Phase III Study on Palbociclib with Anti-HER2 and Endocrine Therapy in HR+/HER2+ Metastatic Breast Cancer Post-Induction Treatment
- Trial ID
- 2024-513540-29-00
- Protocol
- AFT-38
Trial statistics
Diseases & Conditions
Objectives
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 in prolonging progression-free survival (PFS) in participants with hormone receptor-positive, HER2-positive metastatic breast cancer who have not received any prior treatment beyond induction treatment in this setting. This is clinically relevant as prolonging PFS can potentially improve patient outcomes by delaying disease progression and maintaining quality of life.
Secondary objectives include:
- Comparing measures of tumor control, including objective response (OR), clinical benefit rate (CBR), and duration of response (DOR) between the treatment arms.
- Comparing median overall survival and overall survival probabilities at 3-years and 5-years between the treatment groups.
- Comparing safety and tolerability between the treatment arms.
- Comparing the incidence of central nervous system (CNS) metastasis between the treatment arms.
- Comparing patient-reported time to symptom progression as assessed by the FACT-B TOI-PFB.
- Comparing patient-reported breast cancer-specific health-related quality of life (HRQOL) and general health status.
Participants
The clinical trial involves a total of **215 participants** diagnosed with **breast cancer**, specifically focusing on those with hormone receptor-positive, HER2+ metastatic breast cancer. The study population includes both male and female subjects aged **18 years and older**, with no vulnerable populations selected. Participants were chosen based on their ability to comply with the study's requirements, including the ability to swallow oral medication and meet specific baseline body function criteria. The trial does not impose specific lifestyle considerations such as diet or physical activity. Key inclusion criteria include having histologically confirmed HER2+ and hormone receptor-positive metastatic breast cancer, and participants must have completed an acceptable anti-HER2-based induction therapy. The trial does not provide additional information on the general health status or lifestyle habits of the participants.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase III study to evaluate the efficacy and safety of combining **palbociclib** with anti-HER2 therapy and endocrine therapy compared to anti-HER2 therapy and endocrine therapy alone in patients with hormone receptor-positive, HER2-positive metastatic **breast cancer**. The primary objective is to assess progression-free survival (PFS) as determined by the investigator. Secondary endpoints include overall survival, objective response, duration of response, clinical benefit rate, incidence of CNS metastasis, and safety assessments. The trial is expected to conclude by July 31, 2026, with recruitment having commenced on June 21, 2017.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as the ability to swallow oral medication, negative pregnancy test for women of childbearing potential, and adequate organ function. Following successful screening, participants will be randomized into one of the study arms. The trial includes regular follow-up visits to monitor treatment response, adverse events, and compliance with the treatment regimen. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected duration of participant involvement is up to 108 weeks, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. Participants are required to comply with scheduled visits, treatment plans, and laboratory tests throughout the study duration. The trial aims to provide comprehensive data on the comparative effectiveness of the treatment regimens in extending PFS and improving overall outcomes for patients with this specific subtype of metastatic breast cancer.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments. The primary experimental medication is **IBRANCE** (palbociclib), which is available in three different dosages: 100 mg, 75 mg, and 125 mg. These are provided in the form of hard capsules. The route of administration is oral, with a maximum daily dose of 100 mg, 75 mg, or 125 mg, depending on the specific capsule strength. The treatment period is set for a maximum of 108 days. **Palbociclib** is a chemical substance and is not formulated for pediatric use.
In addition to IBRANCE, the trial includes the administration of **EXEMESTANE**, which is provided in tablet form. The active substance, exemestane, is administered orally with a maximum daily dose of 25 mg. The treatment duration is also set for a maximum of 108 days. Exemestane is a chemical substance and is not a pediatric formulation.
**ANASTROZOLE** is another non-experimental treatment used in the study. It is available in tablet form and is administered orally. The maximum daily dose is 1 mg, with a treatment period of up to 108 days. Anastrozole is a chemical substance and is not intended for pediatric use.
**FULVESTRANT** is administered as a solution for injection. The active substance, fulvestrant, is given via injection with a maximum daily dose of 250 mg. The treatment period is set for a maximum of 108 days. Fulvestrant is a chemical substance and is not formulated for pediatric use.
