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Ribociclib and Bicalutamide in AR+ TNBC

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ClinicalTrials.gov Identifier: NCT03090165
Recruitment Status : Active, not recruiting
First Posted : March 24, 2017
Last Update Posted : February 22, 2019
Sponsor:
Collaborators:
Novartis
Big Ten Cancer Research Consortium
Information provided by (Responsible Party):
Ruth O'Regan, M.D., Big Ten Cancer Research Consortium

Tracking Information
First Submitted Date  ICMJE March 1, 2017
First Posted Date  ICMJE March 24, 2017
Last Update Posted Date February 22, 2019
Actual Study Start Date  ICMJE March 2, 2017
Estimated Primary Completion Date September 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 23, 2017)
  • Phase I: Maximum Tolerated Dose [ Time Frame: D1 of treatment to end of cohort cycle (assessed at 28 days) ]
    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
  • Phase II: Clinical benefit rate (CBR) of treatment combination [ Time Frame: D1 of treatment to end of 4 treatment cycles (assessed at 16 weeks) ]
    Compare sum of confirmed complete plus partial responses plus stable disease per response evaluation criteria in solid tumors (RECIST) 1.1 criteria
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03090165 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 23, 2017)
  • Phase I: Objective Response Rate (ORR) [ Time Frame: 2 years ]
    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).
  • Phase I: Duration of Response [ Time Frame: 2 years ]
    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).
  • Phase I: Assess Safety and Tolerability By summarizing counts and percentages grade 3-5 adverse events (NCI CTCAE Version 4) [ Time Frame: 2 years ]
    By summarizing counts and percentages grade 3-5 adverse events (NCI CTCAE Version 4)
  • Phase I: Ribociclib pharmacokinetics [ Time Frame: 2 months ]
    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.
  • Phase II: Progression Free Survival (PFS) [ Time Frame: 2 years ]
    PFS will be summarized using Kaplan-Meier estimates of the median survival times.
  • Phase II: Objective Response Rate (ORR) [ Time Frame: 2 years ]
    by RECIST 1.1 on treatment with combination of bicalutamide and ribociclib in advanced AR+ TNBC
  • Phase II: Overall Survival (OS) [ Time Frame: 5 years ]
    Overall survival is defined by the date of treatment initiation to date of death from any cause.
  • Phase II: Clinical Benefit Rate (CBR) at 16 weeks based on degree of Androgen Receptor (AR) expression by Immunohistochemistry (IHC) [ Time Frame: 16 weeks ]
    CBR at 16 weeks based on degree of AR expression by IHC (AR >0% vs. AR ≥10%).
  • Phase II: Progression Free Survival (PFS) based on degree of AR expression by IHC [ Time Frame: 2 years ]
    PFS based on degree of AR expression by IHC (AR >0% vs. AR ≥10%).
  • Phase II: Estimate Duration of Response [ Time Frame: 2 years ]
    On treatment with combination of bicalutamide and ribociclib in advanced Androgen Receptor (AR)+ Triple Negative Breast Cancer (TNBC)
  • Phase II: Evaluate Safety and Tolerability By summarizing counts and percentages grade 3-5 adverse events (NCI CTCAE Version 4) [ Time Frame: 2 years ]
    By summarizing counts and percentages grade 3-5 adverse events (NCI CTCAE Version 4)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ribociclib and Bicalutamide in AR+ TNBC
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description

OUTLINE: This is a multi-center study.

INVESTIGATIONAL TREATMENT:

  • bicalutamide - 150mg po daily D1 - D28 (Cycle = 28 days)
  • ribociclib po daily D1 - D21 of 28 day cycle

PHASE I SAFETY RUN-IN COHORT:

The maximum tolerated dose (MTD) of bicalutamide in combination with ribociclib will be determined using a standard "3+3" design. The first cohort of 3 subjects will receive ribociclib 400mg po daily D1 - D21 of a 28 day cycle (Dose Level 1). If no DLTs are experienced then the next cohort of 3 subjects will receive ribociclib 400mg po daily D1 - D28 of a 28 day cycle (Dose Level 2). If no DLTs are experienced then the next cohort of 3 subjects will receive ribociclib 600mg po daily D1 - D21 of a 28 day cycle (Dose Level 3). If no DLTs are experienced on Dose Level 3, then 3 additional subjects should be treated at this level before declaring MTD.

DLTs will be assessed within the first cycle (28 days).

PHASE II INVESTIGATIONAL TREATMENT:

  • co-therapy bicalutamide 150mg po daily D1 - D28
  • ribociclib po at the RP2D as determined in the Phase I Safety Run-In Cohort

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 28 days prior to registration

Life expectancy of > 12 weeks as determined by the treating physician.

Hematological:

  • White blood cell (WBC) ≥4 × 10^9/L
  • Absolute Neutrophil Count (ANC) ≥1.5 × 10^9/L
  • Hemoglobin (Hb) ≥9 g/dL
  • Platelets (Plt) ≥100 × 10^9/L

Renal:

  • Creatinine ≤1.5 mg/dL OR
  • Calculated creatinine clearance ≥50 ml/min using the Cockcroft-Gault formula

Hepatic:

  • Bilirubin ≤upper limit of normal (ULN)*
  • Aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN if liver mets.
  • Alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN if liver mets. * For subjects with Gilbert's syndrome, this will apply to direct bilirubin only.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Masking Description:
Open Label
Primary Purpose: Treatment
Condition  ICMJE Triple Negative Breast Cancer
Intervention  ICMJE
  • Drug: ribociclib
    400mg PO
    Other Name: LEE011
  • Drug: ribociclib
    600mg PO
    Other Name: LEE011
  • Drug: Bicalutamide
    150mg PO
Study Arms  ICMJE 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 46 patients.

Interventions:
  • Drug: ribociclib
  • Drug: ribociclib
  • Drug: Bicalutamide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 21, 2019)
11
Original Estimated Enrollment  ICMJE
 (submitted: March 23, 2017)
58
Estimated Study Completion Date  ICMJE September 2019
Estimated Primary Completion Date September 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Metastatic or unresectable AR+ triple-negative breast cancer (TNBC); AR positivity assessed centrally and defined as immunohistochemical (IHC) staining of >0% of tumor nuclei.
  • Written informed consent and Health Insurance Portability and Accountability Act of 1996 (HIPAA) authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
  • One prior line of therapy is allowed.
  • Age ≥ 18 years at the time of consent.
  • 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.
  • 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 capsules/tablets.

Exclusion Criteria:

  • No prior therapy with AR antagonists including but not limited to bicalutamide, enzalutamide, abiraterone and orteronel.
  • No prior therapy with any CDK 4/6 inhibitors.
  • 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.
  • 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).
  • 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 cardiomyopathy with left ventricular ejection fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening. MUGA/ ECHO to be performed within 28 days prior to registration.
    • 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).
    • 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.
    • 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
  • Subject is currently receiving or has received systemic corticosteroids <14 days prior to starting study drugs. 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).
  • Subject is currently receiving warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
  • Subject with a Child-Pugh score B or C.
  • Subjects taking herbal supplements (St. John's Wort, gingko biloba, etc.) should 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03090165
Other Study ID Numbers  ICMJE BTCRC BRE15-024
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ruth O'Regan, M.D., Big Ten Cancer Research Consortium
Study Sponsor  ICMJE Ruth O'Regan, M.D.
Collaborators  ICMJE
  • Novartis
  • Big Ten Cancer Research Consortium
Investigators  ICMJE
Study Chair: Ruth O'Regan, MD Big Ten Cancer Research Consortium
PRS Account Big Ten Cancer Research Consortium
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP