A Study of Letrozole, Palbociclib, and Onapristone ER in People With Metastatic Breast Cancer

NCT04872608 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: 21-194
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The researchers are doing this study to find out whether the study drug onapristone ER, combined with the standard treatment for your cancer (letrozole and palbociclib), is a safe treatment for people who have metastatic or unresectable ER+/PR+/HER2- breast cancer. The researchers will test different doses of the study drug to find the highest dose that causes few or mild side effects.

Conditions

Metastatic Breast Cancer; Unresectable Breast Cancer

Keywords

ER+, PR+, HER2; Letrozole; Palbociclib; Onapristone; 21-194

Outcome Measures

Primary Outcomes (1)

• recommended phase 2 dose (RP2D) of onapristone ER

  The RP2D/MTD will be defined as the dose level at which a dose limiting toxicity (DLT) occurs in at most 1 out of 6 patients in that dose cohort.

  1 year

Study Arms (1)

Letrozole, Palbociclib, and Onapristone ER

EXPERIMENTAL

This study has two stages: a dose-finding stage and a dose expansion stage. Stage 1 of the study will utilize a standard 3+3 dose de-escalation design with a total of three dose levels of onapristone ER, 30mg PO BID, 40mg PO BID, and 50mg PO BID given on a 28-day cycle. Onapristone ER will be given in addition to letrozole 2.5mg QD and each patient's pre-enrollment dose of palbociclib.

Drug: Letrozole; Drug: Palbociclib; Drug: Onapristone ER

Interventions

Letrozole DRUG

Letrozole will be given daily on days 1-28.

Letrozole, Palbociclib, and Onapristone ER

Palbociclib DRUG

Palbociclib will be given daily on days 1-21 and held on days 22-28, as per standard FDA-approved dosing guidelines.

Letrozole, Palbociclib, and Onapristone ER

Onapristone ER DRUG

Onapristone will be given daily on days 1-28.

Letrozole, Palbociclib, and Onapristone ER

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Breast cancer
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed ER+, PR+, HER2- metastatic or unresectable breast cancer
• PR positivity is defined as ≥1% expression by immunohistochemistry (IHC) on fresh or archival tumor tissue
• Tissue samples obtained, stained, and interpreted outside of MSKCC will be accepted
• Those patients who do not have adequate/accessible archival tissue available and for whom biopsy is not a significant risk procedure may be required to consent to pretreatment biopsy
• Completed at least 6 months (+/- 4 weeks) of first-line letrozole/palbociclib without radiological progression or unresolved toxicity
• °Patients who underwent dose reduction of palbociclib to 100mg daily or 75mg daily will be eligible if:
• The dose reduction was implemented ≥4 weeks prior to enrollment
• Patients have demonstrated resolution of all acute toxic effects of prior therapy to NCI CTCAE (Version 5.0) Grade ≤ 1
• ctDNA-positive, defined as:
• °Presence of a tumor-derived somatic mutation in the peripheral blood using the MSK-ACCESS assay after 6 months of letrozole/palbociclib (+/- 4 weeks); at least one mutation should have avariant allele fraction of ≥ 0.5%
• Completed MSK IMPACT testing from primary or metastatic tissue
• Radiologically evaluable or measurable disease per RECIST Version 1.1
• Age ≥ 18 years
• Pre-menopausal patients are eligible as long as they are on LHRH agonist for at least four weeks prior to starting trial therapy and commit to continue LHRH agonist for as long as patient is receiving trial therapy or medical contraindications arise.
• Eastern Cooperative Oncology Group Performance Status (ECOG) of 1 or Karnofsky Performance Status (KPS) of ≥ 70%

You may not qualify if:

• Radiologic disease progression while on treatment with letrozole and palbociclib in the first line prior to enrollment
• History of another invasive malignancy (other than non-melanoma skin cancer or curatively treated in situ carcinoma) with evidence of disease within the past 3 years
• Any psychological, familial, sociological or geographic condition that would potentially hinder compliance with the study protocol
• Known untreated or symptomatic brain metastasis
• Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95mmHg) despite medical treatment. Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment.
• Clinically significant heart disease as evidenced by myocardial infarction or arterial thrombotic event within the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of \< 50% at baseline
• Screening ECG with rate-corrected (using Friderica's correction) QT interval (QTcF) of \>480 msec or a history of cardiac arrythmias
• Refractory nausea and vomiting, requirement for parenteral hydration and/or nutrition, drainage gastrostomy tube, malabsorption, external biliary shunt, or significant small bowel resection that would preclude adequate study drug absorption
• Is pregnant or breastfeeding, and/or expecting to conceive within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Current use of estrogen or progesterone products including intrauterine and implantable contraceptive devices.
• Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study
• Active Hepatitis B (HBsAg positive or hepatitis B virus DNA≥1×10\^3 copy/ml) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
• Use of any prescription medication during the prior 28 days of first onapristone dosing that the investigator judges is likely to interfere with onapristone activity; specifically, strong inhibitors or inducers, or sensitive substrates of cytochrome P450 CYP3A4.

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• Context Therapeutics Inc.: collaborator

Study Sites (1)

Memorial Sloan Kettering Westchester (All Protocol Activities)

Harrison, New York, 10604, United States

Location

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Letrozole; palbociclib

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Komal Jhaveri, MD

  Memorial Sloan Kettering Cancer 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: SPONSOR

Model Details: This is an open label, single institution pilot phase 1b study of the oral progesterone antagonist, onapristone ER (Apristor), used as triplet escalation therapy patients with ER+/PR+/HER2- MBC who do not achieve mCR after six months (+/- 4 weeks) of treatment with letrozole and palbociclib in the first line.

Study Record Dates

• First Submitted: April 29, 2021
• First Posted: May 4, 2021
• Study Start: September 9, 2021
• Primary Completion: April 25, 2023
• Study Completion: April 25, 2023
• Last Updated: April 28, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will share

Locations

US (1)