Clinical trial NCT03462251: Ribociclib and Endocrine Therapy or Chemotherapy With or Without Bevacizumab for Metastatic Breast Cancer in First Line
Official title: A Randomized, Open-label, Multicenter, Two-arm, Phase III Study to Evaluate Efficacy and Quality of Life in Patients With Metastatic Hormone Receptor-positive HER2-negative Breast Cancer Receiving Ribociclib in Combination With Endocrine Therapy or Chemotherapy With or Without Bevacizumab in First Line
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Hormone Receptor Positive Tumor
HER 2 Negative Breast Cancer
Keywords: Breast Cancer
HR positive
HER2 negative
Mamma carcinoma
Lead sponsor: iOMEDICO AG
Sponsor class: INDUSTRY
Collaborators: name: Novartis Pharmaceuticals
First posted: 2018-03-12
Enrollment: 41
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is designed to evaluate the efficacy and safety of first-line treatment ribociclib in combination with aromatase inhibitor (AI) or fulvestrant OR capecitabine with bevacizumab OR paclitaxel with / without bevacizumab in patients with HR-positive, HER2-negative advanced breast cancer with visceral metastasis.

Half of the patients will receive a combination of ribociclib and AI/fulvestrant while the other half will receive capecitabine + bevacizumab or paclitaxel +/- bevacizumab.

Detailed description: This is a prospective, randomized, open-label, two-arm, multicenter, interventional phase III trial in Germany. The study will include adult women with HR-positive, HER2-negative advanced breast cancer with visceral metastases, who received no prior therapy for advanced disease.

158 patients will be enrolled and randomized 1:1 (stratified by the presence of lung and / or liver metastases) to receive Arm A: a combination of ribociclib and AI or fulvestrant; OR Arm B: capecitabine + bevacizumab OR paclitaxel +/- bevacizumab

Treatment will be continued until disease progression, intolerable toxicity or death. Progression-free survival (PFS) will be based on tumor assessments by local radiologists/investigator using RECIST v1.1 criteria. Treatment might be continued beyond RECIST-defined progressive disease (PD) in case of negligible or clinically irrelevant disease progression according to the investigator's discretion until clinically relevant disease progression or symptomatic deterioration.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years.
* Any menopausal status. If pre-/perimenopausal, agreement to receive LHRH agonist (goserelin or leuprorelin) / ovarian ablation in case of randomization to arm A
* Locally confirmed diagnosis of metastatic adenocarcinoma of the breast without prior systemic antineoplastic therapy in the palliative setting.
* Hormone receptor (HR)-positive disease, defined as estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive.
* Human epidermal growth factor receptor 2 (HER2)-negative disease (defined as immunohistochemistry (IHC) status HER2 negative/+ or IHC HER2++ with chromosomal in situ hybridization (CISH)/fluorescent in situ hybridization (FISH) negative).
* Presence of visceral metastases (additional non-visceral metastases are allowed).
* Presence of target and / or non-target lesions according to RECIST v1.1
* Patients eligible for palliative treatment with AI / fulvestrant + ribociclib and capecitabine + bevacizumab or paclitaxel + / - bevacizumab according to the respective SmPCs.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
* Adequate organ and bone marrow function within 7 days prior to randomization.
* Standard 12-lead ECG values: QT Interval Corrected by the Fridericia Correction Formula (QTcF) interval at screening \< 450 msec; Mean resting heart rate 50-90 bpm (determined from the ECG)
* Signed written informed consent prior to beginning of protocol-specific procedures.

Exclusion Criteria:

* Any prior systemic palliative therapy
* Prior treatment with any cyclin-dependent kinase 4/6 (CDK4/6) inhibitor.
* Prior adjuvant or neoadjuvant taxane therapy if last application within 12 months prior to entering the study.
* Patient is concurrently using other anti-cancer therapy.
* Patient has had major surgery within 28 days prior to randomization or has not recovered from major side effects or wound is not fully recovered.
* Patient has received extended-field radiotherapy ≤ 4 weeks or limited-field radiotherapy ≤ 2 weeks prior to randomization.
* Known hypersensitivity to ribociclib, AI, paclitaxel, bevacizumab or any of their excipients, or against peanut, soya, Chinese hamster ovarian cell products or macrogolglycerol ricinoleate-35.
* Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality (e.g. history of myocardial infarction within 6 months prior study entry, long QT syndrome, clinically significant cardiac arrhythmias or systolic blood pressure \> 140 or \< 90 mmHg or diastolic blood pressure \> 90 mmHg).
* Patient has history of arterial thrombosis within 12 months prior to entering the study.
* Patient has proteinuria (≥ 2+ on urine dipstick)
* Patient with congenital bleeding diathesis, acquired coagulopathy or under full dose of anticoagulants.
* Patient is currently receiving strong inducers or inhibitors of CYP3A4/5 or medication with narrow therapeutic window that are predominantly metabolized through CYP3A4/5 and cannot be discontinued 7 days prior to start of study treatment.
* Known presence of cerebral metastases unless at least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment and clinically stable central nervous system tumor at the time of screening.
* Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
* Patient is currently receiving or has received systemic corticosteroids or other chronic immunosuppressive therapy ≤ 2 weeks prior to starting study drug.
* Patients with advanced symptomatic, visceral spread, that are at risk of lifethreatening complications in the short term (including patients with massive uncontrolled effusions \[pleural, pericardial, peritoneal\], pulmonary lymphangitis, and over 50% liver involvement).
* Patient has a known history of HIV infection (testing not mandatory).
* Patient has active untreated or uncontrolled fungal, bacterial or viral infection.
* Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, etc.).
* Participation in prior investigational studies within 30 days prior to randomization or within 5-half lives of the investigational product, whichever is longer.

