Ribociclib and Bicalutamide in AR+ TNBC

A Phase I/II, Single Arm, Non-randomized Study of Ribociclib (LEE011), a CDK 4/6 Inhibitor, in Combination With Bicalutamide, an Androgen Receptor (AR) Inhibitor, in Advanced AR+ Triple-negative Breast Cancer: Big Ten Cancer Research Consortium BRE15-024

This is an open label, multi-institutional, single arm phase II trial of ribociclib in combination with bicalutamide in advanced AR+ triple-negative breast cancer. No randomization or blinding is involved.

Study Overview

• Status: Recruiting
• Conditions: Triple Negative Breast Cancer
• Intervention / Treatment: Drug: ribociclib; Drug: ribociclib; Drug: Bicalutamide

Detailed Description

This is a non-randomized, single arm, open label study of the combination of bicalutamide with ribociclib in subjects with advanced AR+ TNBC. Prior to enrollment on the phase II cohort, a phase I run-in study will be performed to ensure safety and tolerability of the combination of bicalutamide and ribociclib in subjects with advanced AR+ TNBC.

In both the phase I and phase II portions of the study, subjects will receive bicalutamide 150 mg orally, once daily, continuously on Day 1 to Day 28. Each cycle of treatment is 28 days.

In the phase I portion of the study, cohorts of subjects will receive ribociclib in escalated doses orally, once daily in a 28 day cycle. For the phase II portion, the RP2D dose of ribociclib will be based on the phase I run-in.

In the phase II cohort, a two week lead-in of bicalutamide monotherapy will occur before cycle 1 combination therapy (Day -14 to day -1). Then ribociclib will be added on day 1 of cycle 1. This lead-in will be for CTC androgen receptor analysis.

• Study Type: Interventional
• Enrollment (Estimated): 37
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Kari Wisinski, MD; Phone Number: 38 608-265-1700; Email: kbwisinski@medicine.wisc.edu
• Study Contact Backup: Name: Ahran Lee; Phone Number: 14 317-634-5842; Email: alee@hoosiercancer.org

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • University of Illinois Cancer Center
      • Contact: Ayesha Zaidi; Phone Number: 312-413-1902; Email: azaidi22@uic.edu
      • Principal Investigator: Kent Hoskins, MD
  • Michigan
    • Lansing, Michigan, United States, 48910
      • Completed
      • Michigan State University
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Completed
      • Rutgers Cancer Institute of New Jersey
  • New York
    • Rochester, New York, United States, 14642
      • Recruiting
      • University of Rochester Medical Center
      • Contact: Lisa Carrozzi, OCN; Phone Number: 585-533-1905; Email: lisa_carrozzi@urmc.rochester.edu
      • Contact: Kathleen Pratt; Phone Number: 585-533-1908; Email: kathleen_pratt@urmc.rochester.edu
      • Principal Investigator: Ruth O'Regan, MD
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Completed
      • Penn State Cancer Institute
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Recruiting
      • University of Wisconsin
      • Contact: Cancer Connect; Phone Number: 608-262-5223; Email: cancerconnect@uwcarbone.wisc.edu

Participation Criteria

Eligibility Criteria

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

Description

Individuals from populations who are underrepresented in clinical research (e.g., racial and ethnic minorities, women, individuals from rural/frontier communities, older individuals) will be enrolled with a goal of ensuring that all eligible patients are given the opportunity to participate in novel clinical trials and that research findings can be generalizable to the entire population.

Androgen Receptor (AR) positivity definitions -Phase I: Metastatic or unresectable AR+ triple-negative breast cancer (TNBC); AR positivity defined as IHC staining of >0% of tumor nuclei.

OR

-Phase II: Metastatic or unresectable AR+ triple-negative breast cancer (TNBC); AR positivity defined as IHC staining of ≥10% of tumor nuclei.

Inclusion Criteria for Phase I and II study.

In addition to being AR positive as defined in protocol, subjects must also meet all of the following applicable inclusion criteria.

