Clinical Trials /

Phase 0 Study of Metronomic Oral Vinorelbine and Letrozole in HR+/HER2-negative Early Breast Cancer Patients (VENTANA)

NCT02802748

Description:

VENTANA is a "window-of-opportunity" trial that will explore whether, similar to CDK4/6 inhibitors, Oral Metronomic Vinorelbine in combination with Letrozole induces a superior anti-proliferative effect than Letrozole alone.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase 0 Study of Metronomic Oral Vinorelbine and Letrozole in HR+/HER2-negative Early Breast Cancer Patients (VENTANA)
  • Official Title: Randomized, Open-label, Three-arm, Parallel, Phase 0 Study of Metronomic Oral Vinorelbine and Letrozole Versus Letrozole or Vinorelbine Alone in Post-menopausal Women With Hormone Receptor-positive HER2-negative Early Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: SOLTI-1501
  • SECONDARY ID: 2015-004714-24
  • NCT ID: NCT02802748

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
Oral VinorelbineNavelbine®Metronomic Vinorelbine + Letrozole
LetrozoleMetronomic Vinorelbine + Letrozole

Purpose

VENTANA is a "window-of-opportunity" trial that will explore whether, similar to CDK4/6 inhibitors, Oral Metronomic Vinorelbine in combination with Letrozole induces a superior anti-proliferative effect than Letrozole alone.

Detailed Description

      VENTANA is a phase 0 multicenter, window of opportunity, three-arm, randomized clinical trial
      of oral metronomic vinorelbine (VNB) and letrozole versus either treatment alone in
      postmenopausal women with newly diagnosed untreated HR+ and HER2-negative, stage I-III
      operable breast cancer. Other eligibility criteria include primary tumor size 1 cm (cT1-3)
      and N0-1, ECOG PS 0-1 and evaluable diagnostic tumor sample.

      Primary objective is to test if Oral Metronomic Vinorelbine and Letrozole induce a superior
      anti-proliferative effect than either drug alone in patients with early breast cancer defined
      as Luminal by PAM50/HER2-negative. This will be evaluated by measuring the expression of 11
      proliferative genes contained in the PAM50/Prosigna® array (BIRC5, CCNB1, CDC20, CDCA1,
      CEP55, KNTC2, MKI67, PTTG1, RRM2, TYMS and UBE2C), as surrogate biomarker of its anticancer
      activity. By evaluating other breast cancer-related gene signatures (560 genes), the
      antiangiogenic and immunogenic potential of treatment arms will be compared and other genes
      regulated in a treatment-specific manner identified. These analyses will be performed in
      different PAM50-defined subtypes (Luminal, LuminalA or LuminalB). Clinical efficacy and
      safety of treatments will also be evaluated.

      Patients will first undergo screening and mandatory collection of core tumor biopsies for
      study analysis. Patients are randomized (1:1:1) to receive Letrozole 2.5mg daily, oral
      Vinorelbine 50mg 3 days a week or Letrozole 2.5mg daily and oral Vinorelbine 50mg 3 times a
      week. After 3 weeks of treatment, patients will undergo surgery, and both pre-treatment and
      post-treatment surgery samples will be analyzed. Alternatively, if surgery will be delayed, a
      tumor core biopsy will be collected. Anyway, post-treatment sample should be collected within
      5 days after end of treatment in order to observe the biological response.

      Axillar and mammary surgery will be done according to local standards; however, sentinel
      lymph node biopsy previous to surgery is not permitted. Following surgical excision, adjuvant
      treatment will be as per investigator´s choice and local standards of care outside the scope
      of this protocol. End of study is 28 days (±3 days) after last study drug dose with a safety
      follow-up visit.
    

Trial Arms

NameTypeDescriptionInterventions
Metronomic Vinorelbine + LetrozoleExperimentalOral Vinorelbine: 50 mg (30 mg + 20 mg) three times a week, for 3 weeks Letrozole: 2.5mg daily, for 3 weeks
  • Oral Vinorelbine
  • Letrozole
Letrozole aloneActive ComparatorLetrozole: 2.5mg daily, for 3 weeks
  • Letrozole
Metronomic Vinorelbine aloneActive ComparatorOral Vinorelbine: 50 mg (30 mg + 20 mg) three times a week, for 3 weeks
  • Oral Vinorelbine

Eligibility Criteria

        Inclusion Criteria:

          -  Written informed consent for all study procedures in accordance with local regulatory
             requirements before protocol-specific procedures are started.

          -  Postmenopausal status

          -  Histologically confirmed invasive breast carcinoma, with all of the following
             characteristics: Primary tumor greater than or equal to (>/=) 1cm in largest diameter
             (cT1-3) and N0-Stage I to operable Stage III breast cancer

          -  Scheduled or possibility of scheduling primary surgery within study window (surgery or
             biopsy within 5 days after treatment completion)

          -  HR-positive breast cancer defined as ≥1% of anti-ER and/or anti-PgR stained tumor
             cells by IHC (per local assessment)

          -  HER2-negative BC by IHC (score 0 or 1+) and/or FISH/CISH/SISH (defined as a ratio of
             HER2/CEP17<2 or single-probe average HER2 copy number <4 signals/cell), as per local
             assessment.

          -  Known percentage of Ki67-positive tumor cells within pre-treatment sample or
             possibility of local assessment.

