Evaluation of CDK4/6 Inhibitors Abemaciclib, Palbociclib, and Ribociclib in HR+/HER2- Metastatic Breast Cancer: A Randomized Clinical Trial
- Trial ID
- 2024-516204-42-00
- Protocol
- BOOG 2017-03
- Sponsor
- BOOG Study Center B.V.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate whether treatment with a non-steroidal aromatase inhibitor combined with **CDK4/6 inhibition** in the first line, followed by fulvestrant in the second line (strategy A), improves progression-free survival compared to treatment with a non-steroidal aromatase inhibitor in the first line, followed by fulvestrant combined with CDK4/6 inhibition in the second line (strategy B) in women with HR+/HER2- metastatic breast cancer who have not received any prior systemic anticancer therapy for metastatic disease. This is clinically relevant as it aims to optimize treatment strategies for improving patient outcomes in advanced breast cancer.
Secondary objectives include:
- Comparing overall survival (OS).
- Comparing quality of life.
- Comparing safety and tolerability.
- Comparing objective response rate (ORR).
- Comparing cost-effectiveness.
- Determining alterations in genes, proteins, and (mi)RNAs in tumor tissues to select patients primarily resistant to single-agent first-line endocrine therapy.
- Determining circulating tumor DNA (ctDNA) in plasma before and during treatment to investigate the prognostic and possibly predictive values of these measures.
- Evaluating the predictive value of nuclear imaging for the benefit of CDK4/6 inhibitors.
- Developing a limited sampling model for CDK4/6 inhibitors pharmacokinetics (PK) and investigating the relationship between CDK4/6 inhibitors PK exposure and response (efficacy) and common side-effects.
- Determining the prevalence of polymorphisms in CYP3A4 and SULT2A1.
- Evaluating if there is a difference in cognitive functioning over time between patients with HR+/HER2- metastatic breast cancer undergoing different first-line treatments.
- Determining the prevalence of cognitive impairment in patients with HR+/HER2- metastatic breast cancer prior to treatment for metastatic disease and its relation with prior treatments.
Participants
The clinical trial involves **adult women** aged 18 years and older, diagnosed with **HR+/HER2- metastatic breast cancer**. The study population is exclusively female, with no male participants included, and does not involve any vulnerable populations. Participants are required to have a confirmed diagnosis of adenocarcinoma of the breast with locoregional recurrent or metastatic disease that is not suitable for resection or radiation therapy with curative intent. They must not have received any prior systemic anticancer therapy for metastatic disease, except for recently initiated endocrine therapy. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants are expected to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are fully active or capable of self-care. Adequate organ and marrow function is required, and women who are not post-menopausal must undergo ovarian ablation or suppression. The trial does not specify any particular lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of treatment strategies involving **CDK4/6 inhibitors** in women with hormone receptor-positive, HER2-negative metastatic **breast cancer**. This is a randomized, double-blind, controlled trial with an estimated duration extending until December 2028. Participants will be randomly assigned to one of two treatment strategies: Strategy A involves a non-steroidal aromatase inhibitor combined with a CDK4/6 inhibitor in the first line, followed by fulvestrant in the second line upon progression. Strategy B involves a non-steroidal aromatase inhibitor in the first line, followed by fulvestrant combined with a CDK4/6 inhibitor in the second line upon progression. The primary endpoint is progression-free survival after two lines of treatment (PFS2), while secondary endpoints include overall survival, quality of life, safety, and tolerability, among others.
Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, diagnosis, and previous treatments. Participants will undergo regular follow-up visits to assess treatment efficacy and monitor for adverse events. These visits will include clinical evaluations, laboratory tests, and imaging studies as necessary. The end-of-study visit will occur upon completion of the treatment period or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent. The expected length of participant involvement is up to 100 weeks, with conditions for early termination including significant adverse events or the initiation of chemotherapy for breast cancer.
Treatment
The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments**. The experimental medications include **Verzenios** (abemaciclib), **IBRANCE** (palbociclib), and **Kisqali** (ribociclib), all of which are **film-coated tablets** intended for **oral use**. Verzenios is available in dosages of 50 mg, 100 mg, and 150 mg, with a maximum daily dose of 300 mg and a maximum total dose of 150 mg. The treatment period for Verzenios is up to 100 days. IBRANCE is available in dosages of 75 mg, 100 mg, and 125 mg, with a maximum daily and total dose of 125 mg, and a treatment period of up to 100 days. Kisqali is available in a 200 mg dosage, with a maximum daily and total dose of 600 mg, and a treatment period of up to 100 days.
In addition to the experimental medications, the study includes several **non-experimental treatments**. **Goserelin**, a gonadoreline agonist, is administered via **subcutaneous injection** with a maximum dose of 10.8 mg over a period of 120 days. **Estradiol hemihydrate**, used as a diagnostic tracer, is administered through **intravenous bolus injection/IV infusion** with a maximum dose of 3 MBq/kg for a single day. **Anastrozole** and **letrozole**, both non-steroidal aromatase inhibitors, are administered orally with maximum daily doses of 1 mg and 2.5 mg, respectively, over a period of 120 days. **Fulvestrant**, an estrogen receptor antagonist, is administered via **intramuscular use** with a maximum dose of 500 mg over 120 days. **Leuprorelin acetate**, another gonadoreline agonist, is administered via **intramuscular use** with a maximum dose of 11.25 mg over 120 days.
