RTOG 1016 - "Phase III Trial of Radiotherapy Plus Cetuximab versus Chemoradiotherapy in HPV-Associated Oropharynx Cancer"

NOTES:

1)  See Section 5.0 for pre-registration credentialing IMRT (mandatory) & IGRT (mandatory if PTV margins <5mm) requirements.

2)  Prior to 1st registration, sites must register with Computer-Assisted Self Interview (CASI) for access to computer software & iPAD for administration of pt asmts.  Must also set up a CRA user account.

Treatment Plan    (Supplied:  Software & iPAD for pt asmts)

REGISTRATION (Submit w/i 1 wk of study entry)

Mandatory p16 analysis (FFPE tissue block, punch bx, or section from bx)

  â

Only if p16 positive

  â

STRATIFICATION

Mandatory Smoking Hx via CASI

  â

RANDOMIZATION#

Arm 1 (Control) - Cisplatin w/Concurrent RT

Accelerated IMRT:  70Gy x 6 wks

High-Dose DDP:  100mg/m2, IV, Days 1 & 22 (total 200mg/m2)

Arm 2 - Cetuximab w/Concurrent RT

Accelerated IMRT:  70Gy x 6 wks

Cetuximab (Loading Dose)*:  400mg/m2, IV over 120 mins (no RT given this day)

Cetuximab (Subsequent Doses)*:  250mg/m2, IV over 60 mins, q week (administer prior to RT)

*     Must precede 1st 250mg/m2 dose of Cetuximab & 1st RT tx by 5-7 days (Loading Dose day is not included)

**  Administer Wks 2-8 (concurrent w/RT & x 1wk post-RT). 

#   IMRT is mandatory.  IGRT credentialing is mandatory when using PTV margins <5mm.  See Section 5.0 for pre-registration credentialing.

Eligibility

• Histol- or cytol-proven squamous cell carcinoma (including papillary cell carcinoma & basaloid squamous cell carcinoma)of oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls).  NOTE:  PE cytology specimens are allowed for p16 eval, but not cytology smears.  If dx based on cytopathology alone, the pt may require bx of prim tumor for eligibility determination.

• Must be p16 positive, determined by OSU Innovation Center CLIA lab prior to Step 2 (Randomization).

• Meas disease (clinically or radiographically) at prim site or nodal stations.  Tonsillectomy or local excision of the primary w/o removal of nodal disease is allowed.  Excision removing gross nodal disease but w/intact prim site is allowed.  Limited neck dissections retrieving <4 nodes are allowed & considered non-therapeutic nodal excisions.  No neck FNAs.  Bx specimens from prim or nodes must be >3-5mm.

• Clinical stage T1-2, N2a-N3 or T3-4, any N (AJCC 7th edition), w/no distant mets. 

• Zubrod 0-1.

• Age >18.

• ANC >1500 cells/mm3; platelets >100,000 cells/mm3; Hgb >8.0g/dl (transfusion/other intervention to achieve Hgb is allowed); bili <2mg/dl; SGOT or SGPT <3x ULN; serum creat <1.5mg/dl or CrCl >50ml/min (by 24-hr collection or estimated by Cockroft-Gault).

• Must provide smoking hx (for stratification) via CASI head & neck risk factor survey tool.

• Negative serum pregnancy test w/i 2 wks pre-regist (if applicable).

• Women/Men of reproductive potential must use effective contraception throughout tx phase & >60 cays following last study tx.

• HIV+ pt w/no prior AIDS-defining illness & CD4 cells >350/mm3 are allowed.  HIV status must be known pre-regist.  No seropositivity for Hep B (Hep B surface antigen positive or anti-hepatitis B core antigen positive) or seropositive for Hep C (anti-Hep C antibody positive).  Pts who are immune to Hep B (anti-Hep B surface antibody positive) are eligible.  HIV+ pts must not have multi-drug resistant HIV infection or other concurrent AIDS-defining condition.

