CALGB 90802 - "Randomized Phase III Trial Comparing Everolimus versus Everolimus Plus Bevacizumab for Advanced Renal Cell Carcinoma Progressing After Treatment with Tyrosine Kinase Inhibitors"

Treatment Plan    (Supplied Drug:  Bevacizumab)

1 Cycle = 28 Days.  Continue until disease progression or unacceptable toxicity.

Arm A

Everolimus:  10mg, PO, QD

Arm B

Everolimus:  10mg, PO, QD

Bevacizumab:  10mg/kg, IV over 90 mins (initial dose)*, Days 1 & 15

*  2nd dose over 60 mins; all subsequent doses over 30 mins.

Eligibility

• Renal cell carcinoma w/some component of clear cell histology.

• Mets or unresec.

• >1 prior VEGFR tyrosine kinase inhibitor tx and must have progressed/been intolerant to tx.

• No prior systemic therapy w/VEGF binding agent.

• No prior systemic therapy w/any mTOR inhibitor.

• Prior cytokine therapy is allowed.

• Any systemic therapy must be completed >4 wks pre-regist.

• >2 wks since any prior RT (including palliative).

• No major surgery, open bx, or significant traumatic injury w/i 4 wks pre-regist.  Must be fully recovered from any procedure(s).  These are NOT considered major procedures:  thoracentesis, paracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic US procedures, mediastinoscopy, skin bxs, incisional bxs, & routine dental procedures.

• Must have meas disease by RECIST (lesions that can be accurately meas in >1 dimension [longest to be recorded] as >2cm w/conventional techniques or >1cm by spiral CT).

• No active brain mets.  Treated, stable brain mets for >3 mos are allowed if they meet the following:

  • No ongoing need for steroids

  • No progression or hemorrhage after tx for >3 mos by clinical exam & MRI or CT

  • Stable dose of anticonvulsants is allowed

  • Tx for brain mets may include whole brain RT, radiosurgery (RS, gamma knife, LINAC, or equiv), or a combination

  • No CNS mets treated by neurosurgical resection or brain bx w/i 3 mos prior to Day 1

  • Baseline brain MRI/CT is required

• No serious non-healing wound, ulcer, or bone fx.

• No arterial thrombotic event w/i 6 mos pre-regist.  No clinically significant vascular disease or any other arterial thrombotic event.

• No DVT or PE w/i past 6 mos, unless on stable therapeutic anticoagulation.

• Pts receiving anti-platelet agents & therapeutic anticoagulation are eligible.

• No inadequately controlled HTN (systolic >160 &/or diastolic >90 on meds), or any prior hypertensive crisis or hypertensive encephalopathy.

• No known severe impairment of lung function (>Grade 2 dyspnea or cough) OR either:

  • Requirement for supplemental oxygen

  • If obtained, FEV1 or FVC <50% of predicted, or single breath DLCO <35% of predicted, or resting room oxygen saturation <90%.

• No active or severe liver disease.  No positive serology for anti-HBC or - HCV antibodies.  HBV seropositive pts are allowed if closely monitored for evidence of active HBV infection by HBV DNA testing & they agree to suppressive therapy w/lamivudine or other HBV-suppressive therapy until >4 wks after last dose of Everolimus.

• No NYHA Class >2 CHF.

• No active bleeding or chromic hemorrhagic diathesis or increased risk for bleeding.

• No abdominal fistula, GI perforation, or intra-abdominal abscess w/i 6 mos pre-tx initiation.

• No ongoing immunosuppressive therapy.

• Archival tissue must be available for submission, but is optional for pts to participate in correlative studies.

• No pregnant or nursing women.  Negative serum or urine pregnancy test w/i 16 days pre-regist (if applicable; see study definition).

• Age >18.

• ECOG perf status 0-2 or Karnofsky >60%.

• Granulocytes >1500/uL; platelets >100,000/uL; calc CrCl >30mL/min (modified Cockroft-Gault formula - see protocol); bili <1.5x ULN; SGOT <2.5x ULN; fasting serum triglycerides <200mg/dL; serum cholesterol <300mg/dL; fasting serum glucose <1.5x uLN; UPC ratio <1.0 or urine protein <1+.

• PRESTUDY REQUIREMENTS:

  Within 16 days pre-regist:  All lab studies, H&P

  Within 28 days pre-regist:  Brain CT or MRI, chest/abdomen/pelvis CT or MRI, bone scan.  PETs are not allowed for tumor msmt

  Within 42 days pre-regist:  Baseline exams used for screening

  • H&P, pulse, BP, wt, perf status

  • Tumor msmts

  • CBC/diff/platelets

  • Serum creat

  • LDH, albumin, glucose

  • SGOT, SGPT, alk phos, bili

  • Triglycerides, cholesterol

  • Serum or urine HCG (if applicable)

  • HBsAg, HBsAb, HB core antibody, HCV Ab

  • HBV DNA testing (in carriers, lamivudine or other HBV suppressive therapy is required)

  • UPC ratio/Dipstick

  • Brain CT or MRI

  • Chest/abdomen/pelvis CT/MRI

  • Bone scan

  • Tissue, urine, & blood samples (w/pt's consent)*

  *  For correlative studies:  Archival PE tissue from prim & mets tissue, 6mL EDTA plasma (lavender top), 5mL urine, & four (2.7mL each) citrate plasma (light blue top).  For pharmacogenomic assays (contact KCCOP for FedEx Acct #):  10mL whole blood (lavender top).  Ship all samples Mon-Fri only (overnight delivery) to CALGB Path Coordinating Office; Columbus, OH.  Collect & process samples per protocol.  Freeze plasma at -80^oC (or temp storage at -20^oC) until shipment on dry ice.  Store urine at < -20^o as soon as possible after collection & ship on dry ice.  Refrigerate blood until shipped on cold pack (ship same day as drawn).

• Signed informed consent.