• Histological or cytological confirmed, metastatic or unresectable triple-negative breast cancer (TNBC). TNBC will be defined as expression of ER<10%, PR< 10% and HER2 negative either by IHC (0, 1+ are negative, 2+ equivocal) or in situ hybridization method (ratio <2.0 is negative).
• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Up to 3 prior line of systemic therapy for metastatic disease is allowed. Combination therapy will be considered 1 line.
• Age ≥ 18 years at the time of consent.
• ECOG Performance Status of 0, 1 or 2 within 28 days prior to registration.
• Life expectancy of > 12 weeks as determined by the treating physician.
• Measurable disease according to RECIST 1.1 within 28 days prior to registration.

• No active central nervous system (CNS) metastatic disease. NOTE: Subjects with CNS involvement must meet ALL of the following to be eligible:

  • At least 28 days from prior definitive treatment of their CNS disease by surgical resection, stereotactic body radiation therapy (SBRT) or whole brain radiation treatment (WBRT) at the time of registration
  • AND asymptomatic and off systemic corticosteroids and/or enzyme-inducing anti-epileptic medications for brain metastases for >14 days prior to registration.
• Prior cancer treatment must be completed at least 14 days prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤grade 1 or to baseline prior to initiation of that therapy.
• Screening rate-corrected QT interval (QTc) must be <450msec and a resting heart rate of at least 50-90 bpm via a standard 12-lead ECG within 28 days prior to registration.
• Demonstrate adequate bone marrow and organ function as defined in the protocol; all screening labs to be obtained within 28 days prior to registration.
• Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to registration. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or they are naturally postmenopausal for at least 12 consecutive months, or her male partner has had a vasectomy at least 6 months prior to screening (The sterilized male partner must be her only sexual partner.).
• Females of childbearing potential and males must be willing to abstain from heterosexual activity or must agree to use adequate contraception (hormonal or barrier method) for the duration of study participation and for 3 weeks after discontinuation of study treatment.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.
• Able to swallow bicalutamide and ribociclib tablets.

Exclusion Criteria:

• Prior therapy with AR antagonists including but not limited to bicalutamide, enzalutamide, abiraterone and orteronel.
• Prior therapy with any CDK 4/6 inhibitors with the exception of participation in a window or preoperative study for Stage I-III operable breast cancer..
• Active infection requiring systemic therapy.
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
• Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least three years.
• Treatment with any investigational drug within 14 days prior to registration or within 5 half-lives of the investigational product, whichever is longer. Immunotherapies such as PD-L1 or PD-1 inhibitors only require a 14 day window, regardless of half-life. Investigational imaging agents are not included in this definition and are allowed.
• Subject who has received radiotherapy <14 days prior to registration, and who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia and any adverse events deemed by the investigator to be unlikely to interfere with the study drug safety).
• Subject has had major surgery within 14 days prior to registration or has not recovered from major side effects of the surgery (tumor biopsy is not considered as major surgery).
• Known hypersensitivity to any of the excipients of ribociclib or bicalutamide.
• Any 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).
• Known history of HIV infection (testing not mandatory).
• Any concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate subject 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.).

• Subjects with any of the following conditions are excluded:

  • Serious or non-healing wound, ulcer, or bone fracture.
  • History of abdominal fistula, gastrointestinal perforation, or intra- abdominal abscess within 28 days prior to registration.
  • Any history of cerebrovascular accident (CVA) or transient ischemic attack within 12 months prior to registration.
  • Any history of arterial or venous thrombosis/thromboembolic event, including pulmonary embolism within the past 12 months prior to registration.
  • 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 registration.
  • Symptomatic congestive heart failure (New York Heart Association III-IV) or documented current cardiomyopathy with left ventricular ejection fraction (LVEF) <50%
  • Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia) or clinically significant, complete left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block).
  • Any episode of atrial fibrillation in the prior 12 months.
  • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.
  • 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. See ManualDocuments/Info tab of the EDC for list of medications.
  • Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening.
• Currently receiving any known strong inducers or inhibitors of CYP3A4/5 which cannot be discontinued 7 days prior to starting study drug (see Appendix 1 for details).
• Subject is currently receiving or has received systemic corticosteroids <14 days prior to starting study drugs. The following uses of corticosteroids are permitted: a short duration (<5 days) of systemic corticosteroidssingle doses, any duration of topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
• Subject is currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), novel oral anticoagulants (NOACs) or fondaparinux is allowed.
• In subjects with a diagnosis of cirrhosis, sSubjects with a Child-Pugh score B or C are excluded. Please see chart in the ManualDocuments/Info tab of the electronic data capture system (EDC) for Child-Pugh score calculation. If subject does not have diagnosed or suspected cirrhosis, the Child-Pugh score does not need to be calculated.
• Subjects taking herbal supplements (St. John's Wort, gingko balboa, etc.) must discontinue these supplements 14 days prior to study registration.
• Consumption of grapefruit, grapefruit hybrids, pummelos, star-fruit, Seville oranges or products containing the juice of each within 7 days prior to study registration.

