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Ribociclib and Letrozole Treatment in Ovarian Cancer

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ClinicalTrials.gov Identifier: NCT03673124
Recruitment Status : Recruiting
First Posted : September 17, 2018
Last Update Posted : August 29, 2019
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Gynecologic Oncology Group

Brief Summary:
The study evaluates the response to treatment with Ribociclib and Letrozole in patients with low grade serous cancer of the ovary, fallopian tube or peritoneum.

Condition or disease Intervention/treatment Phase
Low Grade Serous Carcinoma Drug: Ribociclib Drug: Letrozole Phase 2

Detailed Description:

Ribociclib (formerly LEE011) is an orally bioavailable, highly selective small molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). Ribociclib has been approved by the United States Food and Drug Administration (U.S. FDA) and the European Commission as an initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor based on a randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2). Additional marketing authorizations are under review by health authorities. Additional phase III clinical trials for the treatment of hormone receptor positive (HR+) breast cancer patients, as well as several other phase I or II clinical studies are being conducted.

Letrozole is a highly potent, orally active non-steroidal competitive inhibitor of the aromatase enzyme system. It effectively inhibits the conversion of androgens to estrogens both in vitro and in vivo. It is indicated both as first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer as well as for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Based on encouraging results in women with advanced hormone-receptor-positive breast cancer, a clinical trial for women with recurrent low-grade serous carcinoma is warranted. Furthermore, such a trial would have great appeal to women with recurrent low-grade serous carcinoma, a cohort with limited therapeutic options. Although low-grade serous carcinoma is a rather uncommon histologic subtype, prolonged overall survival results in a relatively high prevalence.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 51 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Ribociclib (LEE011) Plus Letrozole in Women With Recurrent Low-Grade Serous Carcinoma of the Ovary, Fallopian Tube or Peritoneum
Actual Study Start Date : December 14, 2018
Estimated Primary Completion Date : July 30, 2020
Estimated Study Completion Date : July 30, 2021


Arm Intervention/treatment
Ribociclib and letrozole
Ribociclib 600mg oral daily for 3 weeks then 1 week off plus Letrozole 2.5 mg oral daily
Drug: Ribociclib
600 mg by mouth daily for 21 days followed by 7 days off treatment

Drug: Letrozole
2.5 mg by mouth daily




Primary Outcome Measures :
  1. Response rate [ Time Frame: From date of protocol entry to date of first documented response assessed up to 5 years ]
    Determine the response rate of patients receiving the combination of Ribociclib and Letrozole


Secondary Outcome Measures :
  1. Clinical benefit (CR, PR, SD) rate [ Time Frame: From date of protocol entry to first documented response assessed up to 5 years ]
    Determine the clinical benefit (CR, PR, and SD) rate of patients receiving the combination of letrozole + Ribociclib.

  2. Toxicity assessment (nature, frequency, and maximum degree of toxicity) [ Time Frame: every 4 weeks assessed up to 5 years ]
    determine the nature, frequency, and maximum degree of toxicity associated with this combination using CTCAE v5.0

  3. Progression-free survival [ Time Frame: From date of protocol entry to date of first documented progression or death assessed up to 5 years ]
    determine the progression-free survival of women receiving the combination of letrozole + Ribociclib.

  4. Overall survival [ Time Frame: From date of protocol entry to date of first documented progression or death assessed up to 5 years ]
    determine the overall survival of women receiving the combination of letrozole + Ribociclib.


Other Outcome Measures:
  1. ER expression [ Time Frame: At time of primary and secondary outcome analysis up to 5 years ]
    determine the expression of estrogen receptor (ER) and correlation with response and clinical benefit.

  2. Mutation analysis of genomic signatures [ Time Frame: At time of primary and secondary outcome analysis up to 5 years ]
    determine genomic signatures associated with response and clinical benefit of the combination of letrozole + Ribociclib

  3. PR expression [ Time Frame: At time of primary and secondary outcome analysis up to 5 years ]
    determine the expression of progesterone receptor (PR) and correlation with response and clinical benefit.

  4. ki-67 expression [ Time Frame: At time of primary and secondary outcome analysis up to 5 years ]
    determine the expression of proliferative index (ki-67) and correlation with response and clinical benefit.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Patients eligible for inclusion in this study must meet all of the following criteria:

  1. Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements.
  2. Age > 18 years at time of study entry.
  3. Willingness and ability to comply with study and follow-up procedures.
  4. Histological confirmation of diagnosis of low-grade serous carcinoma of ovary, fallopian tube or peritoneum; Original diagnosis of de novo low-grade serous carcinoma or Original diagnosis of serous borderline tumor with subsequent diagnosis of low-grade serous carcinoma.

    • In order to prevent inclusion of patients with high-grade serous carcinoma, diagnosis of low-grade serous carcinoma will be verified as part of screening review by a gynecologic pathologist. Tissue for confirmation can be from primary tumor or recurrence.

  5. Patient must have recurrent, measurable disease by RECIST v1.1.
  6. There are no restrictions on number of prior therapies.
  7. Patient cannot have previously received a prior cyclin dependent kinase inhibitor (CDKi). Patients who were treated with letrozole or another aromatase inhibitor for other indications must have not taken the drug for 6 months prior to initiating letrozole for this trial and may not have progressed on treatment.
  8. Patients must not have remaining ovarian function to be included. In women who have at least one retained ovary, menopause must be confirmed with laboratory confirmation. Women who have ovarian function are eligible but must be placed on hormonal suppression. Menopause must be confirmed with laboratory confirmation, to include an estradiol level as this is assessed within 8 weeks of patient having been on tamoxifen.
  9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
  10. Resolution of all acute toxic effects of prior therapy or surgical procedures to National Cancer Institute (NCI) CTCAE Grade ≤ 1.
  11. Patient has adequate bone marrow and organ function as defined by the following laboratory values at screening:

    • Absolute neutrophil count ≥1.5 × 109/L
    • Platelets ≥100 × 109/L
    • Hemoglobin ≥9.0 g/dL
    • Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication
    • INR ≤1.5
    • Serum creatinine <1.5 mg/dL or creatinine clearance ≥50 mL/min
    • In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x ULN. If the patient has liver metastases, ALT and AST <5 x ULN
    • Total bilirubin < ULN; or total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN in patients with well-documented Gilbert's Syndrome.
  12. Patient with available standard 12-lead ECG with the following parameters at screening:

    • QTcF interval at screening <450msec (using Fridericia's correction)
    • Resting heart rate 50-90bpm
  13. Must be able to swallow ribociclib and letrozole capsules/tablets.

Patients eligible for this study must not meet any of the following criteria:

  1. Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole.
  2. Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. Patients with known brain metastases are excluded.
  3. Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:

    • At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment
    • Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases.
  4. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
  5. Patient has a known history of HIV infection (testing not mandatory).
  6. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.).
  7. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following:

    • 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 screening
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV)
    • Documented cardiomyopathy
    • Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
    • Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block)
    • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:

      • Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.
      • Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days prior to starting study drug) or replaced by safe alternative medication
      • Inability to determine the QT interval on screening (QTcF, using Fridericia's correction)
      • Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening
  8. Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug (see Table 1 for details):

    • Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
    • That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
    • Herbal preparations/medications, dietary supplements.
  9. Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives if the investigational product, which is longer.
  10. Patient is currently receiving warfarin or other coumadin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed. Direct-Acting Oral Anticoagulants (DOACS) are permitted.
  11. Patient is currently receiving or has received systemic corticosteroids ≤2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)
  12. Patient who has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 weeks prior to starting study drug, and who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom ≥25% of the bone marrow (Ellis, 1961) was irradiated.
  13. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered as major surgery).
  14. Patient with a Child-Pugh score B or C.
  15. Patients who are pregnant or breastfeeding.
  16. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study and for 3 weeks after study drug discontinuation. Highly effective contraception methods include:

    • Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
    • Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.

