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Diarrhea Prophylaxis in Patients With HER2+ Breast Cancer Treated With Trastuzumab and Neratinib, Followed by Neratinib Monotherapy

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ClinicalTrials.gov Identifier: NCT03094052
Recruitment Status : Recruiting
First Posted : March 29, 2017
Last Update Posted : April 17, 2018
Sponsor:
Collaborator:
Puma Biotechnology, Inc.
Information provided by (Responsible Party):
Jo Chien, University of California, San Francisco

Brief Summary:
This is a study to evaluate the toxicity profile of neratinib in combination with trastuzumab in patients with early stage breast cancer with the use of anti-diarrheal prophylaxis. The anti-diarrheal medications being tested in this trial are loperamide and crofelemer. Crofelemer is an anti-diarrheal, enteric-coated drug product for oral administration. It is the only botanical drug currently approved by the FDA for oral administration and is approved for the treatment of diarrhea associated with HAART. Crofelemer has a novel mechanism of action, acting directly and simultaneously on 2 distinct intestinal luminal chloride channels. It is an inhibitor of both the cyclic adenosine monophosphate (cAMP)-stimulated cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion (Cl-) channel found on the apical membranes, and the calcium-activated Cl- channels (CaCC) at the luminal membrane of enterocytes. The CFTR Cl-channel and CaCC regulate Cl and fluid secretion by intestinal epithelial cells. Crofelemer acts by blocking Cl- secretion and accompanying high volume water loss in diarrhea, normalizing the flow of Cl- and water in the GI tract.

Condition or disease Intervention/treatment Phase
HER2-positive Breast Cancer Drug: Neratinib Drug: Trastuzumab Drug: Crofelemer Drug: Loperamide Phase 2

Detailed Description:

This is an open-label adjuvant/post neoadjuvant single arm phase 2 trial.

Patients will receive:

Neratinib 240 mg orally once a day for up to 52 weeks while receiving concurrent trastuzumab. After the completion of trastuzumab maintenance therapy (determined by treating physician), neratinib will continue as monotherapy for 12 months. Neratinib is to be taken continuously in 21-day cycles with no rest between cycles unless related to toxicity.

Intensive daily loperamide prophylaxis for the first 2 cycles and then as needed.

Crofelemer 125 mg bid for the first two cycles then as needed.

Each cycle is 21 days. Clinic visits and laboratory studies are planned on day 1 of every cycle for the first 4 cycles, then q4 cycles thereafter. An end of treatment visit will occur 28 days after the last dose of neratinib. Patients who permanently discontinue treatment due to unacceptable toxicity will be followed-up for 28 days after the last dose of neratinib.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 23 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This is an open-label adjuvant/post-neoadjuvant single arm phase 2 trial. There will be 23 patients recruited. If pertuzumab is approved in the adjuvant setting during the course of the study, the protocol will be amended to allow pertuzumab. This trial will open as a single-institution trial at UCSF and expand to include 1-2 other sites as needed.
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 Adjuvant Trastuzumab and Neratinib Followed by Neratinib Monotherapy, and Intensive Anti-diarrhea Prophylaxis
Actual Study Start Date : January 4, 2017
Estimated Primary Completion Date : December 1, 2018
Estimated Study Completion Date : December 2, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Neratinib, trastuzumab, crofelemer, loperamide
  • Neratinib 240 mg orally once a day for up to 52 weeks while receiving concurrent trastuzumab. After the completion of trastuzumab maintenance therapy, neratinib will continue as monotherapy for 12 months. Neratinib is to be taken continuously in 21-day cycles with no rest between cycles unless related to toxicity.
  • Intensive daily loperamide prophylaxis for the first 2 cycles (42 days) and then as needed. Days 1-14: 4 mg 3 times daily. Days 15-42: 4 mg twice per day.
  • Crofelemer 125 mg bid for the first 2 cycles then as needed.
  • Trastuzumab as indicated by the treating physician. Patients must plan to receive at least 4 months of trastuzumab (and thus 4 months of concurrent neratinib) to be eligible for this study
Drug: Neratinib
Drug: Trastuzumab
Drug: Crofelemer
Drug: Loperamide



Primary Outcome Measures :
  1. Incidence of grade 3 or greater diarrhea with 2 cycles (6 weeks) of prophylactic loperamide and crofelemer, according to NCI CTCAE Version 4.0 [ Time Frame: 2 cycles (6 weeks) ]


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

Inclusion Criteria:

A patient will be eligible for this study if she/he meets any of the following criteria.

