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

• 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: Puma Biotechnology, Inc.
• Information provided by (Responsible Party): Puma Biotechnology, Inc.

Tracking Information

• First Submitted Date: February 17, 2015
• First Posted Date: March 27, 2015
• Results First Submitted Date: February 28, 2022
• Results First Posted Date: May 6, 2022
• Last Update Posted Date: May 6, 2022
• Actual Study Start Date: February 2015
• Actual Primary Completion Date: April 22, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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.

Current Secondary Outcome Measures (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 (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: 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: 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Early Stage HER2+ Breast Cancer

Intervention

• 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 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.

Recruitment Information

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

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Canada, France, Germany, Spain, United States

Administrative Information

• NCT Number: NCT02400476
• Other Study ID Numbers: 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

• 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: Puma Biotechnology, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Chief Scientific Officer; Puma Biotechnology, Inc.

• PRS Account: Puma Biotechnology, Inc.
• Verification Date: January 2021