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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04872608
Recruitment Status : Recruiting
First Posted : May 4, 2021
Last Update Posted : September 13, 2021
Context Therapeutics
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

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.

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Unresectable Breast Cancer Drug: Letrozole Drug: Palbociclib Drug: Onapristone ER Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: ctDNA-guided Adaptive Therapy Escalation in ER+ MBC: A Phase 1b Study With Letrozole, Palbociclib and Onapristone ER
Actual Study Start Date : September 9, 2021
Estimated Primary Completion Date : September 9, 2023
Estimated Study Completion Date : September 9, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Letrozole, Palbociclib, and Onapristone ER
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
Letrozole will be given daily on days 1-28.

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

Drug: Onapristone ER
Onapristone will be given daily on days 1-28.

Primary Outcome Measures :
  1. recommended phase 2 dose (RP2D) of onapristone ER [ Time Frame: 1 year ]
    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Breast cancer
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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:

    1. The dose reduction was implemented ≥4 weeks prior to enrollment
    2. 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%
  • Women of child-bearing potential:

    • Must have a negative pregnancy test within 14 days prior to commencement of study treatment
    • Agreement to remain abstinent (refrain from heterosexual intercourse) or use nonhormonal contraceptive methods with a failure rate of <1% per year during the treatment period and for 120 days after the last dose and agreement to refrain from donating eggs during this same period
    • Note: for women with therapy-induced amenorrhea, baseline measurements of FSH and/or estradiol are needed to ensure menopausal status.
  • Adequate hematologic and organ function demonstrated within 14 days prior to initiation of study treatment, defined by the following:

    • Absolute neutrophil count ≥ 1.2K/ µL
    • Hemoglobin ≥ 9 g/dL
    • Platelet count ≥ 100,000/ µL
  • Total bilirubin ≤ 1.5 x ULN
  • Serum albumin ≥ 2.5 g/dL
  • AST and ALT ≤ 2.5 x ULN
  • Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation
  • INR < 1.5 x ULN and aPTT < 1.5 x ULN

    °For patients requiring anticoagulation therapy with warfarin, a stable INR between 2-3 is required. If anticoagulation is required for a prosthetic heart valve, then stable INR between 2.5-3.5 is permitted.

  • At least 4 weeks post-op from any major surgical procedure
  • Patients with asymptomatic brain metastases which have been treated with surgery or radiation and demonstrate stability for ≥ 3 months will be allowed
  • Able to swallow tablets whole, without crushing

Exclusion Criteria:

  • 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.

Information from the National Library of Medicine

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 identifier (NCT number): NCT04872608

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Contact: Komal Jhaveri, MD 646-888-5145
Contact: Joshua Drago, MD 646-888-6971

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United States, New Jersey
Memoral Sloan Kettering Basking Ridge (Limited Protocol Activities) Recruiting
Basking Ridge, New Jersey, United States, 07920
Contact: Komal Jhaveri, MD    646-888-5145      
Memoral Sloan Kettering Monmouth (Limited protocol activities) Recruiting
Middletown, New Jersey, United States, 07748
Contact: Komal Jhaveri, MD    646-888-5145      
Memorial Sloan Kettering Monmouth (Limited Protocol Activities) Recruiting
Middletown, New Jersey, United States, 07748
Contact: Komal Jhaveri, MD    646-888-5145      
Memorial Sloan Kettering Bergen (Limited Protocol Activities) Recruiting
Montvale, New Jersey, United States, 07645
Contact: Komal Jhaveri, MD    646-888-5145      
United States, New York
Memorial Sloan Kettering Commack (Limited protocol activities) Recruiting
Commack, New York, United States, 11725
Contact: Komal Jhaveri, MD    646-888-5145      
Memorial Sloan Kettering Westchester (All Protocol Activities) Recruiting
Harrison, New York, United States, 10604
Contact: Komal Jhaveri, MD    646-888-5145      
Memorial Sloan Kettering Cancer Center (All Protocol Activities) Recruiting
New York, New York, United States, 10065
Contact: Komal Jhaveri, MD    646-888-5145      
Principal Investigator: Komal Jhaveri, MD         
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Context Therapeutics
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Principal Investigator: Komal Jhaveri, MD Memorial Sloan Kettering Cancer Center
Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center Identifier: NCT04872608    
Other Study ID Numbers: 21-194
First Posted: May 4, 2021    Key Record Dates
Last Update Posted: September 13, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to:

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Memorial Sloan Kettering Cancer Center:
ER+, PR+, HER2
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Protein Kinase Inhibitors
Fertility Agents, Female
Fertility Agents
Reproductive Control Agents