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

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ClinicalTrials.gov Identifier: NCT02400476
Recruitment Status : Recruiting
First Posted : March 27, 2015
Last Update Posted : August 21, 2018
Sponsor:
Information provided by (Responsible Party):
Puma Biotechnology, Inc.

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

Condition or disease Intervention/treatment Phase
Early Stage HER2+ Breast Cancer Drug: Neratinib Drug: Loperamide Drug: Colestipol Drug: Budesonide Phase 2

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 650 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 2015
Estimated Primary Completion Date : February 2020
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Drug: Neratinib
Other Name: Nerlynx

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.
Drug: Neratinib
Other Name: Nerlynx

Drug: Loperamide
Drug: Budesonide
9 mg extended release tablets once daily with or without food for 28 days

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.
Drug: Neratinib
Other Name: Nerlynx

Drug: Loperamide
Drug: Colestipol
2 g twice daily with or without food for one 28 day cycle

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.
Drug: Neratinib
Other Name: Nerlynx

Drug: Loperamide
Drug: Colestipol
2 g twice daily with or without food for one 28 day cycle

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.
Drug: Neratinib
Other Name: Nerlynx

Drug: Loperamide



Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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)

  2. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged ≥18 years at signing of informed consent
  2. Histologically confirmed stage 1 through stage 3c primary adenocarcinoma of the breast
  3. Documented HER2 overexpression or gene-amplified tumor by a validated approved method
  4. 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
  5. The last dose of trastuzumab must have been given >2 weeks and ≤1 year (365 days) from enrollment
  6. 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).
  7. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO)
  8. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1
  9. 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.]
  10. 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.
  11. Recovery (ie, to Grade 1 or baseline) from all clinically significant AEs related to prior therapies (excluding alopecia, neuropathy, and nail changes)
  12. Provide written, informed consent to participate in the study and follow the study procedures

Exclusion Criteria:

  1. Clinical or radiologic evidence of local or regional recurrence of disease or metastatic disease prior to or at the time of study entry
  2. Currently receiving chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer
  3. 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
  4. 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
  5. QTc interval >0.450 seconds (males) or >0.470 (females), or known history of QTc prolongation or Torsade de Pointes (TdP)
  6. 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)

  7. Active, unresolved infections
  8. 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
  9. Currently pregnant or breast-feeding
  10. 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)
  11. Clinically active infection with hepatitis B or hepatitis C virus
  12. 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
  13. 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
  14. Unable or unwilling to swallow tablets

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02400476


Contacts
Contact: Puma Biotechnology, Inc. (424) 248-6500 clinicaltrials@pumabiotechnology.com

  Show 52 Study Locations
Sponsors and Collaborators
Puma Biotechnology, Inc.
Investigators
Study Director: Clinical Development Senior Vice President Puma Biotechnology, Inc.

Responsible Party: Puma Biotechnology, Inc.
ClinicalTrials.gov Identifier: NCT02400476     History of Changes
Other Study ID Numbers: PUMA-NER-6201
2015-004374-15 ( EudraCT Number )
First Posted: March 27, 2015    Key Record Dates
Last Update Posted: August 21, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Puma Biotechnology, Inc.:
HER2 +
Breast Cancer
Neratinib
Nerlynx
Loperamide
Colestipol
Budesonide

Additional relevant MeSH terms:
Breast Neoplasms
Diarrhea
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Signs and Symptoms, Digestive
Signs and Symptoms
Budesonide
Loperamide
Antidiarrheals
Colestipol
Anti-Inflammatory Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Gastrointestinal Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Sequestering Agents