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A Randomized Non-Comparative Multicenter Phase II Study of Everolimus/Sorafenib or Sunitinib in Patients With Metastatic Renal Cell Carcinoma (RCC)

Phase 2
18 Years
85 Years
Not Enrolling
Locally Metastatic Malignant Neoplasm

Thank you

Trial Information

A Randomized Non-Comparative Multicenter Phase II Study of Everolimus/Sorafenib or Sunitinib in Patients With Metastatic Renal Cell Carcinoma (RCC)

In the phase I study of the combination of everolimus and sorafenib, clinical benefit was
observed in patients with no prior systemic therapy. There was no evidence of
pharmacokinetic interaction and acceptable toxicity at a dosage of sorafenib of 400 mg twice
daily (BID) and everolimus 5 mg daily. Based on these data and the need for more effective
front-line therapy for renal cell carcinoma, the plan is to investigate this regimen in
patients who have not undergone prior therapy. A sunitinib arm is being included as a
concurrent reference to help provide a guideline of an activity level and toxicity that
would be meaningful to move forward to a phase III study. Therefore, this study is designed
as a non-comparative investigation and patients will be randomized in a 2:1 ratio to
everolimus/sorafenib or to sunitinib, respectively.

Inclusion Criteria


1. Histologically- or cytologically-confirmed renal cell carcinoma, which is
unresectable or metastatic and of any of the following histologies: clear cell,
papillary, chromophobic, oncocytic, unclassified, or mixed. A component of clear cell
histology must be present. Tumors with pure collecting duct histology are not

2. Cytoreductive nephrectomy is allowed but not required

3. Evidence of RECIST-defined measurable disease (lesions that can be accurately
measured in at least one dimension with the longest diameter ≥ 20mm using
conventional techniques or ≥ 10 mm with spiral CT scan)

4. Male or female at least 18 years old

1. Female patients must be either surgically sterile or postmenopausal, or if of
childbearing potential must have a negative pregnancy test (serum or urine)
prior to enrollment and agree to use effective barrier contraception during the
period of therapy, and for 3 months after the end of treatment/end of
participation in the study. Oral, implantable, or injectable contraceptives may
be affected by cytochrome P450 interactions, and are therefore not considered
effective for this study.

2. Male patients must be surgically sterile or must agree to use effective
contraception during the period of therapy, and for 3 months after the end of
treatment/end of participation in the study.

3. The definition of effective contraception will be based on the judgment of the

5. ECOG performance status 0-1

6. Adequate bone marrow function:

1. ANC ≥ 1500/uL

2. platelet count ≥ 100,000/uL

3. hemoglobin ≥ 9.0 g/dL

7. Adequate hepatic function:

1. Total bilirubin ≤ 1.5 X ULN

2. AST (SGOT) ≤ 2.5 X ULN

3. ALT (SGPT) ≤ 2.5 X ULN

8. Adequate renal function as determined by either:

1. Calculated or measured creatinine clearance ≥ 40 mL/min (for calculated
creatinine clearance, Cockroft-Gault equation will be used)

Modified Cockcroft-Gault formula:

((140 - age (yrs)) x (actual weight(kg))) / (72 x serum creatinine(mg/dl))

* Multiply by another factor of 0.85 if female

2. Serum creatinine ≤ 1.5 X ULN

9. Able to swallow oral medications

10. Total fasting serum cholesterol ≤ 300 mg/dL

11. Resolution of any pre-existing toxicity from prior therapy to NCI CTCAE V3.0 ≤ grade
1 (with the exception of hypertension, hypothyroidism)

12. Signed and dated informed consent document

13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures.

14. More than 28 days since any prior therapy, including investigational agents and
surgical procedures.


1. Collecting duct renal cell carcinoma is excluded. Transitional cell carcinoma of the
renal pelvis is excluded.

2. Prior systemic regimens for renal cell carcinoma (neoadjuvant therapy is acceptable
as long as it did not include sunitinib, sorafenib, everolimus, or temsirolimus). A
prior therapy which was started and stopped after no more than four weeks of therapy
will not constitute a prior systemic regimen.

3. Prior surgery, radiation therapy, or systemic therapy for renal cell carcinoma within
4 weeks of starting study treatment.

4. History of or known brain metastasis, spinal cord compression, or carcinomatous
meningitis, or new evidence of brain or leptomeningeal disease on screening CT or MRI
scan (evaluation for CNS disease is required to be performed for eligibility).

5. Any of the following within 6 months prior to study drug administration: myocardial
infarction, unstable or severe angina, coronary or peripheral artery bypass graft,
NYHA functional Class II, III, IV congestive heart failure, cerebrovascular accident
or transient ischemic attack, or pulmonary embolism.

6. Ejection fraction lower than institutional lower limit of normal by echocardiogram or

7. Hypertension that is unable to be controlled with medications to a blood pressure of
≤ 150/90.

8. Hypothyroidism that is unable to be controlled with medications such that FT4 is
outside of normal limits.

9. QTc prolongation (QTc interval ≥ 480 msecs) or any other clinically significant ECG

10. Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome
(AIDS)-related illness (because of the immunosuppressive effects of therapy).
Testing for HIV in the absence of a history or symptoms is not required.

11. Hepatitis B or C (because of the risk of reactivation). The following serologies are
acceptable for enrollment: HBsAg-/anti-HBc-/anti-HBs-; HBsAg-/anti-HBc+/anti-HBs+;
HBsAg-/anti-HBc-/anti-HBs+. The following serologies are not acceptable for
enrollment: HBsAg+/anti-HBc+(IgM+/-)/anti-HBs-. If the following serologies are
obtained, additional testing will be required to ascertain the patient's hepatitis B
status: HBsAg-/anti-HBc+/anti-HBs-.

12. "Currently active" second malignancy other than non-melanoma skin cancers. Patients
are not considered to have a "currently active" malignancy if they have completed
therapy and are considered to have a less than 30% risk of relapse.

13. Current treatment on another clinical trial.

14. Pregnant or breastfeeding.

15. Chronic treatment with systemic steroids or other immunosuppressive agent.

16. On oral vitamin K antagonist medication (except low dose warfarin) (other
anticoagulants are allowed).

17. History of malabsorption syndrome, disease significantly affecting gastrointestinal
function or major resection of stomach or small bowel that could interfere with
absorption, distribution, metabolism, or excretion of study drugs.

18. Any serious and/or unstable pre-existing medical, psychiatric, or other condition
(including lab abnormalities) that could interfere with subject safety or obtaining
informed consent. Examples of such include uncontrolled diabetes as defined by
fasting serum glucose >1.5 x ULN (Note: optimal glycemic control should be achieved
before starting trial therapy), nonhealing wound, severe infection, severe
malnutrition, ventricular arrhythmias, active ischemic heart disease, chronic liver
or renal disease, or active upper GI tract ulceration.

19. 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.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response

Outcome Description:

Computerized Tomography Scans (CT) done at Screening and every 2 cycles For Partial Response (PR) or Complete Response (CR), changes in tumor measurements must be confirmed by repeat studies no less than 4 weeks after the criteria for response are first met (RECIST 1.1 criteria) For Stable Disease (SD), follow-up measurements must have met the SD criteria at least once after study entry at a minimum of 12 weeks after study entry

Outcome Time Frame:

12-18 weeks

Safety Issue:


Principal Investigator

Andrea Harzstark, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of California, San Francisco


United States: Food and Drug Administration

Study ID:

UCSF CC# 12521



Start Date:

July 2012

Completion Date:

April 2016

Related Keywords:

  • Locally Metastatic Malignant Neoplasm
  • Renal Cell Carcinoma
  • Neoplasms
  • Carcinoma
  • Carcinoma, Renal Cell
  • Neoplasms, Second Primary