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

• ClinicalTrials.gov Identifier: NCT03184090
• Recruitment Status: Completed
• First Posted: June 12, 2017
• Last Update Posted: June 21, 2022
• Sponsor: MedSIR
• Information provided by (Responsible Party): MedSIR

Tracking Information

• First Submitted Date: June 6, 2017
• First Posted Date: June 12, 2017
• Last Update Posted Date: June 21, 2022
• Actual Study Start Date: June 28, 2017
• Actual Primary Completion Date: October 27, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 8, 2017)

• 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 [ Time Frame: Baseline-Up to 24 months ]
  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.
• clinical activity of the combination of palbociclib and endocrine therapy after prior progression to palbociclib in endocrine-sensitive patients. [ Time Frame: Baseline-Up to 24 months ]
  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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 8, 2017)

• Compare clinical activity with molecular patterns of resistance. [ Time Frame: Baseline-Up to 24 months ]
  Patients with molecular patterns of resistance (Rb loss, biomarkers significant inhibition), mutations and expression profiles will be compared against patients without.
• 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 [ Time Frame: Baseline-Up to 24 months ]
  measure histoscore (Hscore) levels of the above targets

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: August 28, 2017)

• Measure senescence and apoptosis (Ki67 and active caspase 3) in subgroups of patients with varying clinical responses. [ Time Frame: Baseline-Up to 24 months ]
  Measure histoscore (Hscore) levels of Ki67 and active caspase 3
• Measure differences in expression profile, assessed by RNA microarrays [ Time Frame: Baseline-Up to 24 months ]
  Differences in expression profiles, assessed by RNA microarrays.
• Correlation between inhibitory effects of palbociclib and clinical response [ Time Frame: Baseline-Up to 24 months ]
• Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs grade 3 and 4 and Serious Adverse Events) [ Time Frame: Baseline-Up to 24 months ]
• Compare inhibitory effects of palbociclib and clinical response in patients with visceral disease or patients who received prior (neo) adjuvant hormonal therapy [ Time Frame: Baseline-Up to 24 months ]

Original Other Pre-specified Outcome Measures (submitted: June 8, 2017)

• Measure senescence and apoptosis (Ki67 and active caspase 3) in subgroups of patients with varying clinical responses. [ Time Frame: Baseline-Up to 24 months ]
  Measure histoscore (Hscore) levels of Ki67 and active caspase 3
• Measure differences in expression profile, assessed by RNA microarrays [ Time Frame: Baseline-Up to 24 months ]
  Differences in expression profiles, assessed by RNA microarrays.
• Correlation between inhibitory effects of palbociclib and clinical response [ Time Frame: Baseline-Up to 24 months ]
• Safety and tolerability of the combination of palbociclib plus endocrine therapy after previous treatment with palbociclib plus endocrine therapy [ Time Frame: Baseline-Up to 24 months ]
  Grade 3 and 4 AEs and serious adverse events (SAEs) for the different drug combinations.
• Compare inhibitory effects of palbociclib and clinical response in patients with visceral disease or patients who received prior (neo) adjuvant hormonal therapy [ Time Frame: Baseline-Up to 24 months ]

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Breast Cancer

Intervention

• Drug: Palbociclib
  palbociclib in combination with endocrine therapy (investigator's choice)
• Drug: Endocrine therapy (non IMP)
  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.

Study Arms

Experimental: Palbociclib + Endocrine Therapy

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.

Interventions:

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 8, 2017): 33
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: October 27, 2020
• Actual Primary Completion Date: October 27, 2020 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy, Spain

Administrative Information

• NCT Number: NCT03184090
• Other Study ID Numbers: MedOPP089; 2015-003892-31 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: MedSIR
• Original Responsible Party: Same as current
• Current Study Sponsor: MedSIR
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Javier Cortes, MD PhD; Hospital Universitario Ramon y Cajal

• PRS Account: MedSIR
• Verification Date: June 2022