Open‐label Phase II Study of Everolimus Plus Endocrine Therapy in Post‐Menopausal Women with ER+, HER2‐ Metastatic Breast Cancer :Chloe trial
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Tadahiko Shien1, Akihiko Shimomura2, Yukari Uemura3, Hiroaki Kato4, Masahiro Kitada5, Yuichiro Kikawa6, Eiichi Shiba7, Tatsuya Yoshida8, Takashi Morimoto9, Tetsuya Toyama10, Tomohiko Aihara11, Hirofumi Mukai12.
1.Department of Breast and Endocrine Surgery, Okayama University Hospital. 2.Department of Breast and Medical Oncology, National Cancer Center Hospital. 3.Division of Biostatistics,Clinical Research Support Center,Tokyo University Hospital 4.Department of Thoracic Surgery, Teine Keijinkai Hospital
5.Department of Surgery, Asahikawa Medical University, Asahikawa. 6.Department of Breast Surgery, Kobe City Medical Center General Hospital 7.Osaka Breast clinic. 8.Department of Breast Surgery, Kanagawa Cancer Center. 9.Department of Breast Surgery, Yao Municipal Hospital 10.Department ofOncology, Immunology and Surgery, Nagoya City University, Graduate School of Medical Science. 11.Keimeikai‐Aihara Hospital 12.Division of Breast and Medical Oncology, National Cancer Center Hospital East.
tshien@md.okayama‐u.ac.jp

Background

Eligibility criteria

For patients with metastatic or recurrent hormone receptor‐positive breast cancer who are not in a life‐threatening
condition, it is common to treat with endocrine therapy prior to chemotherapy so as to preserve their quality of life
(QOL) (N Engl J Med, 1998; 339:974‐84). Since drug resistance develops during endocrine therapy in patients withhormone receptor‐positive breast cancer, several methods for overcoming such resistance have been investigated.
Current counter‐measures to these drug‐resistance phenomena include switching to chemotherapy while also
continuing hormone therapy. In terms of the latter, endocrine therapies which utilize different mechanisms of action,
along with agents that suppress altered signaling pathways causing drug‐tolerance, are considered at present. It has
been previously reported that application of an mTOR inhibitor (everolimus) to endocrine therapy‐resistant breast
cancer cells restored their sensitivity to endocrine therapy (Clin Cancer Res, 2005; 11 (14): 5319‐28). The BOLERO‐2
trial showed a statistically significant difference in PFS between the group treated with the combination ofeverolimus and exemestane (7.8 months) and the group treated with exemestane alone (3.2 months) (p<0.0001); thehazard ratio was 0.45 with 95% confidence intervals of 0.38‐0.54. Accordingly, both preclinical and clinical studies
have demonstrated that everolimus was effective in overcoming resistance to endocrine therapy. Furthermore, arecent preclinical study demonstrated the improvement of dependency of estrogen receptors to genomic pathway by
the application of a PI3K inhibitor or an mTOR inhibitor (rapamycin) to hormone receptor‐positive breast cancer cells,suggesting the possibility that mTOR inhibitors potentiate the effect of endocrine therapy（Sci Transl Med, 2015 Apr
15;7（283）:283ra51）. Since endocrine therapy generally causes few adverse events, the patient’s QOL may be
maintained for a long time if the introduction of chemotherapy can be postponed. Therefore, we planned this study
to examine whether concomitant administration of everolimus with endocrine therapy further prolongs PFS inpatients with breast cancer whose hormone sensitivity still remains. At present, a Phase II study (BOLERO‐4 trial; NCT01698918) is ongoing abroad to evaluate the efficacy and safety of combined use of everolimus with letrozole asinitial therapy for metastatic ER‐positive HER2‐negative breast cancer. However, patients in this study areadministered everolimus from the beginning of study regardless of their hormone sensitivity. Since our study will beconducted with patients whose hormone sensitivity remains, the subject background is different between theBORELO‐4 trial and our study. If our Phase II study supports the hypothesis that additional administration ofeverolimus to patients whose hormone sensitivity remains can prolong the administration period of AI agentsthrough postponing the acquisition of drug‐resistance, we have planned a subsequent Phase III study to confirm theusefulness of everolimus in respect of cost‐effectiveness and cost‐utility due to prolongation of the entire period ofhormone therapy by early administration of everolimus to ER‐positive aromatase‐sensitive breast cancer. Therefore,
we plan to assess QOL in this Phase III study after confirmation of the core hypothesis.

Inclusion criteria

Objectives
This study is conducted on patients with recurrent metastatic cancer with the following three objectives:
1, To examine whether additional administration of everolimus significantly prolongs progression‐free survival
period in post‐menopausal patients with ER‐positive HER2‐negative metastatic breast cancer who showed apositive response to an aromatase inhibitor (AI agent) as a primary endocrine therapy.
2, To examine the effect on the incidence of adverse events from the additional administration of everolimus to anAI agent.
3, To explore the biomarkers related to the efficacy of everolimus.

Study design
Postmenopausal patients with ER‐positive HER2‐
negative metastatic breast cancer who maintained SD or
better response for 5 months following treatment witharomatase inhibitors as a primary endocrine therapy

1, Patients who are histologically diagnosed as having breast cancer.
2, The cancer is immunohistochemically ER‐positive (>10%) and HER2‐ negative (0/1+) (or HER2‐negative based on ISH testing).
3, Patients who have one or more measurable lesions according to RECIST (Ver 1.1).
As for bone lesions, patients who have measurable osteolytic or osteolytic osteoblastic lesions by CT or MRI (≥ 1cm in length)
are eligible.
4, Patients with metastatic breast cancer that satisfy one of following two conditions:1) Patients with remote metastasis judged not to be indicated for surgical resection at the first visit.
2) Patients with metastatic breast cancer except for local recurrence (the term local here refers to the chest wall surroundedby the following areas: upward to subclavian margin, downward to costal arch, inward to medial sternal margin and outward
to the frontal margin of latissimus dorsi muscle). Patients with local recurrence which is not indicated for surgical resection
due to diffuse lesions are eligible.
5, If patients received post‐operative endocrine therapy, a 12 month or longer period must have passed since the end of the last
administration. History of post‐operative chemotherapy and elapsed time from chemotherapy, as well as the regimen of post‐
operative endocrine therapy, do not matter.
6, Among patients who start the treatment with an AI agent within 5‐7 months previously. Patients who have not received
chemotherapy or received just 1 regimen of chemotherapy.
7, Patients who have no history of treatment with everolimus. 8, Patients who are post‐menopausal women.
9, Patients with ECOG performance status (PS) of 0 or 1. Patients with PS2 due to bone metastasis is allowed.
10, If patients have received radiation therapy, a 14 day or longer period must have passed since the end of the last radiation
session.
11, Adequate organ functions. 12. Written informed consent.

Treatment allocation adjustment factors:
study site, post‐operative disease‐freeRandomization

Group A ‐ Standard treatment:
continued administration of anaromatase inhibitor

TreatmentGroup A ‐ Standard treatment; the AI agent thatthe patient is currently taking is continuouslyadministered until progression.
Group B ‐ Test treatment; In addition to the AI
agent that the patient is currently taking,everolimus at an initial dose of 10 mg is orally
administered once a day continuously untilprogression. Everolimus administration will bestarted within 2 weeks after study registration.

Group B ‐ Experimental treatment:
continued administration of anaromatase inhibitor + everolimus

Endpoints & Statistical Methods
Primary endpoint

Exclusion criteria

Progression‐free survival (PFS)

1, Patients who have active double cancer (simultaneous double cancer or metachronous double cancer within 5 years ofdisease‐free period). Carcinoma in situ (intraepithelial carcinoma and mucosal carcinoma) that is judged to be already cured
will not be classified as active double cancer
2, Patients who have a history of serious drug hypersensitivity.
3, Patients who have serious concomitant diseases (including pulmonary fibrosis or interstitial pneumonia, uncontrollable
diabetes, serious cardiac dysfunction, renal failure, hepatic insufficiency, cerebrovascular disease and ulcer(s) requiring ablood transfusion).
4, Patients who have an active infectious disease requiring systemic treatment.
*Patients who are HBs antigen positive and HBc antibody positive, and/or HBs antibody positive.
*Patients who are infected with HCV or have a history of HCV infection.
5, Patients who have active hemorrhagic diathesis or who are being treated with an oral vitamin K antagonist.
6, Patients with cerebral metastasis that is symptomatic or requires treatment.
7, Patients who have been administered medicines known as potent CYP3A inhibitors or CYP3A inducers (rifabutin, rifampicin,clarithromycin, ketoconazole, itraconazole, voriconazole, ritonavir, or telithromycin).
8, Patients who have been treated with hormone replacement therapy.
9, Patients who have a mental disorder that affects the informed consent process.
10, Patients who are judged to be inappropriate to participate in this study on the basis of physician’s assessment.

Secondary endpoints
Overall survival (OS); response rate (RR); disease control rate (DCR); adverse events; time to treatment failure (TTF); and theproportion of patients who continued administration of AI agents for 1 year after the randomized allocation.

Study Hypothesis
The clinical hypothesis of this study is that the test treatment group (continuous administration of an AI agent + everolimus) issuperior to the standard treatment group (continuous treatment of an AI agent alone) in regard to PFS.
‐ Median progression free survival (PFS) of ER+ HER2‐ MBC in general, 12 months‐ Assumed median PFS in standard arm after randomization, 10 months‐ 5.4 months prolongation expected by additional everolimus (hazard ratio, 0.65)

Sample size and follow‐up period‐

Planned number of patient registrations: 130 patients (65 patients in each group)‐

One‐sided alpha, 0.1; power, 0.8‐

Registration period: From July 2016 to June 2018‐

Study period: From July 2016 to June 2020 (2 years after the final patient registration) Total study period: 4 years‐

The protocol will not be revised in case of prolongation of study period within 6 months.

This study will be conducted under the framework of a CSPOR‐BC (Comprehensive Support Project for Oncological Research of Breast Cancer) project.