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Breast Diseases

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Capecitabine

Capecitabine, 1000 mg/m2, twice daily by mouth, on Days 1 to 14, followed by a 7 day rest in each 21 day cycle given in combination with WX-671 once daily by mouth, Days 1-21 inclusive.

Capecitabine, 1000 mg/m2, twice daily by mouth, on Days 1 to 14, followed by a 7 day rest in each 21 day cycle given in combination with placebo once daily by mouth, Days 1-21 inclusive.

capsules taken per os once daily until progression or toxicity

WX-671

capsule taken per os once daily until progression or toxicity

placebo

Lori Goldstein, MD

Nadia Harbeck, MD

This randomized, double-blind, placebo controlled phase II trial is studying how well capecitabine works when given in combination with WX-671 or when given alone in treating patients receiving first-line therapy for her2negative metastatic breast cancer.

Combination of Oral WX-671 Plus Capecitabine vs. Capecitabine Monotherapy in First-line Her2-negative Metastatic Breast Cancer

A Phase 2, Two-arm, Double-blind, Multi-center, Randomized Study of the Combination of Oral WX-671 Plus Capecitabine vs. Capecitabine Monotherapy in First-line Her2-negative Metastatic Breast Cancer

U.S. Army Medical Research and Development Command

Heidelberg Pharma AG

Carcinoma

Pharmaceutical Solutions

Anti-Infective Agents

Central Nervous System Depressants

Paclitaxel

Bevacizumab

Albumin-Bound Paclitaxel

Mitogens

Ethanol

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Bevacizumab and eribulin

In this study all patients will receive:

* Eribulin 1.23 mg/m2 on days 1, 8 every 3 weeks intravenously
* Bevacizumab 15 mg/kg every 3 weeks intravenously or Bevacizumab 10 mg/kg every 2 weeks intravenously

In this study, Bevacizumab and Eribulin are considered to be the "investigational study drugs". Bevacizumab is provided as 25 mg/ml concentrate for infusion. Vials contain 100 mg of Bevacizumab in 4 ml and/or 400 mg in 16 ml. Eribulin is provided as vials containing 1 mg/2 mL Eribulin as a 500 µg/mL solution in ethanol/water

Bevacizumab and eribulin

Clinical Research Technology

Daniele Generali, MD

Teresa Gamucci, MD

Lucia Del Mastro, MD

Domenico Amoroso, MD

Michelangelo Russillo, MD

Barbara Pistilli, MD

Ferdinando Riccardi, MD

Raffaella Ruocco, MD

Grazia Arpino, MD

Michelino De Laurentiis, MD

Vincenzo Montesarchio, MD

Alberto Zambelli, MD

Andrea Michelotti, MD

Giacomo Allegrini, MD

Francesco Cognetti, MD

Stefano Pepe, MD

Fabio Puglisi, MD

In the second-line treatment setting for MBC, many agents, including antitubulin drugs (Taxanes, Vinorelbine) and antimetabolites (Capecitabine, Gemcitabine), have demonstrated activity, but no agent is clearly superior. Although some combinations of cytotoxic agents provide a small progression-free survival advantage, none has demonstrated an OS advantage, and toxicity is generally greater than for single agents. At present, there is no standard for this treatment setting. New treatments that could delay disease progression without systemic toxicity would represent a significant advancement.

Metastatic breast cancer (MBC) is incurable, and the majority of patients succumb to their disease within 2 years of diagnosis.

Patients with MBC usually receive treatment with endocrine or cytotoxic chemotherapeutic agents, and treatment decisions are generally guided by the hormone receptor and Human Epidermal Growth Factor Receptor 2-Negative status of the disease, the number and location of metastases, and prior treatment history in both adjuvant and metastatic settings. In first- and second-line treatment settings of Metastatic Breast Cancer, numerous cytotoxic chemotherapy agents have demonstrated activity, including anti-tubulin drugs (Taxanes, Vinorelbine), Anthracyclines, and anti-metabolites (Capecitabine, Gemcitabine). However, no single agent has demonstrated a clear survival advantage over another, and use of sequential single-agent therapies is the most frequent approach. The choice of chemotherapy agent(s) is often determined by a number of factors, including history of prior therapy, treatment-free interval, and patient preference. Thus, no single standard treatment exists for patients with advanced disease. Patients who progress during or after their first treatment for Metastatic Brest Cancer typically have a short progression-free interval of 4-6 months and survive for 8-12 months. New treatment modalities are needed to improve clinical outcome and maintain the quality of life for these patients.

Safety and Efficacy Study of Eribulin in Combination With Bevacizumab for Second-line Treatment HER2- MBC Patients

A Phase II Single Arm Trial Evaluating the Efficacy and Safety of Eribulin in Combination With Bevacizumab for 2-Line Treatment of HER 2-Negative Metastatic Breast Cancer Progressing After 1-Line Therapy With Bevacizumab and Paclitaxel

ORR will be evaluated for those patients who have a response to second-line treatment as defined per RECIST version 1.1 in patients with measurable disease according to RECIST version 1.1. ORR will be based on the best overall response (BOR) as defined by RECIST Guidelines v. 1.1.

Second-line progression-free survival, defined as the time from first dosing to the first documented disease progression or death from any cause, whichever occurs first.

OS is defined as the time from first dosing in second line to death from any cause.

Clinical Benefit Rate is the proportion of patients with a complete or partial response or with stable disease at 24 weeks.

Duration of response measures the length of the response in those patients who responded to treatment.

