A Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety of Palbociclib + Anti-HER2 Therapy + Endocrine Therapy vs. Anti-HER2 Therapy + Endocrine Therapy After Induction Treatment for Hormone Receptor Positive (HR+)/HER2-Positive Metastatic Breast Cancer
Overview
- Phase
- Phase 3
- Intervention
- palbociclib
- Conditions
- HER-2 Positive Breast Cancer
- Sponsor
- Alliance Foundation Trials, LLC.
- Enrollment
- 518
- Locations
- 106
- Primary Endpoint
- Progression-free Survival (PFS) as Assessed by Investigator
- Status
- Active, not recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
The primary objective of this study is to demonstrate that the combination of palbociclib with anti-HER2 therapy plus endocrine therapy is superior to anti-HER2-based therapy plus endocrine therapy alone in improving the outcomes of subjects with hormone receptor-positive, HER2+ metastatic breast cancer.
Detailed Description
Subjects will be randomized into one of two treatment arms following minimum of 4 and maximum of 8 cycles of induction treatment with anti-HER2 therapy. Arm A subjects will receive the experimental therapy, palbociclib, in addition to their current anti-HER2 therapy and endocrine therapy. Arm B subjects will continue to receive the anti-HER2 therapy. It is expected that the addition of palbociclib to the first-line treatment of HER2 disease will delay the onset of therapeutic resistance and ultimately prolong the survival of patients with metastatic breast cancer. The study is designed to treat the subset of patients with HER2+ disease who are also hormone receptor positive (HR+). It is also expected that palbociclib will modulate the endocrine resistance in HER2+/HR+ disease and potentiate the benefits of anti-HER2 therapy. Lastly, the current study includes a comprehensive molecular characterization of the disease at study entrance which will allow us to investigate the benefits of palbociclib in subsets of HER2+/HR+ disease such as PIK3CA mutant.
Investigators
Eligibility Criteria
Inclusion Criteria
- •(Preliminary Screening)
- •Signed Preliminary Screening Informed Consent Form obtained prior to any study specific assessments and procedures
- •Age ≥18 years (or per national guidelines)
- •Patients must have histologically confirmed invasive breast cancer that is metastatic or not amenable for resection or radiation therapy with curative intent. Histological documentation of metastatic/recurrent breast cancer is not required if there is unequivocal evidence for recurrence of the breast cancer.
- •Patients must have histologically confirmed HER2+ and hormone receptor positive (ER+ and/or PR+), metastatic breast cancer. ER, PR and HER2 measurements should be performed according to institutional guidelines, in a CLIA-approved setting in the US or certified laboratories for Non-US regions. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines.
- •Patients must agree to provide a representative formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) from primary breast or metastatic site (archival) OR at least 15 freshly cut unstained slides from such a block, along with a pathology report documenting HER2 positivity and hormone receptor positivity.
- •Patients should be willing to provide a representative tumor specimen obtained from recently biopsied metastatic disease if clinically feasible. This is recommended but optional tissue.
- •Inclusion Criteria (Randomization Screening)
- •Signed Main Informed Consent Form obtained prior to any study specific assessments and procedures
- •Age ≥ 18 years (or per national guidelines)
Exclusion Criteria
- •(Randomization)
- •Concurrent therapy with other Investigational Products.
- •Prior therapy with any CDK 4/6 inhibitor.
- •History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib.
- •Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A isoenzymes within 7 days of randomization (see Section 8.6.3 for list of strong inhibitors or inducers of CYP3A isoenzymes).
- •Uncontrolled current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.
- •Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 7 days prior to randomization, irrespective of the method of contraception used, are excluded from this study because the effect of palbociclib on a developing fetus is unknown. Breastfeeding must be discontinued prior to study entry.
- •Patients on combination antiretroviral therapy, i.e. those who are HIV-positive, are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib.
- •QTc interval \>480 msec, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes.
- •Patients with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis
Arms & Interventions
Arm A
Palbociclib 125 mg daily + AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestratnt) until confirmed disease progression
Intervention: palbociclib
Arm A
Palbociclib 125 mg daily + AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestratnt) until confirmed disease progression
Intervention: trastuzumab
Arm A
Palbociclib 125 mg daily + AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestratnt) until confirmed disease progression
Intervention: pertuzumab
Arm A
Palbociclib 125 mg daily + AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestratnt) until confirmed disease progression
Intervention: letrozole
Arm A
Palbociclib 125 mg daily + AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestratnt) until confirmed disease progression
Intervention: Anastrozole
Arm A
Palbociclib 125 mg daily + AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestratnt) until confirmed disease progression
Intervention: Exemestane
Arm A
Palbociclib 125 mg daily + AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestratnt) until confirmed disease progression
Intervention: Fulvestrant
Arm B
AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestrant) until confirmed disease progression
Intervention: pertuzumab
Arm B
AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestrant) until confirmed disease progression
Intervention: letrozole
Arm B
AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestrant) until confirmed disease progression
Intervention: Anastrozole
Arm B
AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestrant) until confirmed disease progression
Intervention: Exemestane
Arm B
AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestrant) until confirmed disease progression
Intervention: Fulvestrant
Outcomes
Primary Outcomes
Progression-free Survival (PFS) as Assessed by Investigator
Time Frame: 7 years 3 months
The time from registration to disease progression or death.
Secondary Outcomes
- Incidence of CNS Metastasis(24 months)
- Patient Reported Outcomes(24 months)
- Duration of Response (DOR)(72 months)
- Clinical Benefit Rate(24 months)
- Incidence of Grade 3 or Higher Adverse Events (as Graded by NCI CTCAE v 4.0)(24 months)
- Overall Survival (OS)(7 years 3 months)
- Objective Response Rate (OR: CR or PR)(24 months)
- 3 and 5 Year Survival Probabilities(5 years)