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A Phase I/II Study of Sorafenib and Everolimus in Patients With Advanced Solid Tumors and Gemcitabine-Refractory Metastatic Pancreatic Cancer

Phase 1
18 Years
Not Enrolling
Pancreatic Cancer, Acinar Cell Adenocarcinoma of the Pancreas, Duct Cell Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage IV Pancreatic Cancer

Thank you

Trial Information

A Phase I/II Study of Sorafenib and Everolimus in Patients With Advanced Solid Tumors and Gemcitabine-Refractory Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES: I. To determine the 6-month overall survival of patients with previously
treated gemcitabine-refractory metastatic pancreatic cancer treated with the combination of
sorafenib and everolimus. II. To determine the recommended Phase II dose of everolimus when
administered in combination with sorafenib in patients with advanced solid tumors.
SECONDARY OBJECTIVES: I. To determine the response rate, median survival, time to
progression, CA 19.9 decline and toxicity spectrum of the combination in this patient
population. II. To characterize the pharmacokinetic profiles of sorafenib and everolimus
when given in combination. III. To explore the biomarkers that correlate with response to
the study combination in patients previously treated with gemcitabine-refractory metastatic
pancreas cancer. OUTLINE: This is a phase I, dose-escalation study of everolimus, followed
by a phase II study. Patients receive oral everolimus once daily and oral sorafenib
tosylate twice daily on days 1-28. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity. After completion of study treatment, patients are
followed every 3 months for up to 1 year.

PLEASE NOTE: This study was intended to be a Phase 1/Phase 2 study, but the study never
progressed to Phase 2.

Inclusion Criteria


- Phase I only: Histologically or cytologically confirmed solid tumors that are
advanced and refractory to or lack life-prolonging treatments; patients with
histologically or cytologically confirmed renal cell carcinoma and hepatocellular
carcinoma will be eligible

- Phase II: Histologically or cytologically proven metastatic adenocarinoma of pancreas
that had progressed after one prior gemcitabine-containing regimen, or progressed
within 6 months of the completion of gemcitabine-containing adjuvant regimen

- Patients must have measurable or assessable disease

- ECOG performance status 0-1

- Adequate hematological, renal and liver functions as determined by the following:

- ANC > 1500 cells/mm^3

- Hemoglobin >= 9g/dL

- Platelets >= 100,000 cells/mm^3

- Serum creatinine within institutional ULN OR >= 60mll/min for patients with
creatinine levels above institutional ULN

- Bilirubin =< 1.5 x ULN

- ALT (SGPT) =< 2.5 times ULN (< 5 x ULN for patients with abnormal values
attributable to liver metastases)

- AST(SGOT) =< 2.5 times ULN (< 5 x ULN for patients with abnormal values
attributable to liver metastases)

- INR =< 1.5 (Anticoagulation is allowed if target INR =< 1.5 on a stable dose of
warfarin or on a stable dose of LMW heparin for > 2 weeks at the first dose of
study agent)

- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND Fasting
triglycerides =<2.5 x ULN (in case one or both of these thresholds are exceeded,
the patient can only be included after initiation of appropriate lipid lowering

- Ability to understand and willingness to sign a written informed consent; a signed
informed consent must be obtained prior to any study specific procedures

- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of treatment

- Women of childbearing potential and men must agree to use adequate contraception
(barrier method of birth control) prior to study entry and for the duration of study
participation; men should use adequate birth control for at least three months after
the last administration of sorafenib and everolimus


- Phase II: Patients in whom histological or cryological diagnosis is not consistent
with adenocarcinoma including adenosquamous, islet cell, cystoadenoma or
cystadenocarcinoma, carcinoid, small or large cell carcinoma or lymphoma

- Phase II: Adenocarcinoma arising from a site other than the pancreas (distal bile
duct, ampulla of vater or periampullary duodenum)

- Prior therapy with approved or investigational agents within 4 weeks prior to the
start of treatment plan in this protocol

- Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN

- Any active infections

- Cardiac disease:

- Congestive heart failure > class II NYHA; patients must not have unstable angina
(anginal symptoms at rest) or new onset angina (began within the last 3 months)
or myocardial infarction within the past 6 months

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

- Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or
diastolic pressure > 90 mmHg despite optimal medical management

- Cerebrovascular accident including transient ischemic attacks within the past 6

- Pulmonary hemorrhage/bleeding event >= CTCAE Grade 2 within 4 weeks of first
dose of study drug

- Any other hemorrhage/bleeding event >= CTCAE Grade 3 within 4 weeks of first
dose of study drug - Serious non-healing wound, ulcer, or bone fracture

- Known or suspected allergy to sorafenib, everolimus, other rapamycins (sirolimus,
temsirolimus), their excipients, or any agent given in the course of this trial

- Any condition that impairs patient's ability to swallow whole pills

- Any malabsorption problem

- Presence of central nervous system or brain metastases

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
of first study drug

- Urine protein: creatinine ratio >=1.0 at screening

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months of baseline

- Inability to comply with study and/or follow-up procedures

- History of concurrent malignancy or history of a second malignancy within the past 5

- Unable to provide informed consent

- Concomitant use of any medications or substances that are inhibitors or inducers of
CYP3A enzyme, which include but not limited to phenytoin, carbamazepine,
barbiturates, rifampin, Phenobarbital or St. Johns Wort

- Phase II: Prior treatment with mTOR inhibitors (e.g., sirolimus, temsirolimus,
everolimus) or Ras-MAPK inhibitors (e.g., sorafenib)

- Any unresolved chronic toxicity greater than CTCAE grade 2 from previous anticancer
therapy (except alopecia)

- Patients 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; close contact with those who have
received attenuated live vaccines should be avoided during treatment with everolimus
(Examples of live vaccines include intranasal influenza, measles, mumps, rubella,
oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines)

- Severely impaired lung function as defined as spirometry and DLCO that is 50% of the
normal predicted value and/or O2 saturation that is 88% or less at rest on room air;
patients are not required to undergo mandatory respiratory function tests at
screening to be eligible unless medically necessary

- Severe and/or uncontrolled non-malignant liver disease such as cirrhosis or severe
hepatic impairment defined as Child-Pugh class C

- A known history of HIV seropositivity

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods; if barrier
contraceptives are being used, these must be continued throughout the trial by both
sexes; hormonal contraceptives are not acceptable as a sole method of contraception

- Women of childbearing potential that have a positive urine or serum pregnancy test
within 7 days prior to the start of treatment

- Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate
contraception during the study and for 8 weeks after the end of treatment

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall survival (Phase II)

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Wen Wee Ma

Investigator Role:

Principal Investigator

Investigator Affiliation:

Roswell Park Cancer Institute


United States: Food and Drug Administration

Study ID:

I 150109



Start Date:

August 2009

Completion Date:

December 2012

Related Keywords:

  • Pancreatic Cancer
  • Acinar Cell Adenocarcinoma of the Pancreas
  • Duct Cell Adenocarcinoma of the Pancreas
  • Recurrent Pancreatic Cancer
  • Stage IV Pancreatic Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Pancreatic Neoplasms
  • Carcinoma, Acinar Cell



Roswell Park Cancer InstituteBuffalo, New York  14263
University of Colorado Cancer CenterDenver, Colorado  80262