• No cancers from an oral cavity site or neck carcinoma of unknown prim site origin, even if p16 positive.

• No adenopathy below the clavicles.

• No gross total excision of both prim & nodal disease.

• No prior invasive malignancy (except non-melanoma skin cancer) unless disease-free >3 yrs.

• No prior systemic chemo for study cancer. 

• No prior RT to region of study cancer that would result in overlap of RT therapy fields.

• No unstable angina &/or CHF requiring hospitalization w/i last 6 mos.

• No transmural MI w/i last 6 mos.

• No acute bacterial or fungal infection requiring IV antibiotics at regist.

• No COPD exacerbation or other respiratory illness requiring hospitalization or precluding study therapy w/i 30 days pre-regist.

• No hepatic insufficiency resulting in clinical jaundice &/or coagulation defects (liver function & coagulation lab tests are not required for study entry).

• No AIDS pts based on current CDC definition w/immune compromise greater than noted above (however, HIV test is not required for study entry).

• No prior allergic reaction to Cisplatin or Cetuximab.

• No prior Cetuximab or other anti-EGFR therapy.

• PRESTUDY REQUIREMENTS:

  • Eligibility-related tissue collection (submit w/i 1 wk of study entry; approx 5 business days from receipt of samples to reporting results)*@

  • Smoking hx (CASI)*

  • Hx**

  • Rad Onc exam**

  • Med Onc exam**

  • ENT or H&N surgeon exam**

  • Chest imaging**#

  • Perf status***

  • CBC/diff/ANC***

  • Total bili, SGOT or SGPT***

  • Creat or CrCl***

  • Serum pregnancy test (if applicable)***

  • Na, K, Cl, HCO3, glucose, Ca, Mg, albumin (w/i 2 wks pre-tx)

  • Dental asmt (w/i 8 wks pre-tx)

  • Swallowing eval via CTCAE v4 (w/i 4 wks pre-tx)

  • Audiogram (w/i 12 wks pre-tx)

  • EKG (recommended)##

  • Whole body PET/CT (recommended)##

  • Nutrition/Feeding Tube eval (recommended w/i 2 wks pre-tx)

  • CT or MRI or PET/CT neck w/contrast**#

  • QOL asmts###

  • CASI Risk Factor Survey###

  • Specimen collection for banking (tissue & blood)###@@

  *       Prior to Step 2 Registration

  **     Within 8 wks pre-regist

  ***   Within 2 wks pre-regist

  #       CT neck w/contrast & chest CT (w/ or w/o contrast) OR MRI neck & chest CT (w/ or w/o contrast) OR CT neck & PET/CT neck & chest (w/ or w/o contrast).  CT or PET/CT of neck used for RT planning may also be used for staging.

  ##    Within 8 wks pre-tx

  ###  With pt's consent, prior to start of tx.

  @     H&E stained slides from area w/highest grade of tumor & 1 paraffin blockof tumor (recommended) or two 2mm core punches.  Contact KCCOP for specimen plug kit.  If site will not release block or punches, then submit >10 five micron  unstained slides cut onto positive charged (adherent) slides. 

  @@ Contact KCCOP for kit.  See Appendix VI for collection instructions.  Tissue:  H&E stained slide and PE block or punch bx (or 10 unstained slides ONLY if block or punches not available).  Ship ambient.  Blood:  5-10mL whole blood in 1 red-top tube; 5-10mL anticoagulated whole blood in EDTA tube #1 (purple/lavender top); & 5-10mL anticoagulated whole blood in EDTA tube #2 (purple/lavender top).  Process blood samples per protocol & send frozen on dry ice via overnight carrier (Mon-Wed only).  Send all specimens to RTOG Biospecimen Resource; San Francisco, CA (note different addresses for frozen vs non-frozen specimens).

• Signed informed consent including consent for mandatory tissue submission for p16 central review & consent to participate in CASI asmt on smoking hx.