Clinical trial NCT03184090: Molecular Mechanisms of Resistance and Sensitivity to Palbociclib Re-challenge in ER+ mBC
Official title: An International, Non-controlled Phase II Trial to Identify the Molecular Mechanisms of Resistance and Sensitivity to Palbociclib Re-challenge Upon Progression to a Palbociclib Combination in ER-positive Metastatic Breast Cancer Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Lead sponsor: MedSIR
Sponsor class: OTHER
First posted: 2017-06-12
Enrollment: 33
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is an international, open-label, non-controlled, multicenter phase II clinical trial with two different primary objectives: a biological and a clinical objective.

From a clinical point of view, the objective is to assess the clinical benefit of the combination of palbociclib and hormonotherapy in patients with advance breast cancer that had previously received endocrine therapy in combination with palbociclib and had achieved clinical benefit during palbociclib treatment with subsequent disease progression.

From a biological point of view, the challenge is to define a molecular profile that allow identifying patients that could benefit more from continuing on palbociclib after progression on a prior palbociclib-containing regimen

Detailed description: Eligible patients will receive palbociclib capsules orally for 21 days every four weeks in combination with endocrine therapy (physician's choice based on prior administered agent including tamoxifen, exemestane, fulvestrant, anastrozole, or letrozole).

Patients will receive treatment until disease progression (with the exception of patients who develop isolated progression in the brain), unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.

Patients discontinuing the study treatment period will enter a post-treatment follow-up period during which survival and new anti-cancer therapy information will be collected every six months (± 14 days) from the last dose of investigational product. The treatment follow-up period will conclude at six months after the last patient has received first treatment dose in the study.

Eligibility criteria: Inclusion Criteria:

* Pre- and postmenopausal women age ≥ 18 years (Premenopausal women must be treated with LHRH analogues for at least 28 days prior to study entry)
* Hormone receptor-positive \[estrogen receptor (ER) and/or progesterone receptor (PR)\] and HER2-negative
* Locally advanced or mBC that had previously received no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced disease.
* Inmmediate previous treatment with palbociclib in combination with endocrine therapy had achieved clinical benefit during palbociclib-based treatment
* Evidence of measurable and biopsable metastatic disease is required
* Confirmed disease progression on immediate previous palbociclib plus endocrine therapy.
* Last dose of palbociclib administered no later than eight weeks and not earlier than three weeks from study entry.
* No prior use of at least one of the reasonable endocrine therapy options: tamoxifen, fulvestrant, letrozole/anastrozole, or exemestane.
* Patients agree to collection of blood samples (liquid biopsy) and collection of metastatic tumour sample (biopsy) at the time of inclusion and progression (if appropriate).
* Adequate organ function.
* Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures

Exclusion criteria

* HR or HER2 unknown disease.
* HER2-positive disease based on local laboratory results \[performed by immunohistochemistry/fluorescence in situ hybridization (FISH)\].
* Locally advanced breast cancer candidate for a local treatment with a radical intention.
* Formal contraindication to endocrine therapy.
* Progressing central nervous system (CNS) disease.
* Patients with exclusive non-measurable/evaluable disease.
* Other malignancies within the past five years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix.
* Major surgery (defined as requiring general anaesthesia) or significant traumatic injury within four weeks of start of study drug, or patients who have not recovered from the side effects of any major surgery, or patients that may require major surgery during the course of the study.
* Patients with an active bleeding diathesis, previous history of bleeding diathesis, or anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon as it is used as prophylaxis intention).
* Have a serious concomitant systemic disorder (i.e., active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator).
* Are unable to swallow tablets.
* History of malabsorption syndrome or other condition that would interfere with enteral absorption.
* Chronic daily treatment with corticosteroids with a dose of ≥10 mg/day methylprednisolone equivalent (excluding inhaled steroids).
* QTc \>480 msec on basal assessments, personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
* Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (i.e., hypocalcemia, hypokalemia, or hypomagnesemia).
* Known hypersensitivity to any palbociclib excipients.

Primary outcomes:
measure: molecular patterns of resistance [with a special focus on retinoblastoma (Rb) status] upon progression to palbociclib plus endocrine therapy in patients who previously achieved clinical benefit with the combination
timeFrame: Baseline-Up to 24 months
measure: clinical activity of the combination of palbociclib and endocrine therapy after prior progression to palbociclib in endocrine-sensitive patients.
timeFrame: Baseline-Up to 24 months
Secondary outcomes:
measure: Compare clinical activity with molecular patterns of resistance.
timeFrame: Baseline-Up to 24 months
measure: Measure changes of immunostaining of Rb targets (E2F, DNMT, HIF1alpha, and SKP2) as a result of CDK4 and CDK6 inhibition and the potential predictive value of cyclin D, cyclin E, p16, p18, p21, and p27, in CDK4, and CDK6 inhibition
timeFrame: Baseline-Up to 24 months
Other outcomes:
measure: Measure senescence and apoptosis (Ki67 and active caspase 3) in subgroups of patients with varying clinical responses.
timeFrame: Baseline-Up to 24 months
measure: Measure differences in expression profile, assessed by RNA microarrays
timeFrame: Baseline-Up to 24 months
measure: Correlation between inhibitory effects of palbociclib and clinical response
timeFrame: Baseline-Up to 24 months
measure: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs grade 3 and 4 and Serious Adverse Events)
timeFrame: Baseline-Up to 24 months
measure: Compare inhibitory effects of palbociclib and clinical response in patients with visceral disease or patients who received prior (neo) adjuvant hormonal therapy
timeFrame: Baseline-Up to 24 months
Locations:
city: Milan
country: Italy
facility: Istituto Europeo di Oncologia
city: Udine
country: Italy
facility: Azienda Sanitaria Universitaria Integrata di Udine
city: Badalona
country: Spain
facility: ICO Badalona
state: Barcelona
city: L'Hospitalet de Llobregat
country: Spain
facility: ICO l'Hospitalet
state: Barcelona
city: A Coruña
country: Spain
facility: Clinico Universitario A Coruña
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Castellón De La Plana
country: Spain
facility: Hospital Provincial de Castellón
city: Cordoba
country: Spain
facility: Hospital Reina Sofia
city: Madrid
country: Spain
facility: Hospital La Paz
city: Reus
country: Spain
facility: Hospital Sant Joan de Reus
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología - IVO
Study officials:
affiliation: Hospital Universitario Ramon y Cajal
name: Javier Cortes, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: