Anti-hormonal Therapie With Ribociclib in HR-positive / HER2- Negative Metastatic Breast Cancer (AMICA)

Anti-hormonal Maintenance Treatment With the CDK4/6 Inhibitor Ribociclib After 1st Line Chemotherapy in Hormone Receptor Positive / HER2 Negative Metastatic Breast Cancer: A Phase II Trial

This is a multicenter, prospective, randomized, open-label, controlled phase II study to test the addition of the CDK4/6 inhibitor ribociclib to anti-hormonal treatment as maintenance therapy in patients with disease control (at least stable disease) after 1st line chemotherapy.

Study Overview

• Status: Completed
• Conditions: Breast Cancer Metastatic
• Intervention / Treatment: Drug: Ribociclib; Drug: Anastrozole; Drug: Letrozole; Drug: Exemestane; Drug: Fulvestrant

Detailed Description

Although 1st line chemotherapy is effective in women with HR-positive HER2-negative breast cancer, PFS is usually around 6-8 months and 2nd or 3rd line treatments are by far less effective. Well tolerated maintenance treatments with the potential to prolong PFS and even OS are urgently needed. This study evaluates the impact of the addition of a CDK4/6 inhibitor to an anti-hormonal maintenance treatment of physicians´ choice.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Ravensburg, Germany, 88212
    • Studienzentrum Onkologie Ravensburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements.
2. Female patients.
3. Age ≥ 18 years old.
4. Histologically confirmed HER2-/HR+ locally advanced or metastatic invasive breast carcinoma assessed on the primary tumor and/or on the metastatic lesions (preferred).
5. Willingness and ability to provide archived formalin fixed paraffin embedded tissue block or a partial block from primary surgery and/or tumor or metastasis biopsy, which will be used for further breast cancer research.
6. Maintenance endocrine therapy could have already been started up to 6 weeks before randomization, but after achievement of tumor response or stable disease.
7. Maintenance therapy must be preceded prior to randomization by at least 4 cycles of a mono- or polychemotherapy. Tumor response or stable disease needs to be maintained to allow entry into the trial. Study treatment must start within 8 weeks of the last dose of chemotherapy.
8. Previous therapy with maximum one line of anti-hormonal treatment is allowed.
9. Previous neoadjuvant/adjuvant therapy is allowed. In case of cancer other than breast cancer, treatment should be completed more than 5 years before study entry.
10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
11. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.03 Grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
12. The patient must be accessible for scheduled visits, treatment and follow-up. Patients registered on this trial must be treated at the participating center which could be the Principal or a Co- investigator's site.
13. Life-expectancy > 6 months.
14. The subjects need to be either A) of non-childbearing potential (documented postmenopausal or post hysterectomy) or B) childbearing potential with negative urinary pregnancy test (in this case patients need to use highly effective non-hormonal contraceptive).

Exclusion Criteria:

1. Uncontrolled/untreated central nervous system lesions.
2. Known severe hypersensitivity reactions to compounds similar to one of the investigational (active substance or peanut, soya or other excipients) and supportive treatment.