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: Arm A - Phase I; Dose Escalation Cohort 1 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 400mg PO daily on days 1-21 of a 28 day cycle. Cohort 2 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 400mg PO daily on days 1-28 of a 28 day cycle. Cohort 3 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 600mg PO daily on days 1-21 of a 28 day cycle. Experimental: Arm B - Phase II Investigational Treatment The maximum safe dose of ribociclib in combination with bicalutamide will be given to up to 25 patients.

Drug: ribociclib; 400mg PO; Other Names: LEE011; Drug: ribociclib; 600mg PO; Other Names: LEE011; Drug: Bicalutamide; 150mg PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Maximum Tolerated Dose	Phase I: Maximum tolerated dose (MTD) for subjects receiving ribociclib and bicalutamide without experiencing dose-limiting toxicity(s) (DLT) per Common Terminology Criteria for Adverse Events (CTCAE) v4	D1 of treatment to end of cohort cycle (assessed at 28 days)
Phase II: Clinical benefit rate (CBR) of treatment combination	Compare sum of confirmed complete plus partial responses plus stable disease per response evaluation criteria in solid tumors (RECIST) 1.1 criteria	D1 of treatment to end of 4 treatment cycles (assessed at 16 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Objective Response Rate (ORR)	The objective response rate is the proportion of all subjects with confirmed PR or CR according to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment).	2 years
Phase I: Duration of Response	Duration of overall response-the period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since treatment started).	2 years
Phase I: Assess Safety and Tolerability By summarizing counts and percentages grade 3-5 adverse events (NCI CTCAE Version 4)	By summarizing counts and percentages grade 3-5 adverse events (NCI CTCAE Version 4)	2 years
Phase I: Ribociclib pharmacokinetics	Time points: Peak Plasma Concentration (Cmax) Pre dose and 2-hours post-dose (±15 min) pharmacokinetic samples will be collected on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 2 Day 15.	2 months
Phase II: Progression Free Survival (PFS)	PFS will be summarized using Kaplan-Meier estimates of the median survival times.	2 years
Phase II: Objective Response Rate (ORR)	by RECIST 1.1 on treatment with combination of bicalutamide and ribociclib in advanced AR+ TNBC	2 years
Phase II: Overall Survival (OS)	Overall survival is defined by the date of treatment initiation to date of death from any cause.	5 years
Phase II: Estimate Duration of Response	On treatment with combination of bicalutamide and ribociclib in advanced Androgen Receptor (AR)+ Triple Negative Breast Cancer (TNBC)	2 years
Phase II: Evaluate Safety and Tolerability By summarizing counts and percentages grade 3-5 adverse events (NCI CTCAE Version 4)	By summarizing counts and percentages grade 3-5 adverse events (NCI CTCAE Version 4)	2 years

Collaborators and Investigators

• Sponsor: Kari Wisinski
• Collaborators: Novartis; University of Wisconsin, Madison; Big Ten Cancer Research Consortium
• Investigators: Principal Investigator: Kari Wisinski, MD, University of Wisconsin, Madison

Publications and helpful links

Helpful Links

• Big Ten Cancer Research Consortium Website

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2018
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: March 1, 2017
• First Submitted That Met QC Criteria: March 23, 2017
• First Posted (Actual): March 24, 2017

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: bicalutamide; LEE011; ribociclib; Triple Negative Breast Neoplasms; CDK 4/6 inhibitor
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Androgen Antagonists; Bicalutamide
• Other Study ID Numbers: BTCRC BRE15-024

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