Trial 1B-10-8

A Phase I/II Dose-Escalation Study of XL147 or XL765 in Combination with Letrozole in Subjects with Hormone Receptor-Positive and HER2-Negative Breast Cancer Refractory to a Non-Steroidal Aromatase Inhibitor.

Type: Cancer Therapy
Phase: Phase I/II
Status: Closed to Accrual with Ongoing Follow-up
Treatments: Chemotherapy: Systemic
Randomized: No
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Trial Leaders/Researchers: Agustin Garcia, M.D.
Other Trial Staff: Kristy Watkins, R.N., Nancy Perez, R.N., Yvonne Flores, D.M., Anayansi Miloud, D.M.

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You may participate in this study if:

	Requirement
1	Histologically confirmed breast cancer that is ER+ and/or PGR+
2	Negative for HER2 overexpression by IHC or for HER2 gene amplification by fluorescent in-situ hybridization (FISH) or equivalent method
3	Recurrent or metastatic breast cancer that is refractory to a non-steroidal aromatase inhibitor
4	For subjects enrolled in Phase II of both treatment arms: [a] At least fifteen 4-10 micron tumor tissue sections (at least 15 unstained slides, 20 preferably, without cover slips), or a tissue block of the subject’s tumor should be identified, be in the possession of the participating site/institution, and be designated for shipment to the sponsor. [b] Fresh tumor biopsies obtained prior to day 1 of treatment are required for at least 15 subjects in each arm.
5	At least 30 subjects in each arm (Phase II) must have measurable disease
6	Post-menopausal female at least 18 years of age
7	ECOG performance status of < / = 1
8	AGC = / > 1.5; platelets = / > 100,000; Hgb = / > 9.0
9	Bilirubin < / = 1.5 x uln; SGOT & SGPT < / = 2.5 x uln
10	Creatinine < / = 1.5 x uln or calculated creatinine clearance = / > 60 ml/min
11	PT/ INR or PTT < / = 1.3 x uln
12	If currently receiving bisphosphonates, the subject must have received the bisphosphonates for at least 2 months before starting study treatment
13	Subjects previously treated with letrozole must be able to tolerate the approved dose and schedule of letrozole
14	No other diagnosis of malignancy or evidence of other malignancy for 2 years before screening for this study (except non-melanoma skin cancer or in-situ carcinoma of the cervix)
15	Signed an approved study-specific informed consent and HIPAA

You may not participate in this study if:

1	Prior treatment with a selective inhibitor of PI3K, AKT, and/or mTOR (investigational or approved agents).
2	Prior therapy, including [a] small molecule targeted (non-cytotoxic) inhibitors (including investigational kinase inhibitors) within 2 weeks or 5 half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment; [b] RT within 2 weeks before the first dose of study treatment; [c] hormonal therapy (other than non-steroidal aromatase inhibitors) within 2 weeks before the first dose of study treatment; [d] cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) within 3 weeks, or nitrosoureas or mitomycin C within 6 weeks before the first dose of study treatment; [e] biologic therapy (including antibodies, immune modulators, cytokines) within 4 weeks before the first dose of study treatment; [f] any other type of investigational agent within 4 weeks before the first dose of study treatment; [g] major surgery, or not recovered from major surgery, within 4 weeks before the first dose of study treatment.
3	Must have received no more than two prior cytotoxic chemotherapeutic regimens for metastatic breast cancer
4	Has not recovered from toxicity due to prior therapy to Grade < / = 1 or to pre-therapy baseline. Subjects with Grade 2 peripheral neuropathy or Grade 2 alopecia related to prior therapies are eligible.
5	Subject has only non-measurable lesions other than bone, skin, or chest wall metastasis (e.g., pleural effusion, ascites, others).
6	Untreated, symptomatic, or progressive brain metastases
7	Subject has to start cytotoxic chemotherapy due to rapid PD involving major organs
8	Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant cardiac arrhythmias, hypertension, or any of the following within 3 months: [a] symptomatic CHF; [b] unstable angina pectoris; [c] stroke; [d] MI
9	Baseline corrected QT interval (QTc) >470 ms
10	Diagnosis of uncontrolled DM
11	Prior hormone replacement therapy within 14 days of the start of study treatment or may need to initiate hormone replacement therapy during the study
12	Known to be positive for HIV
13	Previously identified allergy or hypersensitivity to components of the study treatment formulation
14	Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee

For further information on a study, please contact the Clinical Investigation Support Office at (323) 865-0451, or clinical.trials@med.usc.edu.

To schedule a consultation with the hospital, please call our New Patient Referrals Office at (323) 865-3111.