CALGB 80405 - "A Phase III Trial of Irinotecan/5FU/Leucovorin or Oxaliplatin/5FU/Leucovorin with Bevacizumab, or Cetuximab (C225), or with the Combination of Bevacizumab and Cetuximab for Patients with Untreated Metastatic Adenocarcinoma of the Colon or Rectum"

NOTE:  Please read Leucovorin Shortage memo.

Treatment Plan     (Supplied Drug:  Cetuximab)

Choice of FOLFOX or FOLFIRI at investigator's discretion, but must be declared pre-randomiz & must not change during pt's tx.

PRE-REGISTRATION

K-ras Mutation Testing:

If Mutated K-ras, pt is ineligible

If Wild Type K-ras, pt proceeds to RANDOMIZATION

RANDOMIZATION (1 Cycle = 8 Wks)

Arm A

Bevacizumab:  5mg/kg, IV over 90 mins, q 2 wks (administer b/f FOLFOX* or FOLFIRI** q 2 wks)

(Initial dose over 90 mins, 2nd dose over 60 mins, and all subsequent doses over 30 mins)

Arm B

Cetuximab:  400mg/m2, IV over 2 hrs, Day 1 of Cycle 1 only

Cetuximab:  250mg/m2, IV over 1 hr, weekly (followed by FOLFOX* or FOLFIRI** q 2 wks)

Arm C  - (Closed to further accrual effective 9/15/09)

Cetuximab:  400mg/m2, IV over 2 hrs, Day 1 of Cycle 1 only

Cetuximab:  250mg/m2, IV over 1 hr, weekly

Followed by

Bevacizumab:  5mg/kg, IV over 90 mins, q 2 wks

Followed by

FOLFOX* or FOLFIRI** q 2 wks

*    FOLFOX (q 2 wks)

       Oxaliplatin:  85mg/m2, IV over 2 hrs

      Followed by    

       Leucovorin:  400mg/m2, IV over 2 hrs

       Followed by

      5-FU:  400mg/m2, IV bolus (then 2400mg/m2 CI over 46-48 hrs)

**   FOLFIRI (q 2 wks)

       Irinotecan:  180mg/m2, IV over 90 mins

      Followed by

       Leucovorin:  400mg/m2, IV over 2 hrs

       Followed by

      5-FU:  400mg/m2, IV bolus (then 2400mg/m2 CI over 46-48 hrs)

Eligibility

• Histol- or cytol-documented adenocarcinoma of colon or rectum.  Must be locally adv (unresec) or mets.  Pts w/resected prim tumors who have documented mets are eligible.  Documentation of residual disease by CT or surgeon's notes is required for all pts & histol confirmation of mets is strongly encouraged.

• Pts w/hx of colorectal cancer treated by surgical resection who develop radiological or clinical evidence of mets cancer do not require separate histol or cytol confirmation of mets unless:

  • >5 yrs has elapsed between prim surgery and development of mets OR

  • Prim cancer was Stg I

• At randomiz, intent of tx must be indicated:  palliative or neoadjuv chemo w/potential for resection of all sites of mets.

• Only pts w/wild type K-ras gene as determined by SWOG Solid Tumor Repository or by local CLIA-certified lab are eligible (ALL pts must have >1 H&E slide & 1 paraffin block of previously resected prim colorectal tumor &/or a tumor deposit).  Pts registered & randomized based on local CLIA lab, will have SWOG analysis as confirmation only.

• No prior systemic tx for adv or mets colorectal cancer.  Prior regional chemo (i.e., hepatic arterial infusion) is not allowed.

  • Prior adjuv chemo that included 5-FU alone or in combination w/fluorouracil and oxaliplatin or irinotecan (<6 mos) or RT w/radiosensitizing chemo is allowed.

  • Last course of adjuv chemo must have concluded >12 mos pre-colorectal cancer recurrence.

  • No itraconazole or ketoconazole <4 wks pre-randomiz.

  • No prior exposure to any tyrosine kinase inhibitors or other agents that target VEGF or EGF receptors.

  • No prior tx w/Bevacizumab or Cetuximab.

• No prior RT to >25% of BM (standard adjuv rectal cancer chemoradiation is allowed).  RT must have ended >4 wks pre-randomiz.

• >4 wks pre-randomiz since any major surgery (>2 wks since any minor surgery), and fully recovered from procedure.  Insertion of vascular access device is not major or minor surgery.

• No previous or concurrent malignancy except adequately treated non-melanoma skin cancer, in situ  cervical cancer, or other cancer disease-free >5 yrs.

• With pt's consent,  >1 paraffin block of previously resected prim colorectal tumor &/or tumor deposit available (or appropriate # of unstained slides) for EGFR status. 

• No Gilbert's syndrome or homozygosity for the UGT1A1*28 allele for pts receiving FOLFIRI (UGT1A1 genotyping is not required, but pts known to be homozygous for UGT1A1*28 allele should not receive FOLFIRI for this study).

• No sensory peripheral neuropathy >Grade 2 at baseline for pts receiving FOLFOX.

• No known CNS mets or carcinomatous meningitis.

• No interstitial pneumonia or extensive and symptomatic interstitial lung fibrosis.

• No pleural effusion or ascites causing >Grade 2 dyspnea.

• No predisposing colonic or small bowel disorders w/uncontrolled symptoms (>3 watery or soft stools QD in pts w/o colostomy or ileostomy).  Colostomy or ileostomy pts may be entered at investigator's discretion.

• No uncontrolled seizure disorder or active neurological disease.

• No current CHF (NYHA Class II-IV).

• Any HTN must be well controlled (<160/90) on anti-hypertensive therapy.

• Pts on full-dose anticoagulation are eligible if both of following are met:

  • In-range INR between 2-3 on a stable dose of oral anticoagulant or be on stable dose of low-molecular wt heparin

  • No active bleeding or path condition w/high risk of bleeding

  Anti-platelet agents, or daily prophylactic aspirin or anticoagulation for atrial fib are allowed.

• Significant bleeding episodes w/i 6 mos pre-randomiz are not allowed unless source of bleeding has been resected.  No hx of GI perforation w/i 12 mos pre-randomiz.

• No arterial thrombotic events w/i 6 mos pre-randomiz.  No clinically significant perip artery disease or any other arterial thrombotic event.

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

• No known hypersensitivity to Chinese hamster ovary cell products or recombinant human or murine antibodies.

• No pregnant or nursing women.  Women of childbearing potential must have negative serum or urine pregnancy test (minim sensitivity 25 IU/L or equiv units of Hcg) w/i 72 hrs pre-randomiz.

• ECOG perf status 0-1.

• Age >18.

• Granulocytes >1500/ul; Hgb >9.0g/dL (may be transfused); platelets >100,000/uL; creat <1.5x ULN; bili <1.5mg/dL; albumin >2.5g/dL; UA <1+ protein (pts w/2+ proteinuria must undergo 24-hr urine collection showing <1g of protein/24 hrs or have UPC <1.0 to allow study participation).

• PRESTUDY REQUIREMENTS:

  Within 16 days b/f pre-randomiz:   All bloodwork, H&P

  Within 28 days b/f pre-randomiz:   Any xray or scan utilized for tumor msmt

  Within 42 days b/f pre-randomiz:   Any xray or scan of uninvolved organs not used for tumor msmt

  • H&P, progress notes, pulse, BP, ht, wt, BSA

  • Perf status

  • CBC/diff/platelets

  • Serum creat, BUN

  • Lytes

  • SGOT, SGPT, alk phos, bili

  • LDH, albumin

  • Mg

  • PT/INR (pts receiving coumadin or warfarin)

  • UA

  • Pregnancy test (UCG) - if applicable, w/i 72 hrs pre-regist

  • CXR (PA & lat) - only if CT/MRI of chest is NOT performed

  • CT or MRI (abdomen/pelvis)

  • Eval for resectability

  • Tumor block & 1 H&E slide (MANDATORY for pre-registration [prior to randomiz] for K-ras status & eligibility)*

  • Companion studies (w/pt's consent):

    • Whole blood, serum, & plasma (30mL total blood volume - see protocol for processing/shipping instructions)

    • Tissue block

    • QOL asmt

  *      Pts who consent to the optional correlative study will have tissue retained for this purpose.

• Signed informed consent.