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.
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
Interventions
| Drug | Synonyms | Arms |
|---|
| Oral Vinorelbine | Navelbine® | Metronomic Vinorelbine + Letrozole |
| Letrozole | | Letrozole alone |
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
| Name | Type | Description | Interventions |
|---|
| Metronomic Vinorelbine + Letrozole | Experimental | Oral 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 alone | Active Comparator | Letrozole: 2.5mg daily, for 3 weeks | |
| Metronomic Vinorelbine alone | Active Comparator | Oral Vinorelbine: 50 mg (30 mg + 20 mg) three times a week, for 3 weeks | |
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: | Completed |
| 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
September 20, 2018
