Molecular Mechanisms of Resistance and Sensitivity to Palbociclib Re-challenge in ER+ mBC

NCT03184090 | Completed Phase 2

• 2 other identifiers: MedOPP0892015-003892-31
• Study Type: interventional
• Target: 33
• Locations: 2 countries
• Sites: 15

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

Conditions

Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (2)

• 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

  the percentage of patients with Rb loss \[as defined by loss of expression, copy number variation (CNV), somatic mutation, or methylation dependent silencing\]. The evaluation criteria will be the characterization of the molecular patterns of resistance with greater than 20% prevalence.

  Baseline-Up to 24 months

• clinical activity of the combination of palbociclib and endocrine therapy after prior progression to palbociclib in endocrine-sensitive patients.

  percentage of patients that achieve clinical benefit (CBR) defined as complete response, partial response, or stable disease for at least 24 weeks per RECIST v.1.1.

  Baseline-Up to 24 months

Secondary Outcomes (2)

• Compare clinical activity with molecular patterns of resistance.

  Baseline-Up to 24 months

• 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

  Baseline-Up to 24 months

Other Outcomes (5)

• Measure senescence and apoptosis (Ki67 and active caspase 3) in subgroups of patients with varying clinical responses.

  Baseline-Up to 24 months

• Measure differences in expression profile, assessed by RNA microarrays

  Baseline-Up to 24 months

• Correlation between inhibitory effects of palbociclib and clinical response

  Baseline-Up to 24 months

Study Arms (1)

Palbociclib + Endocrine Therapy

EXPERIMENTAL

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). Treatment will continue 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.

Drug: Palbociclib; Drug: Endocrine therapy (non IMP)

Interventions

Palbociclib DRUG

palbociclib in combination with endocrine therapy (investigator's choice)

Palbociclib + Endocrine Therapy

Endocrine therapy (non IMP) DRUG

Endocrine therapy (physician's choice based on prior administered agent including tamoxifen, exemestane, fulvestrant, anastrozole, or letrozole). Endocrine therapy must be different from previous treatment line.

Palbociclib + Endocrine Therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Adequate organ function.
• Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures

You may not qualify if:

• 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).

Sponsors & Collaborators

• MedSIR: lead

Study Sites (15)

Istituto Europeo di Oncologia

Milan, Italy

Location

Azienda Sanitaria Universitaria Integrata di Udine

Udine, Italy

Location

ICO Badalona

Badalona, Barcelona, Spain

Location

ICO l'Hospitalet

L'Hospitalet de Llobregat, Barcelona, 08007, Spain

Location

Clinico Universitario A Coruña

A Coruña, Spain

Location

Hospital del Mar

Barcelona, 08003, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Location

Hospital Provincial de Castellón

Castellon, Spain

Location

Hospital Reina Sofia

Córdoba, Spain

Location

Hospital La Paz

Madrid, Spain

Location

Hospital Sant Joan de Reus

Reus, Spain

Location

Hospital Virgen del Rocío

Seville, Spain

Location

Hospital Clinico Universitario de Valencia

Valencia, Spain

Location

Hospital Universitari i Politecnic La Fe

Valencia, Spain

Location

Instituto Valenciano de Oncología - IVO

Valencia, Spain

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

palbociclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Javier Cortes, MD PhD

  Hospital Universitario Ramon y Cajal

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 6, 2017
• First Posted: June 12, 2017
• Study Start: June 28, 2017
• Primary Completion: October 27, 2020
• Study Completion: October 27, 2020
• Last Updated: June 21, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

ES (13); IT (2)