A Study Looking the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide

Tracking Information
First Submitted Date ICMJE	February 17, 2015
First Posted Date ICMJE	March 27, 2015
Last Update Posted Date	August 21, 2018
Actual Study Start Date ICMJE	February 2015
Estimated Primary Completion Date	February 2020 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: January 9, 2017)	Incidence of Grade 3 or higher diarrhea [ Time Frame: Length of study (15 months) ]; The primary objective of this study is to characterize the incidence and severity of diarrhea in patients with early-stage HER2 overexpressed/amplified (HER2+) breast cancer treated with neratinib when administered with intensive loperamide prophylaxis, after prior treatment with trastuzumab.
Original Primary Outcome Measures ICMJE; (submitted: March 23, 2015)	Incidence/Severity of diarrhea captured in the clinical study database [ Time Frame: Entire length of study (15 months) ]; Review of the incidence and severity of diarrhea.
Change History	Complete list of historical versions of study NCT02400476 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: August 17, 2018)	Incidence of serious adverse events and other adverse events of special interest [ Time Frame: Length of study (15 months) ]Assess the incidence of serious adverse events (SAEs) and other adverse events of special interest (AESI); Incidence and severity of diarrhea [ Time Frame: Length of study (15 months) ]Assess the incidence and severity of diarrhea after the administration of an anti-inflammatory agent, a bile acid sequestrant, or following lower starting doses and dose-escalation regimen of neratinib
Original Secondary Outcome Measures ICMJE; (submitted: March 23, 2015)	Frequency distribution of maximum grade incidence of diarrhea [ Time Frame: Length of study (15 months) ]Review of the frequency distribution of the maximum grade incidence of diarrhea; incidence of serious adverse events (SAEs) and adverse events of special interest (AEOIs).; Incidence of diarrhea by loperamide exposure [ Time Frame: Length of study (15 months) ]Review of the incidence and severity of diarrhea by loperamide exposures; incidence of SAEs and AEOIs.; Severity of diarrhea by loperamide exposure [ Time Frame: Length of study (15 months) ]Review of the incidence and severity of diarrhea by loperamide exposures; incidence of SAEs and AEOIs.
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	A Study Looking the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Loperamide
Official Title ICMJE	An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients With Early-Stage HER2+ Breast Cancer Treated With Neratinib and Intensive Loperamide Prophylaxis
Brief Summary	An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients with Early-Stage HER2+ Breast Cancer Treated with Neratinib and Intensive Loperamide Prophylaxis
Detailed Description	This is an open-label, Phase 2 study that will investigate the incidence and severity of diarrhea in early-stage HER2+ breast cancer patients receiving neratinib with intensive loperamide diarrhea prophylaxis, alone and in combination with an anti-inflammatory treatment or a bile acid sequestrant treatment, who have previously undergone a course of trastuzumab therapy in the adjuvant setting. Patients will receive: Neratinib 240 mg orally once daily with food for thirteen (13) 28-day cycles.; Loperamide daily for two (2) 28-day cycles and then as needed.; For patients enrolled under Amendment 3, an anti-inflammatory treatment for 1 cycle and loperamide to be administered daily for two (2) 28-day cycles and then as needed, thereafter;; For patients enrolled under Amendment 4, colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter;; For patients enrolled under Amendment 5, colestipol for 1 cycle and loperamide to be administered on an as-needed basis only.; For patients enrolled under Amendment 6, 120 mg neratinib for Week 1, followed by 160 mg neratinib starting for Week 2, followed by 240 mg neratinib starting at Week 3 and thereafter. Loperamide will be administered on an as-needed basis only.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Early Stage HER2+ Breast Cancer
Intervention ICMJE	Drug: Neratinib Other Name: Nerlynx; Drug: Loperamide; Drug: Colestipol 2 g twice daily with or without food for one 28 day cycle; Drug: Budesonide 9 mg extended release tablets once daily with or without food for 28 days
Study Arms	Experimental: Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. Interventions: Drug: Neratinib Drug: Loperamide; Experimental: Budesonide and Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. Interventions: Drug: Neratinib Drug: Loperamide Drug: Budesonide; Experimental: Colestipol and Loperamide 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. Interventions: Drug: Neratinib Drug: Loperamide Drug: Colestipol; Experimental: Colestipol with Loperamide as needed 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. Interventions: Drug: Neratinib Drug: Loperamide Drug: Colestipol; Experimental: Neratinib dose escalation 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. Interventions: Drug: Neratinib Drug: Loperamide
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	Recruiting
Estimated Enrollment ICMJE; (submitted: August 17, 2018)	650
Original Estimated Enrollment ICMJE; (submitted: March 23, 2015)	70
Estimated Study Completion Date	March 2020
