FACILE: FeAsibility of First-line RiboCIclib in OLdEr Patients with Advanced Breast Cancer

Phase II, multicenter, single arm trial to assess the feasibility of first line ribociclib in combination with a non steroidal aromatase inhibitor in women or men aged 70 years-old or older, with hormone receptor positive/HER2 negative advanced breast cancer

Elderly patients are generally more susceptible to the side effects of active treatments. Patients entered in clinical trials, especially the elderly, are not completely representative of the "real" population because of selection process. The lack of data collected from a real population turns the indication of treatment a challenging task and expose older patients to a risk of under treatment (fear of excessive toxicity because of the lack of data).

With the aim of covering this gap, we are planning to run a phase II trial evaluating the feasibility of delivering the combination of ribociclib plus NSAI as first-line treatment specifically in a population of breast cancer patients aged ≥70 years.

Primary endpoint:

• The treatment feasibility will be evaluated as the proportion of patients not having experienced disease progression (PD), still on treatment with ribociclib plus NSAI 6 months after the first drug administration

Secondary endpoints:

* Treatment adherence
* Safety and tolerability
* Patient reported outcomes (PROs)
* Overall response rate (ORR)
* Progression free survival (PFS)

Eligibility Criteria:
Inclusion Criteria:

1. Patients male or female, aged 70 years-old or older at the time of informed consent.
2. Patients with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy.
3. Measurable or not measurable but evaluable disease according to RECIST criteria 1.1
4. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen receptor positive and/or progesterone receptor positive breast cancer by local laboratory.
5. Patient has a HER2 negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing.
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
7. Patient has an estimated life expectancy of \> 24 weeks.
8. Patient has adequate bone marrow and organ function as defined by all of the following laboratory values (as assessed by local laboratory):

   1. Absolute neutrophil count ≥1.5 x 109/L
   2. Platelets ≥ 100 x 109/L
   3. Hemoglobin ≥ 9.0 g/dL
   4. Potassium, sodium, calcium corrected for serum albumin and magnesium within normal limits or corrected to within normal limits with supplements before first dose of the study medication
   5. INR ≤ 1.5
   6. Serum creatinine \<1.5 mg/dl or creatinine clearance ≥50mL/min
   7. Total bilirubin \< ULN except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN.
   8. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be \< 2.5 × ULN. If the patient has liver metastases, ALT and AST should be \< 5 × ULN.
9. Patient must have a 12-lead ECG values with all of the following parameters at screening:

   1. QTcF interval at screening \< 450 msec (using Fridericia's correction)
   2. Resting heart rate ≥50 bpm
10. Patient must be able to swallow ribociclib and NSAI tablets
11. Written informed consent must be obtained prior to any screening procedures
12. Patient must be able to communicate with the investigator and comply with the requirements of the study procedures.

Exclusion Criteria:

* 1. Patient has received prior treatment with chemotherapy or hormonal therapy (except for neoadjuvant/ adjuvant chemotherapy), or any CDK4/6 inhibitor.

NOTE:

* Patients who received (neo) adjuvant therapy for breast cancer are eligible. If the prior neo (adjuvant) therapy included letrozole or anastrozole the disease-free interval must be greater than 12 months from the completion of treatment until study entry.
* Patients who received ≤ 28 days of letrozole or anastrozole for advanced disease prior to inclusion in this trial are eligible.

  2. Patient has a known hypersensitivity to any of the excipients of ribociclib or NSAI 3. Patient in concurrently using other anti-cancer therapy. 4. Patient who has not had resolution of all acute toxic effects of prior anti-cancer therapy to NCI CTCAE version 5.0 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).

  5. Patient who has received extended-field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to start of treatment, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). Patient from whom ≥ 25% of the bone marrow has been previously irradiated are also excluded 6. Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.

  7. Patient with central nervous system (CNS) metastases unless they meet all of the following criteria:
  1. At least 4 weeks from prior therapy for CNS disease completion (including radiation and/or surgery) to starting the study treatment.
  2. Clinically stable CNS lesions at the time of study treatment initiation and not receiving steroids and/or enzyme-inducing anti-epileptic medications for the management of brain metastases for at least 2 weeks.

     8. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

     9. Patient has a known history of HIV infection (testing not mandatory). 10. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgement, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.) 11. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:

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  1. History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening
  2. History of documented congestive heart failure (New York Heart Association functional classification III-IV)
  3. Documented cardiomyopathy
  4. Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block)
  5. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:

  i. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia ii. Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (within 5 half-lives or 7 days prior to starting study drug) iii. Inability to determine the QTcF interval on screening f. Systolic Blood Pressure (SBP) \>160 or \<90 mmHg 12. Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug:
  1. Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, pummeloes, star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of CYP3A4/5,
  2. Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.

     13. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment.

     NOTE:
* The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular)