Dovitinib Plus an Aromatase Inhibitor for Metastatic Breast Cancer

Study Overview
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Brief Summary
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This study is for women with confirmed hormone receptor positive HER-2 negative advanced breast cancer with evidence of disease resistance to an aromatase inhibitor. The purpose of this study is to determine how well these medications work together and/or if they have any side effects in patients with hormone-receptor positive metastatic breast cancer who have demonstrated progression of disease after first line hormonal therapy. This research is being done to determine if taking an already approved medicine (aromatase inhibitor) in combination with a new medication (dovitinib) results in better outcomes for patients with this disease. Both dovitinib and an aromatase inhibitor are pills that will be taken at home.

Detailed Description
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This is a Phase I/Phase II open-label single arm trial of dovitinib in combination with anastrozole 1 mg daily, exemestane 25 mg daily, or letrozole 2.5 mg daily. Study subjects will receive the aromatase inhibitor on which they had previously derived clinical benefit.

Official Title
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A Phase I/II Trial of TKI258 (Dovitinib) in Combination With an Aromatase Inhibitor in Patients With Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Dovitinib
* Drug: Aromatase Inhibitors


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients with breast cancer either in the primary or metastatic setting Tumor must be estrogen receptor and/or progesterone receptor positive and Her-2 negative Evidence of disease resistance to an aromatase inhibitor ECOG performance status 0 or 1 Age 18 years or older Adequate laboratory values Able to give written informed consent Measurable disease No more than 2 prior chemotherapy regimens in the metastatic setting Unlimited prior hormonal therapy in the metastatic setting Life expectancy of greater than 3 months Post-menopausal Tumor must be available for central testing for FGFR1 amplification by FISH/CISH Exclusion Criteria: Brain metastases Another primary malignancy within 3 years prior to starting drug therapy with the exception of adequately treated in-site carcinoma of the uterine cervix or skin cancer Chemotherapy within 3 weeks prior to starting study drug or not recovered from side effects of previous therapy Administration of nitrosurea or mitomycin-C within 6 weeks prior to starting study drug or not recovered from side effects of such therapy Administration of biologic therapy within 6 weeks prior to starting study drug or not recovered from side effects of such therapy Radiotherapy within 4 weeks prior to starting study drug or 2 weeks in the case of localized radiotherapy or not recovered from radiotherapy toxicities major surgery, open biopsy or significant traumatic injury within 4 weeks prior to starting study drug or a minor procedure, percutaneous biopsy or placement of a vascular access device within 1 week prior to starting study drug or not recovered from side effects of such procedure or injury Chronic concomitant bisphosphonate therapy for the prevention of bone metastases. Bisphosphonate/ denosumab therapy for the management of bone metastases or for the treatment of osteoporosis s allowed. Impaired cardiac function or clinically significant cardiac disease Impairment of GI function or GI disease that may significantly alter the absorption of dovitinib Cirrhosis, chronic active hepatitis, or chronic persistent hepatitis Known diagnosis of HIV infection Anticoagulation treatment with therapeutic doses of warfarin Any concurrent severe and/or uncontrolled concomitant medical condition that could cause unacceptable safety risks or compromise compliance with the protocol Pregnant or breast-feeding Unwilling or unable to comply with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dovitinib plus aromatase inhibitors<br>Dovitinib with aromatase inhibitor | Drug: Dovitinib<br>* Dovitinib at the recommended Phase 2 dose for 5 consecutive days followed by a 2-day rest<br>* Other names: TKI258;Drug: Aromatase Inhibitors<br>* Patients will receive one of the aromatase inhibitors either anastrozole 1 mg po daily, letrozole 2.5 mg po daily, or exemestane 25 mg po daily<br>* Other names: Aromasin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate | Complete response, partial response, or stable disease at 24 weeks from trial entry as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose | The dose of dovitinib at which 1 or less subjects experience a dose limiting toxicity when administered every day for 5 days followed by 2 days off schedule in combination with an aromatase inhibitor | 4 weeks | 
| Number of Participants With Adverse Events | Number of participants experiencing adverse events | 24 weeks | 
| Pharmacodynamic Effects | Expression of pFGFR, pFRS2, pERK in tumor tissue and VEGF, bFGF, PLGF, sVEGFR1/2 and FGF23 levels in plasma | 24 weeks | 
| Progression-free Survival | Length of time from study entry until progressive disease | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, postmenopausal