Participant compliance with the dosing schedules is monitored throughout the trial. The trial aims to evaluate the efficacy of these treatments in women with HR+/HER2- metastatic breast cancer who have not received prior systemic anticancer therapy for metastatic disease. The study compares two treatment strategies involving the use of non-steroidal aromatase inhibitors and CDK4/6 inhibitors, followed by fulvestrant, to determine the optimal treatment sequence for improving progression-free survival.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival after two lines of treatment (PFS2)**, which is defined as the time from randomization until the occurrence of one of the following: second objective disease progression, objective disease progression on second-line therapy, symptomatic deterioration on second-line therapy leading to discontinuation, initiation of chemotherapy for breast cancer, or death. Secondary endpoints include overall survival, quality of life, safety and tolerability, objective response rate (ORR), cost-effectiveness, type and incidence of grade 3 and 4 serious adverse events, tumor tissue biomarkers, circulating tumor DNA (ctDNA) in plasma, nuclear imaging, pharmacokinetics, pharmacodynamics, pharmacogenomics of CDK4/6 inhibitors, and cognitive functioning assessed by validated online cognitive tests.
The trial will involve the use of CDK4/6 inhibitors in combination with a non-steroidal aromatase inhibitor in the first line, followed by fulvestrant in the second line, compared to a strategy where the non-steroidal aromatase inhibitor is used in the first line followed by fulvestrant combined with CDK4/6 inhibition in the second line. The trial aims to determine if the first strategy improves progression-free survival in women with HR+/HER2- metastatic breast cancer who have not received prior systemic anticancer therapy for metastatic disease.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult women (≥ 18 years of age) with proven diagnosis of adenocarcinoma of the breast with locoregional recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated
- Documentation of histologically or cytologically confirmed diagnosis of estrogen receptor (ER) expression >10% and/or progesterone receptor (PR) expression >10% breast cancer based on local laboratory results. In case ER ≤ 10% and PR >10% the ER and PR expression need to be confirmed in a referral center. Tumor must be HER2-negative as defined by ASCO-CAP guidelines (9). If HER2 status is unavailable then testing must be performed/repeated prior to randomization.
- Previously untreated with any systemic anti-cancer therapy for metastatic HR+ disease, with the exception of recently started (within 28 days of randomization) endocrine therapy.
- Women who are not post-menopausal must receive ovarian ablation or suppression with administration of LHRH agonist.
- Evaluable disease as defined per RECIST v.1.1. Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
- Adequate organ and marrow function defined as follows: 1) ANC ≥1,000/mm3 (1.0 x 10e9 /L); 2) Platelets ≥50,000/mm3 (50 x 10e9 /L); 3) Estimated creatinine clearance ≥ 30 mL/min as calculated using the method standard for the institution; 4) Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert’s disease); 5) AST and ALT ≤3 x ULN (≤5.0 x ULN if liver metastases present);
- Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures 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.
Exclusion Criteria
- Patients with advanced, symptomatic, visceral spread, who are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and over 50% liver involvement).
- Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable without the use of steroids for at least 4 weeks before randomization
- Prior neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor (i.e. anastrozole or letrozole) with disease recurrence while on or within 12 months of treatment.
- Prior treatment with any CDK4/6 inhibitor.
- Patients treated within the last 7 days prior to randomization with: 1) Food or drugs that are known to be CYP3A4 inhibitors (ie, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit, pomegranate or grapefruit/pomegranate juice); 2) Drugs that are known to be CYP3A4 inducers (ie, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John’s wort).
- Major surgery, chemotherapy, any investigational agents, or other anticancer therapy within 2 weeks before randomization. Palliative radiotherapy and/or (neo)adjuvant endocrine treatment within 2 weeks before randomization are allowed, provided that patients have recovered from these treatments. Patients who received prior radiotherapy to ≥25% of bone marrow are not eligible independent of when it was received.
- Diagnosis of any other malignancy prior to randomization, except those that are not believed to influence the patient’s prognosis and do not require any further treatment. This includes, but is not limited to adequately treated basal cell or squamous cell skin cancer and carcinoma in situ of the cervix.
- QTc >480 msec at baseline
- Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery that influences uptake of oral medication
- Known hypersensitivity to letrozole or anastrozole, or any of its excipients, or to any CDK4/6 inhibitors excipients.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Not Recruiting | 01 Oct 2017 | — |
| Netherlands | — | — | 1050 |
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 |
|---|---|---|---|---|---|---|
Verzenios 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 300 | 100 | PRD6705023 |
IBRANCE 75 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 125 | 100 | PRD7907995 |
Kisqali 200 mg film-coated tablets | Test | FILM‑COATED TABLETS | ORAL USE | 600 | 100 | PRD5341543 |
Kisqali 200 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 100 | PRD5341538 |
Kisqali 200 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 100 | PRD5341550 |
Kisqali 200 mg film-coated tablets | Test | FILM‑COATED TABLETS | ORAL USE | 600 | 100 | PRD5341542 |
Verzenios 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 300 | 100 | PRD6701098 |
GOSERELIN | Comparator | PHF00104MIG | SUBCUTANEOUS INJECTION | 10.8 | 120 | SCP111850463 |
ESTRADIOL | Comparator | PHF00245MIG | INTRAVENOUS BOLUS INJECTION/IV INFUSION | 3 | 1 | SCP110317214 |
Verzenios 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 300 | 100 | PRD6701108 |