Clinical Trials /

Ribociclib and Letrozole Treatment in Ovarian Cancer

NCT03673124

Description:

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.

Related Conditions:
  • Low Grade Fallopian Tube Serous Adenocarcinoma
  • Low Grade Ovarian Serous Adenocarcinoma
  • Primary Peritoneal Serous Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ribociclib and Letrozole Treatment in Ovarian Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: GOG-3026
  • NCT ID: NCT03673124

Conditions

  • Low Grade Serous Carcinoma

Interventions

DrugSynonymsArms
RibociclibRibociclib and letrozole
LetrozoleRibociclib and letrozole

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Ribociclib and letrozoleOtherRibociclib 600mg oral daily for 3 weeks then 1 week off plus Letrozole 2.5 mg oral daily
  • Ribociclib
  • Letrozole

Eligibility 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. Patients with grade 1 taxane-induced
             neuropathy, any grade alopecia, amenorrhea, or other toxicities not considered a
             safety risk for the patient as per investigator's discretion are eligible. 1. 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 (unless patient is receiving permitted anticoagulants and the INR is
                  within the therapeutic range of intended use for that anticoagulant within 7 days
                  prior to the first dose of study drug). 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. 14. Patients receiving tamoxifen or toremifine must have washout
             period of 5 half-lives prior to randomization.

        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
                       hypocalcemia, 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 other studies involving investigational drug(s) within 30 days prior
             to randomization or within 5 half-lives of the investigational product (whichever is
             longer) or participation in any other type of medical research judged not to be
             scientifically or medically compatible with this study. If the patient is enrolled or
             planned to be enrolled in another study that does not involve an investigational drug,
             the agreement of Novartis study medical lead is required to establish eligibility.

         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: a short duration (,5
             days) of systemic corticosteriods; any durations of 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

             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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate
Time Frame:From date of protocol entry to date of first documented response assessed up to 5 years
Safety Issue:
Description:Determine the response rate of patients receiving the combination of Ribociclib and Letrozole

Secondary Outcome Measures

Measure:Clinical benefit (CR, PR, SD) rate
Time Frame:From date of protocol entry to first documented response assessed up to 5 years
Safety Issue:
Description:Determine the clinical benefit (CR, PR, and SD) rate of patients receiving the combination of letrozole + Ribociclib.
Measure:Toxicity assessment (nature, frequency, and maximum degree of toxicity)
Time Frame:every 4 weeks assessed up to 5 years
Safety Issue:
Description:determine the nature, frequency, and maximum degree of toxicity associated with this combination using CTCAE v5.0
Measure:Progression-free survival
Time Frame:From date of protocol entry to date of first documented progression or death assessed up to 5 years
Safety Issue:
Description:determine the progression-free survival of women receiving the combination of letrozole + Ribociclib.
Measure:Overall survival
Time Frame:From date of protocol entry to date of first documented progression or death assessed up to 5 years
Safety Issue:
Description:determine the overall survival of women receiving the combination of letrozole + Ribociclib.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Gynecologic Oncology Group

Trial Keywords

  • ovary
  • peritoneum
  • fallopian tube

Last Updated

February 10, 2020