoregionally recurrent or metastatic and not amenable to curative therapy.
• Below-mentioned prior lines of therapy are allowed in the adjuvant and or metastatic ER+/HER2- setting.
• Participants must have had prior endocrine therapy either in the adjuvant or metastatic setting (SERM (tamoxifen, raloxifene, toremifene) or any of the aromatase inhibitors (anastrozole, letrozole, exemestane), or oral selective estrogen receptor degrader (SERD) on a clinical trial either in the adjuvant or metastatic setting
• Participants must have received prior therapy with oral cyclin-dependent kinase (CDK)4/6 inhibitors in the metastatic setting
• Other standard therapies in the metastatic setting (such as mTOR inhibitors) are allowed
• Patients who previously received any one of the standard adjuvant chemotherapy regimens in a curative setting are eligible for this study.
• One line of prior chemotherapy in the metastatic setting is allowed (i.e. any single agent or doublet cytotoxic chemotherapy, not limited to xeloda).
• Histologically and/or cytologically confirmed diagnosis of ER+, PgR+/- and HER2- breast cancer by local laboratory at diagnosis of metastatic disease. Hormone receptor positivity is defined as ER and PgR positivity in at least 1% cells by immunohistochemistry (IHC). HER2-negative breast cancer is defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization test is required.
• Measurable disease, i.e., at least one measurable lesion, as per RECIST 1.1 criteria. A palpable, and measurable breast mass is acceptable.
• Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2
• Adequate organ function as defined by
• aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 times institutional upper limit.
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN), except for subjects with Gilbert's syndrome who may be included if their total bilirubin is ≤ 3.0 × ULN and direct bilirubin ≤ 1.5 × ULN.
• Alkaline phosphatase (ALP) ≤ 2.5 times institutional upper limit with exception that ALP of \< 5 x ULN is acceptable in patients with elevated with ALP due to bone metastases (in the absence of liver metastases).
• Serum creatinine \<1.5 × ULN.

You may not qualify if:

• Prior treatment with an anti-progesterone agent.
• Prior treatment with fulvestrant in the metastatic setting
• Prior treatment with CDK4/6 inhibitors in the neoadjuvant/adjuvant setting
• History of malignancy other than breast cancer within three years prior to registration except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ.
• History or presence of clinically active, and symptomatic central nervous system (CNS) metastasis: If the patient fulfills the following criteria, they will be eligible for the trial:
• Completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the start of study treatment and CNS tumor is clinically stable at the time of screening and patient is not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases.
• Participants with any of the following conditions:
• Clinically significant illness or systemic disease as determined by the treating physicians.
• Active hepatitis or uncontrolled infection or any other clinically significant cirrhosis or other disease that, in the opinion of the investigator would pose a risk to subject safety or interfere with the study evaluation, procedures or completion. Testing for infectious hepatitis is not required for the study. Treating provider may choose additional testing if indicated clinically.
• Patients who have had systemic chemotherapy, or targeted therapy, within two weeks prior to starting study treatment or those who have not recovered from acute effects of any prior therapy to baseline or Grade ≤1. Grade 2 or higher exceptions include alopecia, up to grade 2 neuropathy or other grade 2 adverse events (AEs) or lab values not constituting a safety risk in the pinion of the treating physician. NCI CTCAE v5.0 will be used.
• Co-administration with any prescriptions during the four weeks prior to first onapristone dosing and concerns for possible drug interactions should be discussed with the pharmacist
• Patients who are pregnant or breast feeding
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to registration..
• Symptomatic congestive heart failure (New York Heart Association III-IV)
• Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular block (AV) block (e.g. bifascicular block, Mobitz type II and third-degree AV block).

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• Context Therapeutics Inc.: collaborator

Study Sites (2)

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin, 53705, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

onapristone; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

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

Limitations and Caveats

Study was terminated early, sponsor closed study. Study not powered per protocol.

Results Point of Contact

• Title: Sailaja Kamaraju, MD, MS
• Organization: Froedtert / Medical College of Wisconsin

skamaraju@mcw.edu

414-805-4600

Study Officials

• Kari B Wisinski, MD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

• Sailaja Kamaraju, MD, MS

  Medical College of Wisconsin

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 1, 2021
• First Posted: February 4, 2021
• Study Start: October 5, 2021
• Primary Completion: April 3, 2023
• Study Completion: May 15, 2023
• Last Updated: May 3, 2024
• Results First Posted: May 3, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)