          -  Available pre-treatment core or possibility to take a new biopsy with enough tumor
             sample for study analysis

          -  ECOG performance status of 0 or 1

          -  Adequate organ function, determined by laboratory tests performed within 7 days before
             treatment start

        Exclusion Criteria:

          -  Patients with cT4 or cN2-3 stage breast tumors

          -  Bilateral invasive, multicentric or metastatic breast cancer

          -  Patients with prior excisional biopsy of primary tumor and/or of axillar lymph nodes
             or or sentinel lymph node biopsy

          -  Patients for whom upfront chemotherapy is clinically judged appropriate as optimal
             neoadjuvant treatment

          -  Patients requiring imminent surgical procedure

          -  Any prior treatment for breast cancer except for patients with Lobular Carcinoma In
             Situ (LCIS) treated with surgery or with Ductal Carcinoma In Situ (DCIS) treated
             exclusively with mastectomy. In both cases, surgery must have taken place >5 years
             prior diagnosis of current breast cancer

          -  Other concurrent secondary malignancies, except for appropriately treated non-melanoma
             skin carcinoma, in situ melanoma and/or in situ cervical/colon cancer

          -  Treatment with any investigational medicinal product or participation in another
             therapeutic clinical trial concurrently or in the 28 days prior randomization

          -  Current uncontrolled severe systemic disease that could interfere with the intended
             therapy (e.g. clinical significant cardiovascular disease, pulmonary or metabolic
             disease, wound healing disorders, severe infection, heart failure, ischemic heart
             disease)

          -  Hereditary fructose intolerance

          -  Major surgical procedure or significant traumatic lesion within 28 days prior to
             treatment allocation or anticipated need for major surgery during the course of the
             study treatment, except if related with the breast cancer

          -  Any psychological, family, sociological or geographical circumstance that could
             potentially represent an obstacle to compliance with the study protocol and the
             follow-up schedule; these circumstances will be discussed with the patient before
             enrolment in the trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Changes in the expression of the PAM50 proliferation signature upon treatment in patients defined as Luminal by PAM50
Time Frame:At the time of surgery
Safety Issue:
Description:Outcome measure determined by following formula: Mean suppression of proliferation signature score = 100 − [geometric mean (post treatment proliferation score/pre-treatment proliferation score · 100)]. Comparison of the Oral Metronomic Vinorelbine (VNB)+Letrozole arms versus VNB or Letrozole monotherapy arms in patients defined as Luminal by PAM50.

Secondary Outcome Measures

Measure:Changes in the expression of the PAM50 proliferation signature upon treatment in patients defined as Luminal by IHC and separately, in patients defined as either Luminal A or Luminal B by PAM50.
Time Frame:At the time of surgery
Safety Issue:
Description:Outcome measure determined by following formula: Mean suppression of proliferation signature score = 100 − [geometric mean (post treatment proliferation score/pre-treatment proliferation score · 100)]. Comparison of the 3 treatment arms in the entire study population (evaluable patients defined as Luminal by IHC) and separately, in patients defined as either Luminal A or Luminal B by PAM50
Measure:Changes in % of Ki67-positive cells (per IHC) upon treatment
Time Frame:At time of surgery
Safety Issue:
Description:Comparison of the 3 treatment arms in the entire PAM50-defined Luminal population (LuminalA+LuminalB) and separately, in the LuminalA or LuminalB subtypes.
Measure:Changes in the expression of angiogenic gene signature upon treatment
Time Frame:At the time of surgery
Safety Issue:
Description:Comparison of the 3 treatment arms in the entire PAM50-defined Luminal population (LuminalA+LuminalB) and separately, in the LuminalA or LuminalB subtypes.
Measure:Changes in the expression of immune-response-related gene signature upon treatment
Time Frame:At time of surgery
Safety Issue:
Description:Comparison of the 3 treatment arms in the entire PAM50-defined Luminal population (LuminalA+LuminalB) and separately, in the LuminalA or LuminalB subtypes.
Measure:Changes in the expression of breast cancer related genes (contained in a 560 gene Custom CodeSet) upon treatment
Time Frame:At the time of surgery
Safety Issue:
Description:Expression data of breast cancer genes will be log base 2 transformed and normalized using 5 house-keeping genes Analysis will be performed in the entire PAM50-defined Luminal population (LuminalA+LuminalB) and separately, in the LuminalA or LuminalB subtypes. Aim of this outcome measure is to identify those genes with a significant difference between the VNB+Letrozole arms compared to the VNB or Letrozole monotherapy arms.
Measure:Objective Response Rate (ORR) according to RECIST v1.1, assessed by ultrasound.
Time Frame:Pre-surgery (3 weeks treatment)
Safety Issue:
Description:
Measure:Safety profile
Time Frame:Up to 7 weeks
Safety Issue:
Description:Incidence and severity of Adverse Events (assessed by CTCAE v.4.03) Incidence of treatment interruptions due to toxicity

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:SOLTI Breast Cancer Research Group

Trial Keywords

  • Early Breast Cancer
  • Hormone Receptor-positive
  • Window-of-opportunity
  • PAM50
  • Luminal A
  • Luminal B
  • proliferation signature
  • metronomic vinorelbine
  • letrozole

Last Updated

October 31, 2017