    In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Note: Oral contraceptives are allowed but should be used in conjunction with a barrier method of contraception due to unknown effect of drug-drug interaction. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

  17. Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be potent CYP3A4 inducers, and drugs that are known to prolong the QT interval unless the prohibited concomitant medication can be replaced by other drugs of less potential to inhibit or induce CYP3A4 or prolong QT interval (See Appendix C for Prohibited Concomitant Medications).
  18. Patients whose tumors contain both low-grade serous carcinoma (LGSC) and high-grade serous carcinoma (HGSC)
  19. Patients with history of haemopoietic stem cell or bone marrow transplant.

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 ClinicalTrials.gov identifier (NCT number): NCT03673124


Contacts
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Contact: Jennifer Klein, MEd 215-854-0770 jklein@gog.org

Locations
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United States, Florida
UF Heath Recruiting
Gainesville, Florida, United States, 32610
Contact: Melissa Lynn       melissa.lynn@ufl.edu   
Principal Investigator: Merry Markham, MD         
United States, Georgia
Northside Hospital Recruiting
Atlanta, Georgia, United States, 30342
Contact: Jennifer Cuvo    404-236-8304    jennifer.cuvo@northside.com   
Principal Investigator: Meaghan Tenney, MD         
United States, Illinois
NorthShore University HealthSystem Recruiting
Evanston, Illinois, United States, 60201
Contact: Tara Flanagan    847-570-1768    tflanagan@northshore.org   
Principal Investigator: Mary Tilley Jenkins-Vogel, MD         
United States, New Mexico
New Mexico Cancer Care Alliance/University of New Mexico Comprehensive Cancer Center Recruiting
Albuquerque, New Mexico, United States, 87008
Contact: Sheri Westgate       swestgate@salud.unm.edu   
Principal Investigator: Carolyn Muller, MD         
Southwest Gynecologic Oncology Associates Recruiting
Albuquerque, New Mexico, United States, 87008
Contact: Sheri Westgate       swestgate@salud.unm.edu   
Principal Investigator: Carolyn Muller, MD         
United States, Oklahoma
University of Oklahoma Health Sciences Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: HeeSun Kim       HeeSun-Kim@ouhsc.edu   
Principal Investigator: Laura Holman, MD         
Oklahoma Cancer Care Specialists and Research Institute , LLC Recruiting
Tulsa, Oklahoma, United States, 74146
Contact: Melissa Powell       melissa.powell@ocsri.org   
Principal Investigator: Eric Thomas, MD         
United States, Rhode Island
Women & Infants Hospital Recruiting
Providence, Rhode Island, United States, 02905
Contact: Mary Dionne       mdionne@wihri.org   
Principal Investigator: Katina Robison, MD         
United States, Texas
Parkland Health and Hospital System Recruiting
Dallas, Texas, United States, 75235
Contact: Annette Paulsen       annette.paulsen@utsouthwestern.edu   
Principal Investigator: David Miller, MD         
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: Annette Paulsen       annette.paulsen@utsouthwestern.edu   
Principal Investigator: David Miller, MD         
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Misty Woodall       mwoodall@mdanderson.org   
Principal Investigator: Shannon Westin, MD         
Sponsors and Collaborators
Gynecologic Oncology Group
Novartis
Investigators
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Study Chair: Brian Slomovitz, MD GOG

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Responsible Party: Gynecologic Oncology Group
ClinicalTrials.gov Identifier: NCT03673124     History of Changes
Other Study ID Numbers: GOG-3026
First Posted: September 17, 2018    Key Record Dates
Last Update Posted: August 29, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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.: Yes
Keywords provided by Gynecologic Oncology Group:
ovary
peritoneum
fallopian tube
Additional relevant MeSH terms:
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Carcinoma
Cystadenocarcinoma, Serous
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Cystadenocarcinoma
Adenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Letrozole
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