3. Inadequate organ function immediate prior to randomization including:

   • Hemoglobin < 10 g/dL
   • Absolute neutrophil count (ANC) < 2000/mm³ (< 2.0 x 109/L)
   • Platelets < 100,000/mm³ (< 100 x 109/L)
   • Alanine aminotransferase (ALAT/SGPT) and/or aspartate aminotransferase (ASAT/SGOT) > 2.0 x upper normal limits (ULN). If the patient has liver metastases, ALT and AST should not be ≥5 ULN.
   • Alkaline phosphatase (ALP) > 2.5 x ULN
   • Total serum bilirubin > 1.5 x ULN
   • Serum creatinine >1.5 x ULN or estimated creatinine clearance < 60 mL/min as calculated using the method standard for the Institution
4. Severe and relevant comorbidity that would interact with the participation in the study.
5. Previous malignant disease being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
6. Evidence for active infection including wound infections and anamnestic HIV or hepatitis.
7. QTc >450 msec or a family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes.
8. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (i.e. hypocalcemia, hypokalemia, hypomagnesemia).
9. Any of the following within 6 months prior to randomization: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.03 grade ≥ 2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
10. Other severe acute, uncontrolled or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
11. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry.
12. Patients treated within the last 7 days prior to randomization with drugs known to be CYP3A4 inhibitors or inducers (see section 11.4) or drugs that are known to prolong the QT interval.
13. Pregnant and lactating women.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Anti-hormonal treatment + ribociclib; In the experimental arm ribociclib will be dosed on a flat scale of 600mg/day (corresponding to three 200mg tablets once daily, 3 week on, one week off). Anti-hormonal/endocrine treatment of choice of investigator: anastrozole, exemestane, letrozole, fulvestrant.	Drug: Ribociclib; Ribociclib in addition to endocrine maintenance therapy. Endocrine therapy, at the discretion of the investigator, could have already been started up to 4 weeks before randomization but not later than with first dose of ribociclib.; Other Names: Kisqali; Drug: Anastrozole; 1mg once daily as indicated in the SmPC; Other Names: All marketed medicinal products with this active ingredient.; Drug: Letrozole; 2,5mg once daily as indicated in the SmPC; Other Names: All marketed medicinal products with this active ingredient.; Drug: Exemestane; 25mg once daily as indicated in the SmPC; Other Names: All marketed medicinal products with this active ingredient.; Drug: Fulvestrant; (prefilled syringes with fulvestrant 250mg each), 500mg given once a month, with an additional 500mg dose given two weeks after the first dose as indicated in the SmPC; Other Names: All marketed medicinal products with this active ingredient.
Active Comparator: Anti-hormonal treatment; In the control arm patients will receive endocrine treatment only (of choise of investigator). Anti-hormonal/endocrine treatment of choice of investigator: anastrozole, exemestane, letrozole, fulvestrant.	Drug: Anastrozole; 1mg once daily as indicated in the SmPC; Other Names: All marketed medicinal products with this active ingredient.; Drug: Letrozole; 2,5mg once daily as indicated in the SmPC; Other Names: All marketed medicinal products with this active ingredient.; Drug: Exemestane; 25mg once daily as indicated in the SmPC; Other Names: All marketed medicinal products with this active ingredient.; Drug: Fulvestrant; (prefilled syringes with fulvestrant 250mg each), 500mg given once a month, with an additional 500mg dose given two weeks after the first dose as indicated in the SmPC; Other Names: All marketed medicinal products with this active ingredient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Locally-assessed progression-free survival (PFS)	Primary efficacy endpoint is locally-assessed progression-free survival (PFS) defined as the time elapsed between randomization and tumor progression or death from any cause.	Up to 39 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The impact on overall survival	Overall survival (OS) defined as the time elapsed between treatment randomization and death from any cause	Up to 39 months
The clinical benefit rate	Clinical benefit rate (CBR) defined as the proportion of subjects with best response of complete response, partial response, or stable disease for at least 24 weeks	Up to 39 months
Patient reported outcomes	will be assessed using the General Quality of Life questionnaire (FACT-B), which will be filled in at study entry and every three month thereafter.	Up to 39 months
Number of participants with adverse events, serious adverse events and adverse events of special interest as assessed by CTCAE v4.03.	Number of participants with adverse events, serious adverse events and adverse events of special interest as assessed by CTCAE v4.03 compared between the two treatment-arms.	Up to 33 months
The number of patients who reduced, interrupted or permanently discontinued treatment and the reasons for that.	The number of patients who reduced, interrupted or permanently discontinued treatment and the reasons for that compared between two treatment-arms.	Up to 33 months

Collaborators and Investigators

• Sponsor: German Breast Group
• Investigators: Principal Investigator: Thomas Decker, Prof. Dr., Gemeinschaftspraxis Onkologie Ravensburg

Publications and helpful links

General Publications

• Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, Gupta V, Costa R, Srock S, de Ducla S, Freudensprung U, Mustacchi G. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1351-60. doi: 10.1016/S1470-2045(14)70444-9. Epub 2014 Sep 28.

Helpful Links

• GBG website active studies

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2018
• Primary Completion (Actual): July 21, 2022
• Study Completion (Actual): July 21, 2022

Study Registration Dates

• First Submitted: February 16, 2018
• First Submitted That Met QC Criteria: June 1, 2018
• First Posted (Actual): June 14, 2018

Study Record Updates

• Last Update Posted (Actual): July 7, 2023
• Last Update Submitted That Met QC Criteria: July 6, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Ribociclib; HER2-negative; HR-positive; Anti-hormonal maintainance treatment
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Estrogen Receptor Antagonists; Letrozole; Fulvestrant; Anastrozole; Exemestane
• Other Study ID Numbers: GBG 97

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No