Randomized, Open Label, Clinical Study of the Targeted Therapy, Palbociclib, to Treat Metastatic Breast Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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HER-2 Positive Breast Cancer, Estrogen Receptor Positive Breast Cancer

Intervention / Treatment
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* Drug: palbociclib
* Drug: trastuzumab
* Drug: pertuzumab
* Drug: letrozole
* Drug: Anastrozole
* Drug: Exemestane
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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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) ECOG performance status 0-1 Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption. Serum or urine pregnancy test must be negative within 7 days of randomization in women of childbearing potential. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing potential and male patients randomized into the study must use adequate contraception for the duration of protocol treatment which is 6 months after the last treatment with palbociclib if they are in Arm A and for 7 months after last treatment with trastuzumab if in either Arm A or Arm B Adequate contraception is defined as one highly effective form (i.e. abstinence, (fe)male sterilization OR two effective forms (e.g. non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel / film / cream / suppository). Resolution of all acute toxic effects of prior induction anti-HER2-based chemotherapy regimen to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion) 12 weeks between last dose of chemotherapy-anti-HER2therapy and randomization are allowed. Endocrine therapy could start before study randomization. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Prior Treatment Specifics Patients may or may not have received neo/adjuvant therapy, but must have a disease-free interval from completion of anti-HER2 therapy to metastatic diagnosis ≥6 months. Patients must have received an acceptable, standard, chemotherapy containing anti-HER2 based induction therapy for the treatment of metastatic breast cancer prior to study enrollment. For this study, chemotherapy is limited to a taxane or vinorelbine (only for trastuzumab-based regimen). Eligible patients are expected to have completed 6 cycles of chemotherapy containing anti-HER2-therapy treatment. A minimum of 4 cycles of treatment is acceptable for patients experiencing significant toxicity associated with treatment as long as they are without evidence of disease progression (i.e. CR, PR or SD). The maximum number of cycles is 8. Patients can randomize immediately following completion of their induction therapy, or for those who have already completed induction, a gap of 12 weeks between their last infusion/dose of induction therapy and the C1D1 visit is permitted. Patients are eligible provided they are without evidence of disease progression by local assessment (i.e. CR, PR or SD). Patients with a history or presence of asymptomatic CNS metastases are eligible, provided they meet all of the following criteria: Disease outside the CNS is present. No evidence of interim progression between the completion of induction therapy and the screening radiographic study No history of intracranial hemorrhage or spinal cord hemorrhage Not requiring anti-convulsants for symptomatic control Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade ≥ 3) acute toxicity with no ongoing requirement for corticosteroid Baseline Body Function Specifics Absolute neutrophil count ≥ 1,000/mm3 Platelets ≥ 100,000/mm3 Hemoglobin ≥ 10g/dL Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with documented Gilbert's Syndrome. Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤ 3 × institutional ULN (≤5 x ULN if liver metastases are present). Serum creatinine below the upper limit of normal (ULN) of the institutional normal range or creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN. Left ventricular ejection fraction (LVEF) ≥ 50% at baseline as determined by either ECHO or MUGA 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Palbociclib 125 mg daily + AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestratnt) until confirmed disease progression | Drug: palbociclib<br>* o Starting dose: 125 mg capsule taken orally once per day for 21 days followed by 7 days off to complete 28 day cycle. Dose reductions: 100 mg, 75 mg. allowed. Number of Cycles: until progression or unacceptable toxicity develops<br>* Other names: Ibrance;Drug: trastuzumab<br>* Patients must have received a minimum of 4 and maximum of 8 cycles of induction therapy prior to randomization to Arm A or B, at which point they will continue on antiHER2 therapy and endocrine therapy, with or without palbociclib. Trastuzumab dosing will be determined based on a loading dose of 8mg trastuzumab/kg body weight for Q3WK dosing schedules or a maintenance dose of 6mg/kg trastuzumab/kg dosing weight for Q3WK dosing schedules. Loading dose will be administered on Cycle 1, Day 1.<br>* Other names: Herceptin;Drug: pertuzumab<br>* Patients must have received a minimum of 4 and maximum of 8 cycles of induction therapy prior to randomization to Arm A or B, at which point they will continue on antiHER2 therapy and endocrine therapy, with or without palbociclib.Pertuzumab will be administered at a loading dose of 840 mg infusion and then at a maintenance dose of 420 mg q3wks. If patient is within 5 weeks of receiving loading dose at Cycle 1, Day 1, patient may start with maintenance dose of 420 mg.<br>* Other names: Perjeta;Drug: letrozole<br>* There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for letrozole oral therapy is 2.5 mg orally, once a day.<br>* Other names: Femara;Drug: Anastrozole<br>* There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for anastrozole is 1 mg orally, once a day.<br>* Other names: Arimidex;Drug: Exemestane<br>* There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for exemestane is 25 mg orally, once a day.<br>* Other names: Aromasin;Drug: Fulvestrant<br>* There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for Fulvestrant is 250 mg injections on Day 1 and Day 15 of Cycle 1, and q4weeks thereafter.<br>* Other names: Faslodex;|
| Active Comparator: Arm B<br>AntiHER2 Therapy (trastuzumab/pertuzumab) q3wks + Endocrine Therapy (letrozole, anastrozole, exemstane OR fulvestrant) until confirmed disease progression | Drug: pertuzumab<br>* Patients must have received a minimum of 4 and maximum of 8 cycles of induction therapy prior to randomization to Arm A or B, at which point they will continue on antiHER2 therapy and endocrine therapy, with or without palbociclib.Pertuzumab will be administered at a loading dose of 840 mg infusion and then at a maintenance dose of 420 mg q3wks. If patient is within 5 weeks of receiving loading dose at Cycle 1, Day 1, patient may start with maintenance dose of 420 mg.<br>* Other names: Perjeta;Drug: letrozole<br>* There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for letrozole oral therapy is 2.5 mg orally, once a day.<br>* Other names: Femara;Drug: Anastrozole<br>* There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for anastrozole is 1 mg orally, once a day.<br>* Other names: Arimidex;Drug: Exemestane<br>* There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for exemestane is 25 mg orally, once a day.<br>* Other names: Aromasin;Drug: Fulvestrant<br>* There are several allowed endocrine treatment agents for Arm A and Arm B of this study. Administration is performed on an outpatient, self-administration basis according to local requirements and local standard practice. Endocrine treatment may have started before the patient enters the study. Agents will be administered at the discretion of principal investigator as well as according to standard institutional or regional practice. Recommended dosing regimen for Fulvestrant is 250 mg injections on Day 1 and Day 15 of Cycle 1, and q4weeks thereafter.<br>* Other names: Faslodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) as assessed by Investigator |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Defined as time from date of randomization to date of death due to any cause | 24 months | 
| 3 and 5 year survival probabilities | Survival probabilities will be estimated using the Kaplan-Meier method | 24 months | 
| Objective Response Rate (OR: CR or PR) | Defined as complete response (CR) or partial response (PR) according to RECIST v1.1 | 24 months | 
| Duration of Response (DOR) | Defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or to death from any cause, whichever occurs first | 24 months | 
| Clinical Benefit Rate (CBR: CR or PR or SD ≥ 24 weeks | The Clinical Benefit Rate (CBR) on each treatment arm will be estimated by dividing the number of patients with CR, PR, or SD/Non-CR and Non-PD (for patients with measurable disease) ≥ 24 weeks by the number of patients randomized to the treatment arm. | 24 months | 
| Safety: Type incidence and severity (as graded by NCI CTCAE v 4.0) | Seriousness and attribution to the study medications of AEs and any laboratory abnormalities | 24 months | 
| Patient Reported Outcomes | Time to symptom progression (FACT-B PFB-TOI), breast cancer specific health treatment related quality of life and general health status | 24 months | 
| Incidence of CNS Metastasis | Compare the incidence of CNS metastasis between treatment arms | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, malignant tumor of the breast, HER2+, HR+, metastatic breast cancer