Full Protocol (members only)   Consent Form   HIPAA

CTSU NCCTG N0147 - "A Randomized Phase III Trial of Oxaliplatin (OXAL) Plus 5-Fluorouracil (5-FU)/Leucovorin (CF) with or without Cetuximab (C225) after Curative Resection for Patients with Stage III Colon Cancer"

Treatment Plan    (Supplied Drugs:  Oxaliplatin & Cetuximab)

EFFECTIVE 10/24/08:  TEMPORARILY CLOSED TO ACCRUAL FOR PTS >AGE 70 DUE TO INCREASED TOXICITY ON CETUXIMAB-CONTAINING ARM OF THE TRIAL.

See protocol for info on concurrent administration of drugs, hydration, & pre-medication.

PRE-RANDOMIZATION

          â

If Wild Type KRAS àRANDOMIZATION (Arm A or Arm D) - Vascular Access Device required for both Arms.  PICC lines not recommended.

If Mutated KRAS or KRAS not evaluable àREGISTRATION to Arm G

Arm A - FOLFOX - Oxaliplatin + 5-FU/Leucovorin Regimen (Day 1 of each cycle; q2wks x 12)

Oxaliplatin:  85mg/m², IV in 250-500ml D5W over 120 mins

Leucovorin:  400mg/m², IV in 250ml D5W over 120 mins

5-FU:  400mg/m², IV push

5-FU:  2400mg/m², IV via ambulatory pump over 46-48 hrs (after Leucovorin)

          â

Observation q 6 mos x 5 yrs following randomiz

If Recurrence àEvent Monitoring until 8 yrs from randomiz

Arm D - FOLFOX + C225 - Oxaliplatin + 5-FU/Leucovorin + Cetuximab Regimen (q2wks x 12)

Cycle 1 only

Cetuximab:  400mg/m², IV over 2 hrs, Day 1, Tx Week 1 (give b/f chemo)

Cetuximab:  250mg/m², IV over 1 hr (undiluted 2mg/ml), Day 8, Tx Week 2 (give b/f chemo)

Oxaliplatin:  85mg/m², IV in 500ml D5W, over 120 mins, Day 1

Leucovorin:  400mg/m² IV in 250ml D5W, over 120 mins, Day 1

5-FU:  400mg/m², IV push, Day 1

5-FU:  2400mg/m², IV via ambulatory pump over 46-48 hrs, Day 1

Subsequent Cycles (Cycles 2-12)

Cetuximab:  250mg/m², IV over 1 hr (undiluted 2mg/ml), Days 1 & 8 (give b/f chemo)

Oxaliplatin, Leucovorin, & 5-FU as outlined above.

          â

Observation q 6 mos x 5 yrs following randomiz

If Recurrence àEvent Monitoring until 8 yrs from randomiz

Arm G - Locally-Directed Therapy (Event Monitoring Arm)

Report summary of therapy

Annual status reports until 8 yrs from regist

Eligibility

PRE-RANDOMIZATION

• Histol-documented colon adenocarcinoma.  Gross inferior (caudad) margin of prim tumor must be >12cm from anal verge by rigid proctoscopy.  Rigid proctoscopy performed only in those settings where it is important to establish if tumor is a rectal or colon tumor.  Stg III tumor must have been completely resected.  No Stg IV pts.  If tumor adherence to adjacent structures, en bloc resection must be documented in oper report.  Pts w/tumor-related obstruction or colonic perforation are eligible. 

  NOTE:  Evidence of EGFR in resected tumor is NOT required.

  NOTE:  >1 synchronous prim colon cancer is allowed.  Staging classification will be based on more advanced prim tumor.

  NOTE:  Pts w/positive radial (serosal, circumferential) margins are eligible if there is no evidence that surgeon cut through tumor; no evidence that tumor invaded adjacent tissues; & entire specimen was resected en bloc.

• >1 path-confirmed positive lymph node.

• No evidence of residual involved lymph node disease.  >1 lymph node must be found in path specimen.  Recommended number of identified nodes is >4.

• ECOG perf status 0-2.

• Age >18.

• Must be willing to provide blood and tissue samples for eligibility and research.  Pt has the right to later w/d consent for research studies on blood &/or tissue specimens.  NOTE:  Tumor tissue must be submitted <42 days post-surgery for central KRAS testing prior to randomiz/regist.

• Tumor tissue must be made available for centralized KRAS testing prior to randomiz/regist.

