Clinical Trials /

Targeting PAM50 Her2-Enriched Phenotype With Enzalutamide in Hormone Receptor-Positive/Her2-Negative Metastatic Breast Cancer

NCT04142060

Description:

The main hypothesis of the study is that enzalutamide induces a significant proliferative arrest in HR+/HER2-negative breast cancer falling into the PAM50 HER2-E subtype. Currently, enzalutamide clinical development is ongoing in different prostate cancer indications but the breast cancer development program has been discontinued. As the role of the AR in HR-positive breast cancer and the predictive value of previously identified biomarker are still unclear, further research is needed to effectively utilize enzalutamide in this disease.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Targeting PAM50 Her2-Enriched Phenotype With Enzalutamide in Hormone Receptor-Positive/Her2-Negative Metastatic Breast Cancer
  • Official Title: Targeting the PAM50 Her2-Enriched Phenotype With Enzalutamide in Hormone Receptor-Positive/Her2-Negative Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: ARIANNA (SOLTI-1502)
  • SECONDARY ID: 2019-002806-28
  • NCT ID: NCT04142060

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
EnzalutamideEnzalutamide

Purpose

The main hypothesis of the study is that enzalutamide induces a significant proliferative arrest in HR+/HER2-negative breast cancer falling into the PAM50 HER2-E subtype. Currently, enzalutamide clinical development is ongoing in different prostate cancer indications but the breast cancer development program has been discontinued. As the role of the AR in HR-positive breast cancer and the predictive value of previously identified biomarker are still unclear, further research is needed to effectively utilize enzalutamide in this disease.

Detailed Description

      A strong rationale accumulated over the years suggests that within HR+/HER2-negative breast
      cancer, tumors falling into the PAM50 HER2-enriched subtype have androgen receptor
      (AR)-dependency. To test this hypothesis directly in patients' tumors, we propose an
      exploratory, open-label, non-randomized, two-cohort, multicenter, prospective, phase II study
      which evaluates the effect of enzalutamide on proliferation after 2 weeks (14-21 days) of
      treatment in patients with endocrine-resistant, locally advanced or metastatic
      HR+/HER2-negative breast cancer. After 2 weeks (14-21 days) of treatment, patients will
      continue enzalutamide. Exemestane will be allowed to be added to enzalutamide per
      investigator discretion and will be administered until progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
EnzalutamideExperimentalPatients will be dispensed with oral enzalutamide 160 mg (four 40 mg capsules) as a self-administered single oral daily dose, continuously
  • Enzalutamide

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent for all study procedures according to local regulatory
             requirements prior to beginning specific protocol procedures.

          -  Subjects with progression on or following at least 1 prior standard of care systemic
             anti-cancer therapy.

          -  Female and male patients.

          -  Performance status of 0-2.

          -  Age ≥18 years.

          -  Pre/peri-menopausal and post-menopausal women are allowed; menopausal status is
             relevant for the requirement of goserelin, triptorelin or leuprolide to be used
             concomitantly with enzalutamide. Post-menopausal status is defined either by:

               -  Prior bilateral oophorectomy or

               -  Age ≥60 or

               -  Age < 60 and amenorrhea for ≥ 12 months (in the absence of chemotherapy,
                  tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the
                  post-menopausal range per local standards.

               -  If a patient is taking tamoxifen or toremifene and is aged < 60, then FSH and
                  plasma estradiol levels should be in post-menopausal range per local values.

               -  For women with therapy-induced amenorrhea, measurement of FSH and/or estradiol
                  are needed to ensure menopausal status.

          -  Life expectancy ≥ 12 weeks.

          -  Locally advanced or metastatic breast cancer not amenable to curative intent.

          -  Histologically confirmed HR-positive/HER2-negative disease based on the most recent
             biopsy before signing the informed consent.

               -  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) guideline(73).

               -  ER and/or PR positivity are defined as >1% of cells expressing HR via IHC
                  analysis as per ASCO-CAP guideline (74)

          -  Patients must have a site of disease amenable to safely perform a biopsy, as per
             Investigator's assessment, and be a candidate for tumor biopsy according to the
             treating institution's guidelines.

          -  Possibility of performing a biopsy prior to the start of treatment and its repetition
             after 2 weeks (14-21 days) on the same location. It will be provided formalin-fixed
             paraffin-embedded (FFPE) tumor block. 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. It is recommended to send the biopsy directly to the central lab
             after confirming the existence of a tumor, so as not to delay the inclusion, without
             the need to carry out IHC studies in the same.

               -  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.

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

          -  Patient must be willing to provide biopsy prior to the start of treatment and its
             repetition after 2 weeks (14-21 days) on the same location.

          -  The following subtypes identified in the pre-treatment tumor biopsy, as assessed by
             PAM50 assay at the Central Laboratory:

               -  HER2-E (Cohort A)

               -  Luminal A and Luminal B (Cohort B).

          -  No more than 4 prior lines of chemotherapy regimens for recurrent, locally advanced or
             metastatic breast cancer.

          -  Endocrine resistant disease, defined as the presence of disease recurrence while
             receiving adjuvant endocrine therapy for early stage breast cancer or disease
             progression of locally advanced/metastatic BC under ongoing endocrine therapy. There
             is no limit of previous received hormonal agents.

          -  Measurable and non-measurable (but evaluable) disease per RECIST 1.1 criteria.

          -  Adequate organ function, as determined by the following laboratory tests, within 28
             days prior to enrollment:

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.

               -  Hemoglobin (Hb) ≥ 9 g/dL (red blood cell transfusion and/or erythropoietin
                  allowed 7 days before study treatment).

               -  Platelets ≥ 75,000/mm3.

               -  International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN and
                  activated partial thromboplastin time (aPTT) within therapeutic range

               -  Serum creatinine ≤ 1.5x upper limit of normal (ULN)

               -  AST or ALT ≤ 3 x ULN.

               -  Serum bilirubin ≤ 1.5 upper limit of normal (ULN) unless the patient has
                  documented non-malignant disease (e.g. Gilbert´s syndrome).

          -  Ability to swallow study drug and comply with study requirements.

          -  Resolution of all acute toxic effects of prior therapy or surgical procedures to
             baseline or Grade ≤ 1 (except alopecia or other toxicities not considered to be a
             safety risk for the patient) according to NCI CTCAE version 5.0.

        Exclusion Criteria:

          -  History of current or previously treated CNS metastases or leptomeningeal disease.
             Testing for CNS metastasis is not mandatory.

          -  History of seizure or any condition that may predispose to seizure.

          -  Clinically significant cardiovascular disease within 6 months prior to enrolment
             defined as:

               -  Myocardial infarction.

               -  Inadequately controlled angina or serious cardiac arrhythmia not controlled by
                  adequate medication.

               -  Congestive heart failure (CHF) New York Health Association (NYHA) Class ≥ II.

               -  History of clinically significant ventricular arrhythmias (eg, ventricular
                  tachycardia, ventricular fibrillation, torsade de pointes).

               -  History of Mobitz II second-degree or third-degree heart block without a
                  permanent pacemaker in place.

               -  Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury
                  (mmHg) on 2 consecutive measurements at the screening visit.

               -  Bradycardia as indicated by a heart rate of < 50 beats per minute on the
                  screening electrocardiogram (ECG) recording.

               -  Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or
                  diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the
                  screening visit.

          -  Inability to swallow tablets, extensive reduction surgery of the stomach or small
             bowel or any active gastrointestinal disorder which may impair the absorption of the
             trial treatment (e.g. active peptic ulcer disease; uncontrolled celiac disease).

          -  Major surgical procedure within 4 weeks prior to allocation or anticipation of the
             need for major surgery during the course of study treatment.

          -  Use of medications that could reduce seizure threshold or concomitant treatment with
             potent CYP3A4 inducers.

          -  Treatment with warfarin and coumarin-like anticoagulants. Prophylactic use of low
             molecular weight heparin (LMWH) is allowed.

          -  Fructose intolerance.

          -  Treatment with any anticancer commercially available or investigational drug within 14
             days prior to commencing trial treatment.

          -  Hypersensitivity reaction to the active pharmaceutical ingredient or any of the
             capsule components, including Labrasol, butylated hydroxyanisole, and butylated
             hydroxytoluene.

          -  Current severe disease, infection, or systemic condition that renders the patient
             inappropriate for enrollment in the opinion of the investigator.

          -  Presence of any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule; those
             conditions should be discussed with the patient before registration in the trial.

          -  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 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 enzalutamide.

          -  Treatment with any approved or investigational agent that blocks androgen synthesis or
             targets the AR (eg, abiraterone acetate, ARN-509, bicalutamide, enzalutamide, ODM-201,
             TAK-448, TAK-683, TAK-700); or patients who progressed on Exemestane in
             adjuvant/advanced setting are not allowed; patients who received treatment for < 28
             days or placebo on an investigational study are acceptable
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:changes of the PAM50 11-gene proliferation signature
Time Frame:after 2 weeks (14-21 days) of treatment with enzalutamide
Safety Issue:
Description:Relative changes of the PAM50 11-gene proliferation signature after 2 weeks (14-21 days) of treatment with enzalutamide. These changes will be analyzed according to the formula: Mean suppression = 100 - [geometric mean (post-treatment / pretreatment · 100)].

Secondary Outcome Measures

Measure:Incidence, duration and severity of Adverse Events
Time Frame:during and after 2 weeks (14-21 days) of treatment with enzalutamide
Safety Issue:
Description:Incidence, duration and severity of Adverse Events (AEs) assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 5, including dose reductions, delays and treatment discontinuations.
Measure:Relative changes of 33 gene signatures
Time Frame:after 2 weeks (14-21 days) of treatment with enzalutamide
Safety Issue:
Description:Relative changes of 33 gene signatures and 770 genes after 2 weeks (14-21 days) of treatment with enzalutamide and from week 3 to progression (in those patients who consent for optional biopsy). This study will be performed using the nCounter Breast 360TM panel. Relative changes of 33 gene signatures and 770 genes after 2 weeks (14-21 days) of treatment with enzalutamide and from week 3 to progression (in those patients who consent for optional biopsy). This study will be performed using the nCounter Breast 360TM panel.
Measure:somatic mutations
Time Frame:after 2 weeks (14-21 days) of treatment with enzalutamide
Safety Issue:
Description:Proportion of somatic mutations in samples from both cohorts using a targeted gene sequencing panel.
Measure:AR expression by IHC
Time Frame:before and after 21 days of treatment in Cohorts A and B.
Safety Issue:
Description:Analysis of AR expression by IHC (% nuclear expression in tumoral cell)
Measure:changes in percentage of cells expressing Ki67 by IHC
Time Frame:after 21 days of enzalutamide in HER2-E and Luminal A/B tumors.
Safety Issue:
Description:Relative changes in percentage of cells expressing Ki67
Measure:changes of It-TIL and Str-TIL
Time Frame:pre- and after 2 weeks (14-21 days) of treatment with enzalutamide and progression
Safety Issue:
Description:Analysis of lymphocyte infiltrate on hematoxylin and eosin-stained FFPE-sections. Percentage (%) change in It-TILs and Str-TILs infiltration
Measure:ctDNA levels
Time Frame:during and after 2 weeks (14-21 days) of treatment with enzalutamide
Safety Issue:
Description:Quantification of baseline ctDNA levels and 2 weeks (14-21 days) post-treatment. Determination of quantitative changes at day 21, at progression or at the end of trial due to other reasons
Measure:tumor ORR
Time Frame:after 2 weeks (14-21 days) of treatment with enzalutamide
Safety Issue:
Description:Proportion of patients who have a partial (PR) or complete response (CR) to therapy.

Details

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

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