Everolimus Dose Finding Study for Stage IV or Recurrent Cervical Cancer

Phase I Everolimus Dose Finding Study for the Treatment of Stage IV or Recurrent, Non-resectable, Cervical Cancer With Standard Whole Pelvic Radiation Therapy in Combination With Weekly Cisplatin and Daily Everolimus

This Phase 1, single-site, dose-escalation study is being conducted to determine the maximum tolerated dose (MTD) of RAD001 as part of a specified combination regimen.

This Phase 1, single-site, dose-escalation study is being conducted to determine the MTD of RAD001 as part of a specified combination regimen. The combination regimen will be standard field whole pelvic RT in combination with cisplatin at 40mg/m2 weekly with RAD001 at dose escalation daily starting at 5 mg qod, then 5 mg qd, then 10 mg qd during the period of whole pelvic radiation therapy.

Inclusion Criteria:

• Patients must have at least one measurable site of disease according to Response Evaluation Criteria in Solid Tumors criteria that has not been previously irradiated.

• Female patient aged ≥18 years.

• Patient has life expectancy of at least 12 weeks at study start.

• Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at study start.

• Patient has diagnosis of stage IV or recurrent, non-resectable, cervical cancer at study start.

• Patient has received no prior chemotherapy.

• Patient has adequate hematologic function:

  • Absolute neutrophil count [ANC] ≥1500/μL
  • Platelets ≥100,000/μL
  • Hemoglobin > 9g/dL

• Patient has adequate renal function:

  • Serum creatinine ≤ 2.0 mg/dL
  • Calculated creatinine clearance ≥ 50 mL/min

• Patient has adequate hepatic function:

  • Serum bilirubin ≤1.5 x ULN
  • ALT and AST ≤2.5 × ULN (≤ 5 x ULN in patients with liver metastases)

• INR <1.5 (or < 3 on anticoagulants)

• Patient has fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN.

• Patient is able to provide signed informed consent.

Exclusion Criteria:

• Patient has neuroendocrine or small cell carcinoma of the cervix.

• Patient has previously used any biologic therapy with VEGF, VEGFR, or ErbB1/ErbB2 inhibitors.

• Patient is currently receiving anticancer therapies or has received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.).

• Patient has had a major surgery or significant traumatic injury within 4 weeks of start of study drug; patient has not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patient might require major surgery during the course of the study.

• Patient has had prior treatment with any investigational drug within the preceding 4 weeks before study start.

• Patient is receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period. Patients should also avoid close contact with people who have received live vaccines during treatment with everolimus. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, and TY21a typhoid vaccines.

• Patient has known brain or leptomeningeal metastases.

• Patient has had other malignancies within the past 3 years except for adequately treated squamous cell carcinomas of the skin.

• Patients has any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

  • Symptomatic congestive heart failure of New York Heart Association Class III or IV.
  • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease.
  • Severely impaired lung function defined as spirometry and diffusing capacity (DLCO) that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air.
  • Uncontrolled diabetes as defined by fasting serum glucose >1.5 × ULN.
  • Active (acute or chronic) or uncontrolled severe infections.
  • Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis.

• Patient has a known history of human immunodeficiency virus seropositivity.

• Patient has impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).

• Patient has an active, bleeding diathesis.

• Female patient who is pregnant or breast feeding, or an adult of reproductive potential who is not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial and for up to 8 weeks after ending treatment by both sexes. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of RAD001.)

• Patient has received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus).

• Patient has a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients.

• Patient has history of noncompliance to medical regimens.

• Patient is unwilling to or unable to comply with the protocol.