Study of the Safety and Pharmacokinetics of XL765 (SAR245409) in Adults With Solid Tumors

A Phase 1 Dose-Escalation Study of the Safety and Pharmacokinetics of XL765 Administered Orally Daily to Subjects With Solid Tumors

The purpose of this study is to determine the safety and tolerability of XL765. XL765 is a new chemical entity that inhibits the kinases PI3K and mTOR. In preclinical studies, inactivation of PI3K has been shown to inhibit growth and induce apoptosis (programmed cell death) in tumor cells, whereas inactivation of mTOR has been shown to inhibit the growth of tumor cells.

Inclusion Criteria:

• The subject has a histologically confirmed metastatic or unresectable solid tumor for which standard curative or palliative measures do not exist or are no longer effective, and there are no therapies known to prolong survival.

• The subject has disease that is assessable by tumor marker, physical, or radiologic means.

• The subject is at least 18 years old.

• The subject's weight is at lease 40 kg.

• The subject has an Eastern Cooperative Oncology Group performance status of 0 - 2.

• The subject has adequate organ and bone marrow function.

• The subject has fasting plasma glucose < 120 mg/dL at screening.

• for subjects who are to be enrolled into the Expanded MTD Cohort and Lower-Dose Tumor Genetic Alteration Subjects:

  1. tumor tissue amenable to serial biopsy;
  2. additional informed consent

• The subject is capable of understanding the protocol and has signed the informed consent.

• Sexually active subjects (male and female) must use medically acceptable methods of contraception during the course of the study.

• Female subjects of childbearing potential must have a negative serum pregnancy test at screening.

• If the subject has received more than 3 prior regimens of cytotoxic chemotherapy, more than 2 biologic regimens, or more than 3000 cGy to >25% of his or her bone marrow, the sponsor must determine subject suitability before enrollment.

• The subject has had no other diagnosis of malignancy (unless non-melanoma skin cancer, in situ carcinoma of the cervix, or a malignancy diagnosed ≥ 2 years ago, and has had no evidence of disease for 2 years prior to screening for this study.)

Exclusion Criteria:

• The subject has received anticancer treatment (chemotherapy, radiotherapy, cytokines, or hormones) within 30 days (6 weeks for nitrosoureas, mitomycin C, or bicalutamide) before the first dose of XL765.
• The subject has received radiation to > 25% of his or her bone marrow.
• The subject has not recovered from adverse events, except Grade 2 alopecia, due to other investigational or other agents administered prior to study enrollment.
• The subject has received another investigational agent within 30 days or the first dose of XL765 or a small-molecule kinase inhibitor within 14 days or 5 half-lives.
• The subject is known to have diabetes
• The subject has uncontrolled intercurrent illness including ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• The subject has psychiatric illness/social situation that would limit compliance with study requirements.
• The subject is pregnant or breast feeding.
• The subject is known to be positive for HIV.
• The subject has a known allergy or hypersensitivity to components of the XL765 formulation.
• The subject has a baseline corrected QT interval > 450 ms.