Estimated Primary Completion Date	February 2020 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Aged ≥18 years at signing of informed consent; Histologically confirmed stage 1 through stage 3c primary adenocarcinoma of the breast; Documented HER2 overexpression or gene-amplified tumor by a validated approved method; Patients must have completed a course of prior adjuvant trastuzumab or experienced side effects that resulted in early discontinuation of trastuzumab that have since resolved; The last dose of trastuzumab must have been given >2 weeks and ≤1 year (365 days) from enrollment; Physician assessment confirming that the patient is negative for local or regional recurrence of disease or metastatic disease at the time of study entry, including: Per standard of care, bone scan or positron emission tomography (PET) scan; required only if alkaline phosphatase (ALP) is ≥2 x upper limit of normal (ULN) and/or there are symptoms of metastatic bone disease. A confirmatory imaging study is required if the results from the bone scan are questionable. Per standard of care, computed tomography (CT), magnetic resonance imaging (MRI) or ultrasound of the abdomen and chest; required only if aspartate aminotransferase (AST)/alanine aminotransferase (ALT) or ALP is ≥2 x ULN. Other radiologic assessments may be performed to rule out underlying breast cancer recurrence if indicated and as per standard of care (for patients enrolled starting with Amendment 6.1).; Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO); Eastern Cooperative Oncology Group (ECOG) status of 0 to 1; Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause. [Women are considered postmenopausal if they are ≥12 months without menses, in the absence of endocrine or anti-endocrine therapies.]; Women of childbearing potential must agree and commit to the use of a highly effective non-hormonal method of contraception, ie, intrauterine device, bilateral tubal ligation, vasectomized partner, or abstinence (only when it is the preferred lifestyle of the patient), from the time of informed consent until 28 days after the last dose of the investigational products. Man (male patient) with female partner of childbearing potential must agree and commit to use condom and the female partner must agree and commit to use a highly effective method of contraception (ie, any of the above methods, or for females, hormonal contraception associated with inhibition of ovulation) while on treatment and for 3 months after last dose of investigational products.; Recovery (ie, to Grade 1 or baseline) from all clinically significant AEs related to prior therapies (excluding alopecia, neuropathy, and nail changes); Provide written, informed consent to participate in the study and follow the study procedures Exclusion Criteria: Clinical or radiologic evidence of local or regional recurrence of disease or metastatic disease prior to or at the time of study entry; Currently receiving chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer; Major surgery within <30 days of starting treatment or received chemotherapy, investigational agents, or other cancer therapy, except hormonal therapy (eg, tamoxifen, aromatase inhibitors), <14 days prior to the initiation of investigational products; Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2; including individuals who currently use digitalis, beta -blockers, or calcium channel blockers specifically for congestive heart failure), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia; QTc interval >0.450 seconds (males) or >0.470 (females), or known history of QTc prolongation or Torsade de Pointes (TdP); Screening laboratory assessments outside the following limits: Absolute neutrophil count (ANC) <1,000/μl (<1.0 x 109/L); Platelet count <100,000/μl (<100 x 109/L); Hemoglobin <9 g/dL; Total bilirubin >1.5 x institutional upper limit of normal (ULN) (i n case of known Gilbert's syndrome, <2 x ULN is allowed); Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x institutional ULN; Creatinine Creatinine clearance <30 mL/min (as calculated by Cockcroft-Gault formula or Modification of Diet in Renal Disease [MDRD] formula); Active, unresolved infections; Patients with a second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Patients with other non-mammary malignancies must have been disease-free for at least 5years; Currently pregnant or breast-feeding; Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn's disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any etiology at baseline); Clinically active infection with hepatitis B or hepatitis C virus; Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the Investigator's judgment, make the patient inappropriate for this study; Known hypersensitivity to any component of the investigational products; known hypersensitivity to salicylates; known hypersensitivity to aspartame-containing products for patients with phenylketonuria; known allergies to any of the medications or components of medications used in the trial; Unable or unwilling to swallow tablets
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact: Puma Biotechnology, Inc. (424) 248-6500 clinicaltrials@pumabiotechnology.com
Listed Location Countries ICMJE	Australia, Canada, Spain, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT02400476
Other Study ID Numbers ICMJE	PUMA-NER-6201; 2015-004374-15 ( EudraCT Number )
Has Data Monitoring Committee	Not Provided
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	Not Provided
Responsible Party	Puma Biotechnology, Inc.
Study Sponsor ICMJE	Puma Biotechnology, Inc.
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: Clinical Development Senior Vice President Puma Biotechnology, Inc.
PRS Account	Puma Biotechnology, Inc.
Verification Date	August 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP