Clinical Trials /

Onapristone as Preoperative Treatment for Postmenopausal Women With Hormone Receptor + and HER2- Breast Cancer

NCT04142892

Description:

ONAWA is a window of opportunity, prospective, multicenter, phase 0 trial which evaluates the effect of onapristone (ONA) on proliferation after 3 weeks of treatment in postmenopausal women with ER+/PgR+ and HER2-negative early breast cancer amenable to pre-operative endocrine therapy and surgery.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Onapristone as Preoperative Treatment for Postmenopausal Women With Hormone Receptor + and HER2- Breast Cancer
  • Official Title: A Window of Opportunity Trial of Onapristone as Preoperative Treatment for Postmenopausal Women With Hormone Receptor-Positive and HER2-negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: ONAWA (SOLTI-1802)
  • SECONDARY ID: 2019-001433-13
  • NCT ID: NCT04142892

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
OnapristoneOnapristone

Purpose

ONAWA is a window of opportunity, prospective, multicenter, phase 0 trial which evaluates the effect of onapristone (ONA) on proliferation after 3 weeks of treatment in postmenopausal women with ER+/PgR+ and HER2-negative early breast cancer amenable to pre-operative endocrine therapy and surgery.

Detailed Description

      The main hypothesis is that onapristone, an antiprogestin will induce a significant
      proliferative arrest in HR+/HER2-negative breast cancer. The primary endpoint is chosen based
      on reports which related the 2.7% Ki67 value (natural log of 1) both after a 15 days1 or 3-4
      months of neoadjuvant endocrine treatment with favorable breast cancer relapse free and
      overall survival2,3. Hence, this Ki67 cut-off (Complete Cell Cycle Arrest, or CCCA) has been
      consistently used in recent trials as an acceptable surrogate marker of clinical and
      biological efficacy, even though the achievement of a pathological complete response is very
      unusual in luminal tumors after preoperative endocrine therapy. Trials with biological
      endpoint, including the so-called window of opportunity trials such as the ONAWA study
      provide tumor tissue before and after a short course of a given therapy for biomarker
      analyses of response and resistance. The aim of these studies is to improve the
      investigator's understanding regarding the biologic effect of a given drug, in order to
      better define its target population early in its development without interfering with the
      standard treatment pattern of the patient.
    

Trial Arms

NameTypeDescriptionInterventions
OnapristoneExperimental50 mg given orally (PO), twice a day (BID), in a continuous schedule (QD). 3 weeks of (+/-3 days) of ONA treatment
  • Onapristone

Eligibility Criteria

        Inclusion Criteria:

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

          2. Age ≥ 18 years.

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

          4. Postmenopausal women defined either by:

               1. Age ≥60 or

               2. Age < 60 and amenorrhea for ≥ 12 months and FSH and E2 plasmatic levels in the
                  post-menopausal range per local standards or

               3. Prior bilateral oophorectomy (28 days before Day 1 of the study treatment).

          5. Histologically confirmed invasive breast carcinoma eligible for surgery with all the
             following characteristics:

               1. Primary tumor diameter of at least 15 mm (cT1c-3) as measured by ultrasound (US).

               2. No regional lymph node metastases by imaging or clinical examination (cN0).

               3. ER-positive and PgR-positivity (ER+/PgR+), as assessed locally, defined by
                  American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)
                  clinical practice guidelines.

               4. HER2-negative status, as assessed locally, defined by American Society of
                  Clinical Oncology/College of American Pathologists (ASCO/CAP)

               5. In case of multifocal tumors (defined as the presence of two or more foci of
                  cancer within the same breast quadrant), the largest lesion must be measured in
                  at least one dimension of minimal 15 mm per US. This lesion will be designated as
                  'target' lesion for all subsequent evaluations. ER+/PgR+ and HER2-negative status
                  must be documented in all the tumor foci. Site markers should be placed in each
                  accessible lesion, even if mastectomy is planned, to facilitate correct tumor
                  assessment by the pathologist.

               6. Cells staining positive for Ki67 ≥ 15% as locally assessed.

               7. Available pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor specimen or
                  possibility to obtain one. Minimal sample requirements are: at least 2 tumor
                  cylinders with a minimal tissue surface of 10 mm2, containing ≥10% tumor cells,
                  enough to obtain at least 2 cuts of 10 µm each. Tumor cylinder will be mandatory.

          6. No clinical or radiographic evidence of distant metastases (M0).

          7. Adequate hematologic and organ function within 14 days before the first study
             treatment on Day 1, defined by the following:

               1. Neutrophils (ANC ≥1500/μL).

               2. Hemoglobin ≥9 g/dL (with no need for transfusions).

               3. Platelet count ≥100000/μL.

               4. Serum albumin ≥3 g/dL.

               5. Calculated creatinine clearance of ≥ 60 mL/min based on the Cockcroft-Gault
                  glomerular filtration rate estimation:

                  (140 − age) x (weight in kg) x 0.85 72 x (serum creatinine in mg/dL).

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

               7. Potassium, total Calcium (corrected for serum albumin), Magnesium and Natrium
                  with institutional normal limits or corrected with normal limits with supplement
                  before first dose of study medication.

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

          9. Absence 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.

        Exclusion Criteria:

          1. Inoperable locally advanced or inflammatory (i.e., Stage III) breast cancer.

          2. Metastatic (Stage IV) breast cancer.

          3. Invasive bilateral o multicentric breast cancer.

          4. Patients requiring neoadjuvant chemotherapy or immediate surgical intervention.

          5. Patients who have undergone sentinel lymph node biopsy or tumor excisional biopsy
             prior to study treatment.

          6. Prior malignancy within 3 years prior to randomization, except curatively treated
             non-melanoma skin cancer, in situ cervical cancer or adequately treated Stage I or II
             cancer from which the patient is currently in complete remission or other cancer from
             which the patient has been disease-free for 2 years.

          7. Congenital long QT syndrome or screening QT interval corrected using Fridericia's
             formula (QTcF) > 480 milliseconds or any clinically significant cardiac rhythm
             abnormalities.

          8. Liver function tests documented within the screening period and on Day 1 of treatment
             period:

             d. Total bilirubin >1.5x the upper limit of normal (ULN) unless the patient has
             documented non-malignant disease (e.g. Gilbert´s syndrome) for whom conjugated
             bilirubin must be under ULN.

             e. AST and ALT >2.5x ULN. f. Alkaline phosphatase ALP >2x ULN.

          9. Concurrent, serious, uncontrolled infections or current known infection with HIV
             (testing is not mandatory).

         10. Known hypersensitivity to any of the study drugs, including excipients.

         11. History or clinical evidence of any liver or biliary pathology including cirrhosis,
             infectious disease, inflammatory conditions, steatosis, or cholangitis (including
             ascending cholangitis, primary sclerosing cholangitis, obstruction, perforation,
             fistula of biliary tract, spasm of sphincter of Oddi, biliary cyst or biliary
             atresia).

         12. Known clinically significant history active viral or other hepatitis (e.g., positive
             for hepatitis B surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at
             screening), current drug or alcohol abuse, or cirrhosis.

               -  Patients with past hepatitis B virus (HBV) infection or resolved HBV infection
                  (defined as having a negative HBsAg test and a positive antibody to hepatitis B
                  core antigen [HBcAg] antibody test) are eligible.

               -  Patients positive for HCV antibody are eligible only if polymerase chain reaction
                  (PCR) is negative for HCV RNA.

         13. Chronic adrenal failure or is receiving concurrent long-term corticosteroid therapy.
             The following corticosteroid uses are permitted: single doses, topical applications
             (e.g. for rash), inhaled sprays (e.g. for obstructive airway diseases), eye drops or
             local injections (e.g. intra-articular).

         14. Lack of physical integrity of the upper gastrointestinal tract, malabsorption
             syndrome, or inability to swallow pills.

         15. History of or clinical evidence of significant co-morbidities that, in the judgment of
             the investigator, may interfere with the conduction of the study, the evaluation of
             response, or with informed consent.

         16. Received an investigational product or been treated with an investigational device
             within 30 days prior to first drug administration or plans to start any other
             investigational product or device study within 30 days after last drug administration.

         17. Hormonal treatments for other indications such as osteoporosis, breast cancer
             prevention, hormonal substitutive therapy, such as raloxifene, tamoxifen, estrogen,
             progestins. If a patient is on natural products known to contain progestins, they must
             be stopped 14 days prior to beginning study treatment.

         18. Used any prescription medication during the prior 1 month that the investigator judges
             is likely to interfere with the study or to pose an additional risk to the patient in
             participating, specifically inhibitors or inducers of cytochrome P450 (CYP)3A4.

         19. Major surgical procedure or significant traumatic injury within 30 days prior to
             enrollment.

         20. Assessment by the investigator to be unable or unwilling to comply with the
             requirements of the protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Cell Cycle Arrest (CCCA)
Time Frame:after 3 weeks of ONA therapy
Safety Issue:
Description:CCCA rate determined by Ki67 < 2.7%

Secondary Outcome Measures

Measure:IHC of tumor expression
Time Frame:after 3 weeks of ONA therapy
Safety Issue:
Description:IHC of tumor expression of ER, PgR, CD24, CD44, ALDH1, Ser294-PgR, Ki67
Measure:PAM50 subtype change
Time Frame:after 3 weeks of ONA therapy
Safety Issue:
Description:PAM50 subtype changes upon ONA therapy
Measure:antiproliferative effect
Time Frame:after 3 weeks of ONA therapy
Safety Issue:
Description:Suppression of PAM50 11-gene proliferation signature according to PAM50 subtypes upon treatment.. These changes will be analyzed according to the formula: Mean suppression = 100 - [geometric mean (post-treatment / pretreatment · 100)].
Measure:proliferation score
Time Frame:after 3 weeks of ONA therapy
Safety Issue:
Description:mean suppression of PAM50 11-gene proliferation signature according to PAM50 subtypes
Measure:gene expression changes
Time Frame:after 3 weeks of ONA therapy
Safety Issue:
Description:expression of 770 genes across of 23 categories of BC tumor biology changes in the expression of the 16-PgR target genes
Measure:molecular markers in blood
Time Frame:after 3 weeks of ONA therapy
Safety Issue:
Description:Estradiol and progesterone levels
Measure:identification putative prognostic and predictive biomarkers
Time Frame:after 3 weeks of ONA therapy
Safety Issue:
Description:Development of a gene signature of response to ONA based on changes in the expression of 770 genes by the nCounter Breast 360TM panel in the tumor. Analysis of the presence of ctDNA and its dynamics after ONA treatment.
Measure:Adverse Events (AEs)
Time Frame:after 3 weeks of ONA therapy
Safety Issue:
Description:Incidence, duration and severity of Adverse Events (AEs) assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 5.0, including treatment discontinuations.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:SOLTI Breast Cancer Research Group

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