• Pre-randomiz path review (KRAS analysis) is required.  Registering site must understand path review process & allow sufficient time to complete pre-randomiz & regist/randomiz steps.

• No pregnant or nursing women.  Men/Women of childbearing potential must use effective contraception.

• No distant mets at regist/randomiz.

• No prior chemo or RT for tx of this malignancy.

• No prior therapy w/agent(s) directed against EGFR.

• No prior allergic reaction (known sensitivity) to chimerized or murine monoclonal antibody therapy or documented presence of human anti-mouse antibodies.

• No previous or concurrent malignancy except treated non-melanoma skin cancer, in situ cervical cancer, or lobular carcinoma in situ in 1 breast, or other cancer disease-free >5 yrs.

• No uncontrolled high BP, unstable angina, symptomatic CHF, MI <6 mos pre-randomiz, NYHA class III or IV, symptomatic pulmonary fibrosis or interstitial pneumonitis, active uncontrolled bacterial or viral infection (including HIV or clinically defined AIDS), or systemic fungal infection.

• No other medical condition to make protocol unreasonably hazardous for pt (investigator's opinion).

• No clinically significant peripheral neuropathy at randomiz (CTCAE v3.0 >Grade 2) neurosensory or neuromotor toxicity.

• No concurrent use of other anti-cancer therapy.

• No known allergy to other platinum compounds.

• No hx of GI bleeding that has not been appropriately addressed (investigator's opinion).

• PRESTUDY REQUIREMENTS:

  All tests/procedures are required for pts who are randomized to Arm A or D.  Procedures required for ALL pts (including Arm G) are noted with a $.

  • PE (wt, perf status, ht, medical hx)*

  • CBC, diff, platelets*

  • Serum chem (alk phos, SGOT, total bili, creat, Na, K, Cl, bicarb CO₂, BUN, Mg)*

  • PT (only pts taking Coumadin)*

  • KRAS determination$&

  • CXR or Chest CT (use same method throughout; documentation of recur or new prim is required to be submitted)**

  • Abdominal US, CT, or MRI**

  • Pt & Physician Fact Sheet

  • Translational Research Blood Draw (contact KCCOP for kits)*@$

  • Paraffin-Embedded Tissue or Slide Collection (during primary surgery)#$

  • Serum Pregnancy Test (if applicable, <7 days pre-randomiz)***

  #   Paraffin-Embedded Blocks or Slides

        Pre-randomiz tissue for KRAS determination & central review confirmation of dx are same materials used for translational/pharmacologic studies.

        Normal & tumor tissue preferred.

  1)  ALL diagnostic slides from the resection including those that document extent of disease, radial margin (if positive), those that interface w/adjacent mucosa &/or pre-existing adenoma, and normal colonic mucosa (w/corresponding paraffin block).  Submission of 1 block or slide is not adequate for this review.

  2)  >1 slide documenting nodal mets

  3)  >3 (4 preferable) blocks to correspond w/submitted H&E slides

  4)  1 paraffin-embedded block w/normal colonic mucosa away from tumor (>10cm away or from a negative margin)

  5)  See protocol if unable to release blocks.

  @  Blood:  30ml whole blood in 3 vacutainer tubes (2 lavender top [EDTA] and 1 red top).  Forward blood to Mayo Central Lab for Clinical Trials via kits and prepaid mailers.

  *     <28 days pre-randomiz.  For Translational Research Blood draw, samples must be collected following pre-randomiz, but prior to start of tx.

  **   Within 8 wks pre-randomiz.

  *** Recommended that all blood draws (serum pregnancy & eligibility bloods) both be drawn <7 days pre-randomiz.

  $    Including Arm G pts

  &   Performed through central lab at NCCTG (Rochester, MN).

• Signed informed consent.

RANDOMIZATION FOR ARM A OR D

• Randomization must occur <56 days post-surg.

• KRAS wild-type status determined by central testing.

• <28 days pre-randomiz:  Hgb >9gl/dL, ANC >LNL (e.g., 1500/mm3), platelets >100,000/µL, creat & total bili each <1.5x UNL..

• Negative serum pregnancy test <7 days pre-randomiz (only women of childbearing potential).

• Translational research blood submitted after pre-randomiz, but <28 days pre-randomiz.

REGISTRATION FOR ARM G

• KRAS mutant status determined by central testing, or KRAS status not evaluable.

• Translational research blood submitted after pre-randomiz, but <28 days pre-randomiz