Safety of second line treatment will be evaluated by the frequency of AEs and SAEs, cardiac events, clinically significant abnormal laboratory tests, vital signs, and ECOG PS. All patients who received at least one dose of study treatment will be included in the safety analysis.

QoL and symptom control will be assessed using the FACT-B questionnaire.

Clinical Research Technology S.r.l.

Consorzio Oncotech

Hormones

Everolimus

Fulvestrant

Exemestane

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Hormonal

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Aromatase Inhibitors

Everolimus plus Exemestane -\> progression disease (PD) -\> fulvestrant (ARM 1)

Fulvestrant -\> progression disease (PD) -\> everolimus plus exemestane (ARM 2)

500 mg i.m. on Days 1, 15 and 29 and every 28 days thereafter

Sabino De Placido, MD

This is a multi-center, randomized, open-label, parallel group study designed to evaluate efficacy and safety of fulvestrant followed, at progression, by examestane and everolimus versus examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR+ and HER2- LABC or MBC whose disease has progressed to NSAI in the adjuvant or metastatic setting.

In this study everolimus will be administered in combination with exemestane, which is an irreversible steroidal aromatase inactivator that has demonstrated efficacy in the treatment of postmenopausal patients with ABC. Exemestane is indicated for adjuvant treatment of postmenopausal women with HR+ EBC who have received two to three years of tamoxifen and are switched to exemestane for completion of a total of five consecutive years of adjuvant hormonal therapy. It is also indicated for the treatment of ABC in postmenopausal women whose disease has progressed following tamoxifen therapy (in the USA) or following antiestrogen therapy (in Europe). In 2011, the BOLERO-2 trial reported (5; 33) a significant benefit for HR+ HER2- postmenopausal pretreated women in the ABC setting by combining everolimus with exemestane. In this randomized, double-blind, placebo-controlled trial a statistically significant improvement in PFS by adding everolimus to exemestane versus exemestane alone was reported. Adding everolimus determined a 2.4-fold prolongation in PFS from 3.2 up to 7.4 months and so lowered the risk of cancer progression by 56% for these women. These findings were confirmed by an independent assessment (4.1 vs. 11.0 months, risk reduction: 64%). The QoL data shows positive trend in the everolimus plus exemestane treatment arm.

Fulvestrant and EVerolimus Plus EXemestane in Metastatic Breast Cancer

Fulvestrant Followed by Everolimus Plus Exemestane vs Examestane and Everolimus Followed by Fulvestrant in Postmenopausal Women With HR+ and HER2- Locally Advanced (LABC) or Metastatic Breast Cancer (MBC) Previously Treated With NSAI

The number of events required for the other primary endpoint (PFS1), and the expected time needed to achieve it are derived from previous calculations. Assuming an average accrual rate of 31 pts/month (677pts/22 months), a median PFS1 of 6 months in the Fulvestrant arm (control), a Hazard ratio of 0.70 (implying that a median PFS1 of 8,6 months is expected in the experimental arm, a 2-sided significance level of 0.025 and power of 0.90, 391 events are required for PFS1, that will be achieved in about 22 months (East 6 software).

Overall study size is driven by the endpoint less frequent (PFST). Sample size is planned to identify a Hazard ratio of 0.75, assuming an overall study duration of 36 months, an accrual duration of 24 months, a 2-sided significance level of 0.025 and power of 0.80. Assuming a median PFST of 12 months in the Fulvestrant arm (control), the expected PFST in the experimental arm will be equal to 16 months and 677 subjects need to be enrolled (East 6 software) with an average accrual rate equal to 30.8 patients/month (11 months per year have been considered).

Objective Response Rate (ORR), the Clinical Benefit, the overall survival, and the safety profile and the QOLof of the sequence of fulvestrant followed, at progression by exemestane and everolimus versus the sequence of examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR + and HER2- LABC or MBC previously treated with NSAI in the adjuvant or metastatic setting.

The overall observation period will be divided into three mutually exclusive segments per treatment phase:

1. pre-treatment period: from day of patient's informed consent to the day before first dose of study medication (phase 1) on-treatment period: from day of first dose of study medication to 30 days (minimum washout) after last dose of study medication (phase 2) or first dose of second phase treatment after cross-over
2. post-treatment period: starting at day 31 after last dose of study medication (phase 2)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combination of Oral WX-671 Plus Capecitabine vs. Capecitabine Monotherapy in First-line Her2-negative Metastatic Breast Cancer	NCT00615940	Metastatic Brea...	WX-671 placebo	18 Years -	Heidelberg Pharma AG
Combination of Oral WX-671 Plus Capecitabine vs. Capecitabine Monotherapy in First-line Her2-negative Metastatic Breast Cancer	NCT00615940	Metastatic Brea...	WX-671 placebo	18 Years -	Heidelberg Pharma AG
Safety and Efficacy Study of Eribulin in Combination With Bevacizumab for Second-line Treatment HER2- MBC Patients	NCT02175446	Metastatic Brea... Human Epidermal...	Bevacizumab and...	18 Years -	Consorzio Oncotech
Fulvestrant and EVerolimus Plus EXemestane in Metastatic Breast Cancer	NCT02404051	Metastatic Brea... Breast Cancer Hormone Recepto... Human Epidermal... Locally Advance...	Everolimus Exemestane Fulvestrant	18 Years -	Consorzio Oncotech
Combination of Oral WX-671 Plus Capecitabine vs. Capecitabine Monotherapy in First-line Her2-negative Metastatic Breast Cancer	NCT00615940	Metastatic Brea...	WX-671 placebo	18 Years -	Heidelberg Pharma AG

Spots Global Cancer Trial Database for her2negative

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