**TRIPTORELIN** is provided as a suspension for injection. The active substance, triptorelin, is administered via injection with a maximum daily dose of 3.75 mg. The treatment duration is up to 108 days. Triptorelin is a protein-based substance and is not intended for pediatric use.
**TRASTUZUMAB** is administered as a solution for injection. The active substance, trastuzumab, is given via injection with a maximum daily dose of 600 mg. The treatment period is set for a maximum of 108 days. Trastuzumab is not formulated for pediatric use.
**LETROZOLE** is available in the form of film-coated tablets. The active substance, letrozole, is administered orally with a maximum daily dose of 2.5 mg. The treatment duration is up to 108 days. Letrozole is a chemical substance and is not intended for pediatric use.
**PERTUZUMAB** is provided as a concentrate for solution for infusion. The active substance, pertuzumab, is administered via infusion with a maximum daily dose of 420 mg. The treatment period is set for a maximum of 108 days. Pertuzumab is a protein-based substance and is not formulated for pediatric use.
**LEUPRORELIN** is administered as a prolonged-release suspension for injection. The active substance, leuprorelin, is given via injection with a maximum daily dose of 3.75 mg. The treatment duration is up to 108 days. Leuprorelin is a protein-based substance and is not intended for pediatric use.
**GOSERELIN** is provided in the form of an implant. The active substance, goserelin, is administered via injection with a maximum daily dose of 3.6 mg. The treatment period is set for a maximum of 108 days. Goserelin is a chemical substance and is not formulated for pediatric use.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the efficacy and safety of these treatments in combination with anti-HER2 therapy and endocrine therapy for hormone receptor-positive, HER2-positive metastatic breast cancer.
Efficacy
The efficacy of the clinical trial will be assessed using several key endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which will be evaluated by the investigator. Secondary endpoints include Overall Survival (OS), 3-year and 5-year survival probabilities, Objective Response (OR) defined as Complete Response (CR) or Partial Response (PR), Duration of Response (DOR), and Clinical Benefit Rate (CBR) which includes CR, PR, or Stable Disease (SD) for at least 24 weeks. Additionally, the incidence of Central Nervous System (CNS) metastasis will be monitored.
Patient-reported outcomes will also be considered, focusing on the time to symptom progression using the FACT-B PFB-TOI scale, which assesses breast cancer-specific health treatment-related quality of life and general health status. Safety assessments will include the type, incidence, severity (graded by the NCI CTCAE v. 4.0), seriousness, and attribution of adverse events (AEs) and any laboratory abnormalities to the study medications.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed Preliminary Screening Informed Consent Form obtained prior to any study specific assessments and procedures
- Age ≥18 years (or per national guidelines)
- Participants 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.
- 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 for 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
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 21 Jun 2017 | 129 |
 Germany | Not Recruiting | 21 Jun 2017 | 34 |
 Italy | Not Recruiting | 21 Jun 2017 | 18 |
 Portugal | Not Recruiting | 21 Jun 2017 | 9 |
 Spain | Not Recruiting | 21 Jun 2017 | 113 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
IBRANCE 125 mg hard capsules | Test | HARD CAPSULES | ORAL | 125 | 108 | PRD6503994 |
LETROZOLE | Other | — | ORAL | 2.5 | 108 | SUB08444MIG |
TRIPTORELIN | Other | — | INJECTION | 3.75 | 108 | SUB11324MIG |
ANASTROZOLE | Other | — | ORAL | 1 | 108 | SUB05502MIG |
IBRANCE 75 mg hard capsules | Test | HARD CAPSULES | ORAL | 75 | 108 | PRD6503936 |
TRASTUZUMAB | Other | — | INJECTION | 600 | 108 | SUB12612MIG |
PERTUZUMAB | Other | — | INFUSION | 420 | 108 | SUB16455MIG |
GOSERELIN | Other | — | INJECTION | 3.6 | 108 | SUB07962MIG |
IBRANCE 100 mg hard capsules | Test | HARD CAPSULES | ORAL | 100 | 108 | PRD6503933 |
LEUPRORELIN | Other | — | INJECTION | 3.75 | 108 | SUB08449MIG |