Ribociclib (Ribociclib (LEE-011)) With Platinum-based Chemotherapy in Recurrent Platinum Sensitive Ovarian Cancer

Phase I Trial of Ribociclib (Ribociclib (LEE-011)) With Platinum-based Chemotherapy in Recurrent Platinum Sensitive Ovarian Cancer

Investigators hypothesize that concurrent ribociclib treatment and chemotherapy will enhance the response to platinum-based therapy and maintenance therapy will slow ovarian cancer tumor growth leading to prolongation in progression free survival.

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Carcinoma
• Intervention / Treatment: Drug: ribociclib; Drug: Paclitaxel; Drug: Carboplatin

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • Pennsylvania
    • Bethel Park, Pennsylvania, United States, 15102
      • UPMC Hillman Cancer Center Upper St. Clair
    • Greensburg, Pennsylvania, United States, 15601
      • UPMC Hillman Cancer Center Arnold Palmer at Mountain View
    • Irwin, Pennsylvania, United States, 15642
      • UPMC Hillman Cancer Center Arnold Palmer Medical at Norwin
    • Mount Pleasant, Pennsylvania, United States, 15666
      • UPMC Hillman Cancer Center Arnold Palmer at Mt Pleasant
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
    • Pittsburgh, Pennsylvania, United States, 15237
      • UPMC Hillman Cancer Center Passavant (OHA)
    • Washington, Pennsylvania, United States, 15301
      • UPMC Hillman Cancer Center Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Women ≥18 years old 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.
2. Must have had at least 1 prior line of platinum-based therapy
3. ECOG 0-1 with life expectancy of ≥ 3 months

4. Adequate organ function:

   • Serum creatinine ≤1.5mg/dL or 24-hour clearance ≥50 mL/min
   • AST/ALT <2.5x ULN (or <5x 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/µL, ANC ≥1500/µL
   • 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
5. Screening ECG (defined as the mean of the triplicate ECGs) with QTcF interval at screening ≤450msec (using Fridericia's correction) and resting heart rate 50-90bpm
6. Must be able to swallow ribociclib (LEE-011) tablet/capsule
7. Documented disease recurrence/progression based on GCIG-RECIST
8. Able to provide informed consent and comply with all study protocols
9. Treated CNS metastasis allowed if treatment is complete ≥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.
10. 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 or use and continue highly effective methods of contraception for 3 weeks after discontinuation of study treatment.
11. Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.

Exclusion Criteria:

1. Borderline or low-malignant potential histology.
2. Platinum-resistant disease (as defined as progressive disease within 6 months of completion of chemotherapy with a platinum agent)
3. Grade 3 baseline neuropathy.
4. Known hypersensitivity to any of the excipients of ribociclib (LEE-011), including peanuts and soy
5. Prior use of CDK4/6 inhibitors.
6. Congenital long QT syndrome or family history of unexpected sudden cardiac death
7. 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 PI must concur with this determination).
8. Impairment of gastrointestinal (GI) function or disease that may significantly alter the absorption of the study drugs
9. History of HIV infection
10. 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.).

11. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following:

    a. Heart Association functional classification III-IV) b. Documented cardiomyopathy c. Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening d. 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) e. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: i. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesaemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.

    ii. 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 iii. Inability to determine the QT interval on screening (QTcF using Fridericia's correction) f. Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening g. 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

12. Use of prohibited medications (see section 5.3) that cannot be changed to an alternative therapy

13. 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.

    a. 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)

14. 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.
15. Use of herbal supplements unless discontinued ≥7 days prior to initiation of study drug
16. Consumption of foods which are strong inducers or inhibitors of CYP3A4/5 has to be discontinued 7 days prior to initiation of study drug
17. Pregnancy or lactation
18. Participation in a prior investigational study within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer
19. 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.
20. 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).
21. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI-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).
22. Patient with a Child-Pugh score B or C.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ribociclib; Ribociclib (LEE-011) will be used as concurrent therapy with platinum-based chemotherapy in platinum-sensitive recurrent ovarian cancer. Participants will receive 200, 400, or 600mg of ribociclib per day in combination with carboplatin + paclitaxel. Subjects will receive 6 cycles of carboplatin + paclitaxel given weekly with ribociclib.

Drug: ribociclib; Ribociclib (LEE-011) will be given on days 1-4, 8-11, and 15-18 of a 28 day cycle at 200, 400, or 600mg/day during the dose escalation phase. During the maintenance phase, ribociclib (LEE-011) will be given at 600mg/day, 3 weeks on, 1 week off until progression.; Drug: Paclitaxel; During the escalation phase Paclitaxel will be given on days 1, 8, and 15 of a 28 day cycle.; Drug: Carboplatin; During the escalation phase Carboplatin will be given on days 1, 8, and 15 of a 28 day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal tolerated dose (MTD) of ribociclib (LEE-011) when given with carboplatin + paclitaxel in platinum-sensitive recurrent ovarian cancer	Participants will be observed for the first two treatment cycles (2, 28 day cycles) and maximum tolerated dose will be determined.	56 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants that respond to treatment	Overall response rate (ORR) will be analyzed. The number of patients that respond to treatment (exhibit Partial Response (PR) or Complete Response (CR)) will be recorded. PR is defined as at least a 50% reduction in CA 125 levels (response must be confirmed and maintained for at least 28 days) and/or at least 30% decrease in the sum diameters of target lesions. CR is defined as normalization of CA125 levels ((response must be confirmed and maintained for at least 28 days) and disappearance of all target lesions.	18 months post treatment
Time from treatment until disease progression or death	Progression is defined as one of the following: Patients with elevated CA-125 pretreatment and normalization of CA-125 must show evidence of CA-125 greater than, or equal to, 2 times the upper limit of the reference range on 2 occasions at least 1 week apart or; Patients with elevated CA-125 before treatment, which never normalizes, must show evidence of CA-125 greater than, or equal to, 2 times the nadir value on 2 occasions at least 1 week apart or; Patients with CA-125 in the reference range before treatment must show evidence of CA-125 greater than, or equal to, 2 times the upper limit of the reference range on 2 occasions at least 1 week apart; Increase in at least 20% in sum of diameters of target lesions or any new lesions or unequivocal increase in non-target lesions.; Response determined via measurable disease (measurement of target and non-target lesions) takes precedence over CA125 criteria Stable Disease (SD): CA	18 months post treatment
Number of participants encountering toxicity at each dose level	Patients will potentially be treated with 3 different dose levels of ribociclib in combination with platinum-based chemotherapy.	30 days post treatment
Overall Survival (OS)	The (median) length of time from start of treatment patients are still alive.	Up to 5 years

Collaborators and Investigators

• Sponsor: Ronald Buckanovich
• Investigators: Principal Investigator: Lan G Coffman, M.D., University of Pittsburgh Medical Center

Publications and helpful links

General Publications

• Coffman LG, Orellana TJ, Liu T, Frisbie LG, Normolle D, Griffith K, Uppal S, McLean K, Berger J, Boisen M, Courtney-Brooks M, Edwards RP, Lesnock J, Mahdi H, Olawaiye A, Sukumvanich P, Taylor SE, Buckanovich R. Phase I trial of ribociclib with platinum chemotherapy in ovarian cancer. JCI Insight. 2022 Sep 22;7(18):e160573. doi: 10.1172/jci.insight.160573.

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2017
• Primary Completion (Actual): June 1, 2020
• Study Completion (Actual): August 1, 2022

Study Registration Dates

• First Submitted: February 14, 2017
• First Submitted That Met QC Criteria: February 14, 2017
• First Posted (Actual): February 17, 2017

Study Record Updates

• Last Update Posted (Actual): September 7, 2022
• Last Update Submitted That Met QC Criteria: September 1, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Ovarian Neoplasms; Fallopian Tube Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Carboplatin; Paclitaxel
• Other Study ID Numbers: 18-006; CLEE011XUS28T (Other Identifier: Novartis, Inc)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No