  1. Aged ≥18 years at signing of informed consent.
  2. Histologically confirmed clinical or pathological stage 2 through stage 3c primary adenocarcinoma of the breast.
  3. Documented HER2 overexpression or gene-amplified tumor by a validated approved method.
  4. Patients can have HR+ or HR-negative disease.
  5. Concurrent adjuvant endocrine therapy and bone-modifying agents is allowed
  6. Patients can be premenopausal or postmenopausal
  7. Completion of neoadjuvant or adjuvant chemotherapy
  8. Completion of adjuvant locoregional radiation, if indicated, is required prior to starting study treatment.
  9. At the time of study enrollment, patients must have at least 4 months of adjuvant trastuzumab planned
  10. Clinically no evidence of local, regional, or metastatic disease at the time of study entry
  11. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
  12. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1.
  13. 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].
  14. Trastuzumab can cause embryo-fetal harm when administered during pregnancy and the effects of neratinib on the developing human fetus are unknown. Women of child-bearing potential must agree and commit to use of a highly effective double-barrier method of contraception (e.g., a combination of male condom with an intravaginal device such as the cervical cap, diaphragm, or vaginal sponge with spermicide) or a non-hormonal method, from the signing of informed consent until 28 days after the last dose of neratinib and 7 months after the last dose of trastuzumab, or consent to total sexual abstinence (abstinence must occur from randomization and continue for 28 days after the last dose of neratinib and 7 months after the last dose of trastuzumab). Men without confirmed vasectomy must agree and commit to use a barrier method of contraception while on treatment and for 3 months after the last dose of investigational products, or consent to total sexual abstinence (abstinence must occur from randomization and continue for 3 months after the last dose of study medication).
  15. Recovery (i.e., to Grade 1 or baseline) from all clinically significant AEs related to prior therapies (excluding alopecia, neuropathy, and nail changes).
  16. Provide written, informed consent to participate in the study and follow the study procedures.

Exclusion Criteria:

A patient will be excluded from this study if she/he meets any of the following 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, investigational immunotherapy, or investigational biotherapy for breast cancer.
  3. Major surgery (including breast surgery) within <30 days of starting treatment or received chemotherapy, investigational agents, or other cancer therapy <14 days prior to the initiation of investigational products (except adjuvant endocrine therapy).
  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 seconds (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 Platelets: ≤100,000 /μL Hemoglobin: ≤9 g/dL Serum creatinine or calculated creatinine clearance†: ≥1.5 x upper limit of normal (ULN) OR ≤30 mL/min for patients with creatinine levels >1.5 x institutional ULN Serum total bilirubin: ≥1.5 x ULN OR direct bilirubin ≥ ULN for patients with total bilirubin levels >1.5 x ULN AST (SGOT) and ALT (SGPT): ≥2.5 x ULN

    † Creatinine clearance should be calculated per institutional standard.

  7. 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 5 years.
  8. Currently pregnant or breast-feeding.
  9. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., 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).
  10. Clinically active infection with hepatitis B or hepatitis C virus.
  11. 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.
  12. Known hypersensitivity to any component of the investigational products.
  13. 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): NCT03094052


Contacts
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Contact: Chiara Wabl 415-353-7517 Chiara.Wabl@ucsf.edu
Contact: Ivy Wong 415-353-7873 Ivy.Wong@ucsf.edu

Locations
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United States, California
UCSF Helen Diller Family Comprehensive Cancer Center Recruiting
San Francisco, California, United States, 94115
Contact: Jo Chien    877-827-3222    cancertrials@ucsf.edu   
Principal Investigator: Jo Chien, MD         
Sponsors and Collaborators
University of California, San Francisco
Puma Biotechnology, Inc.
Investigators
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Principal Investigator: Jo Chien, MD University of California, San Francisco

Publications:

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Responsible Party: Jo Chien, Associate Clinical Professor of Medicine, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03094052     History of Changes
Other Study ID Numbers: 167514
NCI-2017-01443 ( Registry Identifier: Clinical Trials Reporting Program (CTRP) )
First Posted: March 29, 2017    Key Record Dates
Last Update Posted: April 17, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Keywords provided by Jo Chien, University of California, San Francisco:
neratinib
trastuzumab
crofelemer
Additional relevant MeSH terms:
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Breast Neoplasms
Diarrhea
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Signs and Symptoms, Digestive
Signs and Symptoms
Trastuzumab
Loperamide
Antidiarrheals
Antineoplastic Agents, Immunological
Antineoplastic Agents
Gastrointestinal Agents