Clinical Trials /

Targeting EGFR/ERBB2 With Neratinib in Hormone Receptor (HR)-Positive/HER2-negative HER2-enriched Advanced/Metastatic Breast Cancer

NCT04460430

Description:

HR+/HER2-negative BC represent ∼70% of all newly diagnosed breast tumours and are responsible for most recurrences and deaths due to this disease, and despite available standard therapies, ∼15-20% of hormone tumours recur at distant sites. As BC is a clinically and biologically heterogeneous disease, intrincsic subtype may play an important role in classifying patients. In this case, HER2-E subtype is present in approximately 6.6-11.0% of HR+/HER2-negative tumors and might express either HER2, estrogen receptor (ER) or progesterone receptor (PR), we also know that HER2-E is present twice as much in metastatic tumors compared to primary tumors and that HER2-E patients may benefit in terms of PFS form an anti-HER2 drug as was showed using retrospective sample in EGF30008 trial. Therefore, incorporation of novel drugs in combination with endocrine therapy (ET) can improve patient outcomes in HR+/HER2-negative BC advanced disease specially in those with HER2-E subtype. Methods NEREA is an open-label, single arm, multicenter phase II study evaluating treatment with neratinib in combination with ET in pre and post-menopausal women and men with locally advanced or metastatic HER2-enriched (HER2-E), HR+/HER2-negative breast cancer who had recurrence or progression while receiving previous ET (either aromatase inhibitors, tamoxifen or fulvestrant) in the adjuvant setting or to treat advanced disease or both. The study will follow a Simon's 2-stage design with one interim and one final efficacy analysis. The primary objective will is assess the efficacy of neratinib in combination with ET is this group of patients, efficacy will be measured as Progression-Free Survival at 6 months (PFS6) defined as the proportion of patients alive and without progression, locally assessed by the investigator through the use of RECIST v.1.1 at 24 weeks after first treatment administration, imaging evaluation will be performed every 8 weeks for the first 12 months following treatment start, and every 12 weeks thereafter. Secondary endpoints include Clinical Benefit Rate at 6 months , Overall Response rate, Duration of response, Time to response and Incidence, duration and severity of Adverse Events. The interim analysis will be conducted when 33 patients are evaluable for the primary endpoint having the potential for at least 3 'on treatment' disease assessment scans. If less than 15 patients achieved a PFS6, the trial will be terminated for futility in favor of the null hypothesis. If more than 28 patients achieved a PFS6, the trial will be stopped in favor of the alternative hypothesis demonstrating activity. If none of the two above-mentioned conditions are attain, up to a further 23 patients may be evaluated, for at least a total of 56 evaluable patients. Therefore, if a total of 28 or more patients achieved a PFS6 at the end of the second stage, then the null will be rejected in favor of the alternative. Eligible patients will receive neratinib 240 mg every day in combination with ET, with either exemestane, fulvestrant or tamoxifen: exemestane 25 mg every day orally, tamoxifen 20mg every day orally or fulvestrant 500 mg administered in two intramuscular injections of 250 mg each at C1D15 and at D1 of each subsequent 28-day cycle at investigator discretion. LHRH agonist will be used in men and premenopausal women if no oophorectomy has been performed previously. All patients will take prophylactic loperamide with a stablished doses scheme during the firs cycle and on demand in subsequent cycles

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Targeting EGFR/ERBB2 With Neratinib in Hormone Receptor (HR)-Positive/HER2-negative HER2-enriched Advanced/Metastatic Breast Cancer
  • Official Title: Targeting EGFR/ERBB2 With Neratinib in Hormone Receptor (HR)-Positive/HER2-negative HER2-enriched Advanced/Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: SOLTI-1718
  • SECONDARY ID: 2019-000710-11
  • NCT ID: NCT04460430

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
Neratinib + endocrine therapyNeratinib + endocrine therapy

Purpose

HR+/HER2-negative BC represent ∼70% of all newly diagnosed breast tumours and are responsible for most recurrences and deaths due to this disease, and despite available standard therapies, ∼15-20% of hormone tumours recur at distant sites. As BC is a clinically and biologically heterogeneous disease, intrincsic subtype may play an important role in classifying patients. In this case, HER2-E subtype is present in approximately 6.6-11.0% of HR+/HER2-negative tumors and might express either HER2, estrogen receptor (ER) or progesterone receptor (PR), we also know that HER2-E is present twice as much in metastatic tumors compared to primary tumors and that HER2-E patients may benefit in terms of PFS form an anti-HER2 drug as was showed using retrospective sample in EGF30008 trial. Therefore, incorporation of novel drugs in combination with endocrine therapy (ET) can improve patient outcomes in HR+/HER2-negative BC advanced disease specially in those with HER2-E subtype. Methods NEREA is an open-label, single arm, multicenter phase II study evaluating treatment with neratinib in combination with ET in pre and post-menopausal women and men with locally advanced or metastatic HER2-enriched (HER2-E), HR+/HER2-negative breast cancer who had recurrence or progression while receiving previous ET (either aromatase inhibitors, tamoxifen or fulvestrant) in the adjuvant setting or to treat advanced disease or both. The study will follow a Simon's 2-stage design with one interim and one final efficacy analysis. The primary objective will is assess the efficacy of neratinib in combination with ET is this group of patients, efficacy will be measured as Progression-Free Survival at 6 months (PFS6) defined as the proportion of patients alive and without progression, locally assessed by the investigator through the use of RECIST v.1.1 at 24 weeks after first treatment administration, imaging evaluation will be performed every 8 weeks for the first 12 months following treatment start, and every 12 weeks thereafter. Secondary endpoints include Clinical Benefit Rate at 6 months , Overall Response rate, Duration of response, Time to response and Incidence, duration and severity of Adverse Events. The interim analysis will be conducted when 33 patients are evaluable for the primary endpoint having the potential for at least 3 'on treatment' disease assessment scans. If less than 15 patients achieved a PFS6, the trial will be terminated for futility in favor of the null hypothesis. If more than 28 patients achieved a PFS6, the trial will be stopped in favor of the alternative hypothesis demonstrating activity. If none of the two above-mentioned conditions are attain, up to a further 23 patients may be evaluated, for at least a total of 56 evaluable patients. Therefore, if a total of 28 or more patients achieved a PFS6 at the end of the second stage, then the null will be rejected in favor of the alternative. Eligible patients will receive neratinib 240 mg every day in combination with ET, with either exemestane, fulvestrant or tamoxifen: exemestane 25 mg every day orally, tamoxifen 20mg every day orally or fulvestrant 500 mg administered in two intramuscular injections of 250 mg each at C1D15 and at D1 of each subsequent 28-day cycle at investigator discretion. LHRH agonist will be used in men and premenopausal women if no oophorectomy has been performed previously. All patients will take prophylactic loperamide with a stablished doses scheme during the firs cycle and on demand in subsequent cycles

Trial Arms

NameTypeDescriptionInterventions
Neratinib + endocrine therapyExperimentalNeratinib plus Fulvestrant, Exemestane or Tamoxifen
  • Neratinib + endocrine therapy

Eligibility Criteria

        Inclusion Criteria:

          -  * Male/female participants who are at least 18 years of age on the day of signing
             informed consent with histologically confirmed diagnosis of locally advanced or
             metastatic, histologically documented hormone receptor positive (ER and/or PR
             expression >1%) and HER2- breast cancer by local testing, not amenable to surgical
             therapy will be enrolled in this study.

               -  HER2 negativity is defined as either of the following by local laboratory
                  assessment: IHC 0, IHC 1+ or IHC2+/in situ hybridisation (ISH/FISH) negative as
                  per American Society of Clinical Oncology (ASCO)-College of American Pathologists
                  Guideline (CAP) guideline82.

               -  ER and/or PR positivity are defined as >1% of cells expressing HR via IHC
                  analysis as per ASCO-CAP guideline83.

          -  The participant (or legally acceptable representative if applicable) provides written
             informed consent for the trial.

          -  Postmenopausal, as defined by at least one of the following criteria:

               -  Age ≥60 years;

               -  Age <60 years and cessation of regular menses for at least 12 consecutive months
                  with no alternative pathological or physiological cause (in the absence of
                  chemotherapy, tamoxifen, toremifene, or ovarian suppression); and serum estradiol
                  and FSH level within the laboratory's reference range for postmenopausal females;

               -  Documented bilateral oophorectomy,

               -  Medically confirmed ovarian failure OR

        Pre/perimenopausal, i.e., not meeting the criteria for being postmenopausal:
        Pre/perimenopausal women can be enrolled if amenable to be treated with the LHRH agonist.
        Patients must have commenced treatment with LHRH agonist at least 4 weeks prior to
        treatment start.

          -  * No more than one prior line of chemotherapy for recurrent locally advanced or
             metastatic disease.

          -  Prior radiation therapy for metastatic disease is permitted. Subjects who were treated
             with radiation therapy may participate as long as at least 2 weeks have elapsed since
             the last dose of radiation therapy or have recovered from the effects of radiation
             before treatment start whichever is the latest.

          -  Disease refractory to aromatase inhibitors or fulvestrant or tamoxifen, defined as
             recurrence during or within 12 months after the end of adjuvant treatment or
             progression during or within 1 months after the end of treatment for advanced disease.
             Notes: Endocrine therapy do not have to be the last treatment prior to first treatment
             administration. Other prior anticancer endocrine therapy in combination with CDK 4/6
             inhibitors or PI3K-pathway-targeted therapies (including PI3K, mTOR, PDK and AKT
             inhibitors) are also allowed. Patients who have received fulvestrant, exemestane and
             tamoxifen may be eligible

          -  * Availability of formalin-fixed paraffin-embedded (FFPE) tumor block, taken less than
             12 months before the start of the treatment during metastatic disease, if not
             available, confirmation by the Medical monitor will be required to include the patient
             in the study. A study-specific pathology report should be associated with the sample
             (every effort should be done to obtain the sample after the previous therapeutic
             regimen for advanced disease). The tumor tissue should be of good quality based on
             total and viable tumor content and must be evaluated centrally for PAM50 analysis
             prior to enrollment. Patients whose tumor tissue is not evaluable for central testing
             are not eligible unless a biopsy from metastatic lesion is performed for this purpose.

             a) Acceptable samples include core needle biopsies for deep tumor tissue or
             excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or
             mucosal lesions or biopsies from bone metastases.

             c) Fine needle aspiration, brushing, cell pellet from pleural effusion and lavage
             samples are not acceptable.

          -  HER2-E subtype as per PAM50 analysis confirmed by the designated laboratory.

          -  * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
             Evaluation of ECOG is to be performed within 7 days prior to the date of enrollment.

          -  * Life expectancy ≥ 12 weeks

          -  * Measurable disease or non-measurable (but evaluable), as defined by RECIST v1.1.
             (Note: Previously irradiated lesions can be considered as measurable disease only if
             disease progression has been unequivocally documented at that site since radiation).

          -  Adequate hematologic and end-organ function

          -  Baseline left ventricular ejection fraction (LVEF) ≥ 50% measured by echocardiography
             (ECHO) or Multiple Gate Acquisition (MUGA) scan.

        Male participants:

        • A male participant must agree to use contraception as detailed in Appendix 3 of this
        protocol during the treatment period and for at least 120 days form the last doses of
        neratinib and refrain from donating sperm during this period.

        Female participants:

          -  A female participant is eligible to participate if she is not pregnant (see Appendix
             3), not breastfeeding, and at least one of the following conditions applies:

          -  Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR

          -  A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the
             treatment period and for at least 120 days from the last dose of neratinib.

        Exclusion Criteria:

          -  Prior treatment with any ERBB2-directed TKI (eg, lapatinib, afatinib, dacomitinib,
             neratinib, tucatinib)

          -  Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or
             cumulative doxorubicin dose >450 mg/m2. If another anthracycline or more than one
             anthracycline has been used, the cumulative dose must not exceed the equivalent of 450
             mg/m2 doxorubicin.

          -  Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart
             failure (New York Heart Association functional classification of ≥2), unstable angina
             (symptomatic angina pectoris within the past 180 days that required the initiation of
             or increase in anti-anginal medication or other intervention), myocardial infarction
             within 12 months of enrollment, or ventricular arrhythmia (except for benign premature
             ventricular contractions).

          -  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 5.0 [CTCAE v.5.0] diarrhea of any
             etiology at baseline).

          -  A WOCBP who has a positive urine pregnancy test within 72 hours prior to C1D1 (see
             Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum
             pregnancy test will be required.

          -  Presence of any acute toxic effects from prior anti-cancer therapy or major surgical
             procedures to NCI CTCAE version 5.0 Grade ≤ 1 (except alopecia or other toxicities not
             considered a safety risk for the patient at investigator´s discretion). Note:
             Placement of central venous access catheter(s) (e.g., port or similar) is not
             considered a major surgical procedure and is therefore permitted.

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with
             indwelling catheters, such as PleurX® are allowed).

          -  Uncontrolled hypercalcemia (>1.5 mmol/L [>6 mg/dL] ionized calcium or serum calcium
             [uncorrected for albumin] >3 mmol/L [>12 mg/dL] or corrected serum calcium >ULN) or
             clinically significant (symptomatic) hypercalcemia

          -  * Has a known additional malignancy that is progressing or has required active
             treatment within the past 3 years. Note: Participants with basal cell carcinoma of the
             skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g. breast carcinoma,
             cervical cancer in situ) that have undergone potentially curative therapy are not
             excluded.

          -  Has known active CNS metastases and/or carcinomatous meningitis. Participants with
             previously treated brain metastases may participate provided they are radiologically
             stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
             (note that the repeat imaging should be performed during study screening), clinically
             stable and on a chronic stable dose of ≤ 2 mg total daily of dexamethasone (or
             equivalent) during the last 14 days.

          -  * Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

          -  * Prior solid organ transplantation

          -  Has an active infection requiring systemic therapy.

          -  * Has a known history of Human Immunodeficiency Virus (HIV).

          -  * Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is
             detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required
             unless mandated by local health authority.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

          -  Unable or unwilling to swallow tablets.

          -  Known hypersensitivity to any component of the investigational product, required
             combination therapy, or loperamide.

          -  Patients being treated with drugs recognized as being strong inhibitors or inducers of
             the isoenzyme CYP3A4/P-gp isoform of cytochrome P450: Ritonavir (antiretroviral),
             carbamazepine, phenobarbital, phenytoin (antiepileptics), St John's wort (Hypericum
             perforatum) (herbal product), rifampicin, Rifabutin (antimycobacterial), Ketoconazole,
             Itroconazole, Voriconazole (antifungal), Telithromycin, Clarithromycin (antibiotic).
             Co-administration with moderate CYP3A4/P-gp inhibitors: fluconazole (antifungal),
             diltiazem, verapamil (calcium-channel blockers), erythromycin (antibiotic), Severe
             hepatic impairment (Child-Pugh C)) within the last 5 days prior to first treatment
             administration.

          -  * Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of neratinib.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-Free survival PFS6 (Efficacy)
Time Frame:at 24 weeks after first treatment administration
Safety Issue:
Description:Proportion of patients alive and without progression (according to RECIST v1.1 criteria)

Secondary Outcome Measures

Measure:Clinical Benefit Rate at 6 months (CBR6)
Time Frame:at 24 weeks after first treatment administration
Safety Issue:
Description:CBR6 defined as a Complete response (CR), Partial response (PR) or Stable Disease (SD) as determined locally by the investigator through the use of RECIST.
Measure:Overall Response rate (ORR)
Time Frame:until objective tumor response, on average 8 months
Safety Issue:
Description:determined locally by the investigator through the use of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria
Measure:Progression free survival (PFS)
Time Frame:until patients progression, on average 8 months
Safety Issue:
Description:determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurs first.
Measure:Duration of response (DoR)
Time Frame:from objective tumor response until patients progression, on average 8 months
Safety Issue:
Description:determined locally by the investigator through use of RECIST v.1.1, or death from any cause, whichever occurs first
Measure:Time to response (TtR)
Time Frame:from first treatment administration to the objective tumor response, on average 8 months
Safety Issue:
Description:defined as the time from first treatment administration to the first objective tumor response (tumor shrinkage of ≥30%) observed for patients who achieved a CR or PR.
Measure:Incidence, duration and severity of Adverse Events (AEs)
Time Frame:from first treatment administration to the end of study, on average 8 months
Safety Issue:
Description:assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 5, including dose reductions, delays and treatment discontinuations.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:SOLTI Breast Cancer Research Group

Last Updated

July 1, 2020