Primary outcomes:
measure: Efficacy in terms of PFS
timeFrame: Up to approximately 15 months.
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to approximately 48 months.
measure: Overall Response Rate (ORR)
timeFrame: Up to approximately 15 months.
measure: Clinical Benefit Rate (CBR)
timeFrame: Up to approximately 15 months
measure: Time To Response (TTR)
timeFrame: Up to approximately 15 months.
measure: Number of participants with Adverse Events
timeFrame: Until 30 days after end of treatment, up to approximately 16 months.
measure: Time to deterioration of ECOG performance status
timeFrame: Until 30 days after end of treatment, up to approximately 16 months
measure: Tolerability of treatment
timeFrame: Until 30 days after end of treatment, up to approximately 16 months.
measure: corrected QT interval (QTc) time
timeFrame: Until 30 days after end of treatment, up to approximately 16 months.
measure: Health-related quality of life (QoL)
timeFrame: Up to 36 months.
measure: Side effects of treatment
timeFrame: Up to 36 months.
measure: Time spent on treatment
timeFrame: Up to 36 months
Other outcomes:
measure: Symptomatic PFS (sPFS)
timeFrame: Up to approximately 15 months.
Locations:
city: Ravensburg
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie
state: Baden-Wuerttemberg
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen, Gynäkologie und Geburtsmedizin
city: Baden-Baden
country: Germany
facility: Klinikum Mittelbaden Baden-Baden Balg
city: Bonn
country: Germany
facility: Gynäkologisches Zentrum Bonn
city: Dortmund
country: Germany
facility: St.-Johannes-Hospital Gynäkologie und Geburtshilfe
city: Dresden
country: Germany
facility: BAG / Onkologische Gemeinschaftspraxis
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Freiburg
country: Germany
facility: Praxis für interdisziplinäre Onkologie & Hämatologie
city: Goslar
country: Germany
facility: Überörtliche Berufsausübungsgemeinschaft MVZ Onkologische Kooperation Harz
city: Halle
country: Germany
facility: Gemeinschaftspraxis für Innere Medizin, Hämatologie, Onkologie, Gastroenterologie
city: Hamburg
country: Germany
facility: OncoResearch Lerchenfeld GmbH
city: Heidelberg
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Kaiserslautern
country: Germany
facility: IDGGQ GbR
city: Kassel
country: Germany
facility: Hämato-Onkologisches Zentrum Kassel MVZ GmbH
city: Leipzig
country: Germany
facility: Praxis Dr. med. Bettina Peuser
city: Mühlheim
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie
city: Münster
country: Germany
facility: Hämatologisch-onkologische Gemeinschaftspraxis
city: Naunhof
country: Germany
facility: Praxis Dr. med. Jens Uhlig
city: Neumarkt
country: Germany
facility: Klinikum Neumarkt
city: Offenburg
country: Germany
facility: Onkologie Offenburg
city: Recklinghausen
country: Germany
facility: Praxis und Tagesklinik für Onkologie und Hämatologie
city: Rötha
country: Germany
facility: Tumorzentrum und Hausarztpraxis Rötha Leipziger-Land
city: Singen
country: Germany
facility: Schwerpunktpraxis für Hämatologie und Internistische Onkologie, Gastroenterologie
city: Speyer
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Stralsund
country: Germany
facility: g.SUND Gynäkologie Kompetenzzentrum Stralsund
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald-Baar Klinikum Villingen-Schwenningen GmbH
city: Westerstede
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie
Study officials:
affiliation: Gemeinschaftspraxis für Hämatologie und Onkologie
name: Thomas Decker, Prof.
role: PRINCIPAL_INVESTIGATOR
References: