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An Open-Label Study to Characterize 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 : Completed
First Posted : March 27, 2015
Results First Posted : May 6, 2022
Last Update Posted : May 6, 2022
Sponsor:
Information provided by (Responsible Party):
Puma Biotechnology, Inc.

Tracking Information
First Submitted Date  ICMJE February 17, 2015
First Posted Date  ICMJE March 27, 2015
Results First Submitted Date  ICMJE February 28, 2022
Results First Posted Date  ICMJE May 6, 2022
Last Update Posted Date May 6, 2022
Actual Study Start Date  ICMJE February 2015
Actual Primary Completion Date April 22, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 12, 2022)
Percentage of Patients With Grade 3 or Higher Diarrhea, According to NCI CTCAE v4.0. [ Time Frame: From first dose of investigational product through 28 days after last dose, up to 15.5 months. ]
The primary objective of this study is to characterize the percentage of patients with Grade 3 or higher 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. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.
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
Current Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2022)
  • Percentage of Patients With Diarrhea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0. [ Time Frame: From first dose of investigational product through 28 days after last dose, up to 15.5 months. ]
    Assess the percentage of patients with diarrhea after the administration of an anti-inflammatory agent, a bile acid sequestrant, or following two different dose-escalation regimens of neratinib, by maximum CTC grade. Grade 1: an increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline. Grade 2: Increase of 4 - 6 stools per day over baseline; moderate increase in ostomy output compared to baseline. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.
  • Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest [ Time Frame: From first dose of investigational product through 28 days after last dose, up to 15.5 months. ]
    Assess the percentage of patients with serious adverse events (SAEs) and other adverse events of special interest (AESI). AESIs were selected based on the known safety profile of neratinib as well as typical key body system toxicity concerns generally reviewed for any new drug. These AESIs were grouped into the following categories: gastrointestinal toxicity (diarrhea and stomatitis), hepatotoxicity, pulmonary toxicity (interstitial lung disease), cardiac toxicity (LVEF decreased), and dermatologic toxicity (rash and nail disorders). The AESIs were analyzed by searching the clinical database for all TEAEs and SAEs using either Standardized MedDRA Queries (SMQs) or, if an applicable SMQ did not exist, a Sponsor-defined list of MedDRA preferred terms.
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 Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief 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 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 Loperamide
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 Loperamide or other prophylactic measures.
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 loperamide, alone and in combination with an anti-inflammatory treatment or a bile acid sequestrant treatment, or neratinib dose escalation, 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 28-day cycles.
  • Loperamide daily for two 28-day cycles and then as needed.
  • Amendment 3, an anti-inflammatory treatment for one cycle and loperamide to be administered daily for two 28-day cycles and then as needed. Closed to enrollment.
  • Amendment 4, colestipol for one cycle and loperamide to be administered one cycle and then as needed. Closed to enrollment.
  • Amendment 5, colestipol for one cycle and loperamide as needed. Closed to enrollment.
  • Amendment 6/6.1, 120 mg neratinib for Week 1 (C1D1-C1D7), followed by 160 mg neratinib for Week 2 (C1D8-C1D14), followed by 240 mg neratinib for Week 3 and thereafter (C1D15 to end of treatment). Loperamide as needed. Closed to enrollment.
  • Amendment 7/7.1, 160 mg neratinib for the first 2 weeks (C1D1 - C1D14), followed by 200 mg neratinib for the next 2 weeks (C1D15 - C1D28), followed by 240 mg neratinib thereafter (C2D1 to end of treatment). Loperamide as needed.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential 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  ICMJE
  • 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 1
    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
  • Experimental: Neratinib Dose Escalation 2
    160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only.
    Interventions:
    • Drug: Neratinib
    • Drug: Loperamide
Publications * Barcenas CH, Hurvitz SA, Di Palma JA, Bose R, Chien AJ, Iannotti N, Marx G, Brufsky A, Litvak A, Ibrahim E, Alvarez RH, Ruiz-Borrego M, Chan N, Manalo Y, Kellum A, Trudeau M, Thirlwell M, Garcia Saenz J, Hunt D, Bryce R, McCulloch L, Rugo HS, Tripathy D, Chan A; CONTROL Study Investigators. Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: the CONTROL trial. Ann Oncol. 2020 Sep;31(9):1223-1230. doi: 10.1016/j.annonc.2020.05.012. Epub 2020 May 25.

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: November 2, 2020)
563
Original Estimated Enrollment  ICMJE
 (submitted: March 23, 2015)
70
Actual Study Completion Date  ICMJE April 22, 2021
Actual Primary Completion Date April 22, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age ≥18; male or female
  • Early breast cancer (stage I-3c)
  • Documented HER2+ tumor: HER2 immunohistochemistry (IHC) 3+ or ISH+
  • Prior course of adjuvant trastuzumab given >2 weeks and ≤1 year from enrollment
  • No evidence of local/regional recurrence or metastatic disease
  • Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
  • Male patients with female partners of childbearing potential must agree and commit to use a condom and women of childbearing potential must not be pregnant and must agree and commit to the use of a highly effective non-hormonal method of contraception
  • Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or ECHO

Exclusion Criteria:

  • Major surgery < 30 days
  • Chemotherapy, investigational agents, other cancer therapy (except hormonal therapy) < 14 days
  • Corrected QT Interval (QTc) >0.450 seconds (males) or >0.470 (females) or other active cardiac disease
  • Significant chronic GI disorder with diarrhea as a major symptom
  • Active, unresolved infections
  • Currently pregnant or breast-feeding
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 Australia,   Austria,   Canada,   France,   Germany,   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 No
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: Yes
Plan Description:

Puma Biotechnology is committed to sharing clinical trial data and information to help physicians and patients make informed treatment decisions, and to help qualified researchers advance scientific knowledge.

In accordance with legal and regulatory requirements, Puma publishes study protocol information and clinical study results on clinical trial registries, including ClinicalTrials.gov and EU Clinical Trials Register. Puma also publishes information about clinical studies in peer-reviewed scientific journals and shares data in scientific meetings.

Puma commits to safeguarding confidentiality and patient privacy throughout the clinical trial data and information sharing process. Any patient-level data will be anonymized to protect personally identifiable information.

Qualified researchers and study participants may submit requests for other study documentation and clinical trial data to clinicaltrials@pumabiotechnology.com for consideration.

Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Clinical study documents and clinical trial data may be requested by qualified researchers and study participants for studies that have been completed for at least 18 months, and for which the indication of the drug has been approved in the US and/or EU, as applicable. Requests will be accepted for up to 24 months after the criteria described in this section are met.
Access Criteria:

Requestors must provide organizational contact information; a detailed research plan, including outcomes; timeline for completion of the research; qualifications of the research team; funding source; and potential conflicts of interest.

Puma will not provide access to patient-level data if there is a reasonable likelihood that individual patients could be identified, or in cases where confidentiality or consent provisions prohibit transfer of data or information to third parties. Additionally, Puma will not disclose information that jeopardizes intellectual property rights or divulges confidential commercial information.

URL: https://www.pumabiotechnology.com/data_sharing_policy.html
Current Responsible Party Puma Biotechnology, Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Puma Biotechnology, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Chief Scientific Officer Puma Biotechnology, Inc.
PRS Account Puma Biotechnology, Inc.
Verification Date January 2021

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