Ribociclib with Carboplatin and Paclitaxel in Treating Patients with Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Status: Active

Description

This phase I trial studies the side effects and best dose of ribociclib with carboplatin and paclitaxel in treating patients with ovarian, fallopian tube, or primary peritoneal cancer that has come back. Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib with carboplatin and paclitaxel may work better in treating patients with ovarian, fallopian tube, or primary peritoneal cancer.

Eligibility Criteria

Inclusion Criteria

  • Women with platinum-sensitive recurrent ovarian, fallopian or primary peritoneal cancer (defined as recurrent disease > 6 months after completing last platinum-based chemotherapy) eligible to receive platinum-based doublet chemotherapy
  • Must have had at least 1 prior line of platinum-based therapy
  • Eastern Cooperative Oncology Group (ECOG) 0-1 with life expectancy of >= 3 months
  • Serum creatinine =< 1.5 mg/dL or 24-hour clearance >= 50 mL/min
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN) (or < 5 x ULN if liver metastasis are present)
  • 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
  • Hemoglobin >= 9 gm/dl
  • Platelets >= 100,000/ul
  • Absolute neutrophil count (ANC) >= 1500/ul
  • International normalized ratio (INR) =< 1.5
  • Potassium, total calcium (corrected for serum albumin), magnesium, and sodium within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication
  • Screening electrocardiogram (ECG) (defined as the mean of the triplicate ECGs) with corrected QT interval by Fridericia (QTcF) interval at screening =< 450 msec (using Fridericia’s correction) and resting heart rate >= 50 beats per minute (bpm)
  • Must be able to swallow ribociclib (LEE-011) tablet/capsule
  • Documented disease recurrence/progression based on Gynecologic Cancer Intergroup (GCIG)-Response Evaluation Criteria in Solid Tumors (RECIST)
  • Able to provide informed consent and comply with all study protocols
  • Treated central nervous system (CNS) metastasis allowed if treatment is completed >= 8 weeks prior to enrollment; patients must be asymptomatic off systemic corticosteroids for at least 4 weeks after completion of radiation therapy; CNS disease must be stable or regressed on repeat imaging performed at least 4 weeks after completion of therapy
  • Women of child-bearing potential (those who have had a menstrual cycle within the last year and have not had a tubal ligation or surgical removal of both ovaries and/or hysterectomy) must agree to abstain from vaginal intercourse and continue highly effective methods of contraception for 3 weeks after discontinuation of study treatment * 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 * Male sterilization (at least 6 months prior to screening); the vasectomized male partner should be the sole partner for that patient * 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

Exclusion Criteria

  • Borderline or low-malignant potential histology
  • Platinum-resistant disease (as defined as progressive disease within 6 months of completion of chemotherapy with a platinum agent)
  • Grade 3 baseline neuropathy
  • Known hypersensitivity to any of the excipients of ribociclib (LEE-011) including peanuts and soy
  • Prior use of CDK4/6 inhibitors
  • Congenital long QT syndrome or family history of unexpected sudden cardiac death
  • 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 or per physician discretion that the previous cancer was adequately treated with curative intent and unlikely to recur (the study principal investigator [PI] must concur with this determination)
  • Gastrointestinal (GI) function or disease that may significantly alter the absorption of the study drugs
  • History of human immunodeficiency virus (HIV) infection
  • Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, cause unacceptable safety risks and contraindicate patient’s 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.)
  • Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following: * 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) at screening * 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 hypomagnesaemia, 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 * 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
  • Use of prohibited medications that cannot be changed to an alternative therapy
  • 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)
  • 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
  • Use of herbal supplements unless discontinued >= 7 days prior to initiation of study drug
  • Consumption of foods which are strong inducers or inhibitors of CYP3A4/5 has to be discontinued 7 days prior to initiation of study drug
  • Pregnancy or lactation
  • Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer
  • 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 was irradiated
  • 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)
  • Patient has not recovered from all toxicities related to prior anticancer therapies to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5 grade =< 1 (Exception to this criterion: patients with any grade of alopecia and/or neuropathy =< grade 2 are allowed to enter the study)
  • Patient with a Child-Pugh score B or C

Locations & Contacts

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: Active
Contact: Ronald J. Buckanovich
Phone: 734-615-1482
Email: ronaldbu@med.umich.edu

Pennsylvania

Pittsburgh
University of Pittsburgh Cancer Institute (UPCI)
Status: Active
Contact: Lan Gardner Coffman
Phone: 412-641-2016
Email: coffmanl@mwri.magee.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of ribociclib (LEE-011) with carboplatin + paclitaxel chemotherapy in platinum-sensitive recurrent ovarian cancer.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity.

II. Determine the response rate (RR) and progression-free survival (PFS) of ribociclib (LEE-011) with platinum + taxane followed by maintenance ribociclib (LEE-011).

III. Further characterize the safety profile of ribociclib (LEE-011) with platinum + taxane in recurrent platinum-sensitive ovarian cancer.

IV. To correlate RR and PFS with Rb mutational status and NFAT4 nuclear localization levels

OUTLINE:

Patients receive ribociclib orally (PO) daily on days 1-4, 8-11, and 15-18 and carboplatin intravenously (IV) and paclitaxel IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After 3 weeks of last dose of carboplatin and paclitaxel, patients who meet the maintenance therapy criteria receive ribociclib PO daily on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up every month for 18 months.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
University of Pittsburgh Cancer Institute (UPCI)

Principal Investigator
Lan Gardner Coffman

Trial IDs

Primary ID 18-006
Secondary IDs NCI-2017-01120
Clinicaltrials.gov ID NCT03056833