RTOG 0837 - "Randomized, Phase II, Double-Blind, Placebo-Controlled Trial of Conventional Chemoradiation and Adjuvant Temozolomide Plus Cediranib Versus Conventional Chemoradiation and Adjuvant Temozolomide Plus Placebo in Patients with Newly Diagnosed Glioblastoma"

ALERT - 8/17/10:  There are possible delays with RTOG's pathology processing and MGMT testing.  For this reason, please identify potential patients with as much lead time as possible.

NOTES:  1)  Must meet RT certification requirements in protocol (IMRT or 3D-CRT) prior to registration.

                2)  KCCOP is not participating in the Advanced Imaging Component mentioned in the protocol.

Treatment Plan    (Supplied Drug:  Cediranib/placebo)

STEP 1 REGISTRATION

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Central Path Review

1)  Histology confirmation

2)  Confirmation of adequacy of tissue for MGMT analysis

3)  Central Review confirmation of tumor tissue must be completed b/f STEP 2 regist

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1)  Analysis for MGMT Methylation

2)  Stratification

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STEP 2 REGISTRATION

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RANDOMIZATION

ARM 1

Placebo:  PO, QD x 3 days

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RT (IMRT or 3D-CRT):  60Gy in 2fx, 5 days/wk, x 6 wks

Temozolomide:  75mg/m2, PO, QD, x 6 wks (42 days)

Placebo:  PO, QD, x 6 wks (42 days)

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Placebo:  PO, QD, x 4 wks (28 days)

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Temozolomide:  150-200mg/m2, PO, Days 1-5, q 28 days (start 28 days +3 days after last day of RT)

Placebo:  PO, QD

12 cycles max after RT ends or disease progression/adverse events.

ARM 2

Cediranib:  20mg, PO, QD x 3 days

   â

RT (IMRT or 3D-CRT):  60Gy in 2fx, 5 days/wk, x 6 wks

Temozolomide:  75mg/m2, PO, QD, x 6 wks (42 days)

Cediranib:  20mg, PO, QD, x 6 wks (42 days)

   â

Cedarinib:  20mg, PO, QD, x 4 wks (28 days)

   â

Temozolomide:  150-200mg/m2, PO, Days 1-5, q 28 days (start 28 days +3 days after last day of RT)

Cediranib:  20mg, PO, QD

12 cycles max after RT ends or disease progression/adverse events.

Eligibility

• Histol-proven glioblastoma or gliosarcoma (WHO Grade IV) confirmed by central review prior to Step 2 regist.

• Tumor tissue determined by central review prior to Step 2 regist must be sufficient size for MGMT analysis.

  • >1 block of tumor tissue (2 blocks is strongly recommended)

  • CUSA-derived material is not allowed.  Fresh frozen tumor tissue is encouraged.

  • Dx by surgical excision (partial or complete).  No stereotactic bx allowed.

  • Send tumor tissue ASAP to maximize likelihood of eligibility.  Submit <28 days post-surgery, because tissue analysis wiwll not be able to be performed in time for tx to commence by the mandatory 6-wk post-surg out limit stipulated in protocol.  Submission of tissue earlier than 28 days post-surg is highly recommended.

• Tumor must have supratentorial component.

• Recovered from effects of surgery, post-op infection, & other complications prior to Step 2 regist.

• Karnofsky >70 prior to Step 2 regist.

• Age >18.

• Within 14 days prior to Step 2 regist:  ANC >1800 cells/mm3; platelets >100,000 cells/mm3; Hgb >10.0g/dl (use of transfusion to achieve this is allowed); BUN <30mg/dl; creat <1.7mg/dl; UA for UPC ratio (if >0.5, a 24-hr urine protein should be done & show <1000mg); bili <2.0mg/dl; SGOT/SGPT <3x INL; systolic BP <140mmHg or diastolic BP <90mmHg (w/ or w/o stable regimen of anti-hypertensive therapy).

• Within 1 wk prior to Step 2 regist:  PT/INR <1.4 for pts not on Warfarin.

• Pts on full dose anticoagulants must meet both of following:

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

  • In-range INR (usually 2-3) on stable dose of PO anticoagulant or on stable dose of LMW heparin.

• Women/Men of reproductive potential must use adequate contraception.

• Negative serum pregnancy test w/i 14 days prior to Step 2 regist (if applicable).

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

• No recur or multifocal malig gliomas.

• No mets below tentorium or beyond cranial vault.

• No prior chemo or radiosensitizers for cancers of head & neck region.  Prior chemo for a different cancer is allowed (except Temozolomide or Cediranib).  No prior use of Gliadel wafers or any other intratumoral or intracavitary tx.

• No prior RT to head or neck (except T1 glottic cancer) resulting in overlap of RT fields.

• No severe, active co-morbidity:

  • Unstable angina &/or CHF requiring hospitalization

  • Transmural MI w/i last 6 mos

  • Recent MI or ischemia by S-T elevations >2mm using EKG w/i 14 days prior to Step 2 regist

  • NYHA >Grade II CHF requiring hospitalization w/i 12 mos prior to Step 2 regist

  • Stroke, CVA, or TIA w/i 6 mos pre-regist

  • Serious & inadequately controlled cardiac arrhythmia

  • Significant vascular disease or clinically significant perip vascular disease

  • Bleeding diathesis or coagulopathy

  • Serious or non-healing wound, ulcer, or bone fx or hx of abdominal fistula, GI perforation, intra-abdominal abscess, major surgical procedure, open bx, or significant traumatic injury w/i 28 days prior to Step 2 regist (except craniotomy for tumor resection).

  • Acute bacterial or fungal infection requiring IV antibiotics at time of Step 2 regist

  • COPD exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at time of Step 2 regist

  • Hepatic insufficiency resulting in clinical jaundice &/or coagulation defects. 

  • AIDS based on current CDC definition.  HIV testing is NOT required for study entry.

  • Active connective tissue disorders that put pt at high risk for RT toxicity (investigator's opinion).

  • Any other major medical illness/psychiatric impairment that prevents administration & completion of protocol therapy (investigator's opinion).

• No pregnant or lactating women.

• No prior allergic reaction to Temozolomide.

• No tx on any other therapeutic clinical protocol w/i 30 days pre-study entry or during study participation.

• No prior allergic reaction attributed to compounds of similar chemical/biologic composition to Cediranib.

• No mean QTc >500msec (w/Bazett's correction) in screening EKG, hx of familial long QT syndrome, or other significant ECG abnormality noted w/i 14 days pre-tx.

• No concurrent VEGF inhibitors.

• No use of enzyme-inducing anti-epileptic drugs (EIAED).  Pts previously taking EIAEDs must have >14 days since last dose of EIAED b/f 1st dose of Cediranib.  See protocol list of acceptable anti-epileptic drugs.

• PRESTUDY REQUIREMENTS:

  • Perf status, VS, ht, wt, H&P*

  • Neuro exam*

  • Steroid dose documentation*

  • Concurrent meds*

  • CBC w/diff*

  • BUN*

  • Creat*

  • UA*

  • Bili*

  • SGOT, SGPT*

  • Complete metabolic panel, Mg, LDH, phosphorous*

  • PT/INR, PTT (w/i 7 days prior to Step 2 regist)

  • Pregnancy test (if applicable)*

  • Troponin T or I*

  • TSH, Free T4*

  • Echo/MUGA (if increased risk of LVEF)**

  • EKG*

  • Standard contrast-enhanced MRI (Done pre-op & post-op [post-op scan done w/i 28 days prior to Step 1 regist])*

  • Tumor block(s) for Central Path Review (eligibility & MGMT status) - MANDATORY#

  • Tissue, serum, plasma, whole blood for DNA, & clean-catch urine for banking (w/pt's consent)**##

  *      Within 14 days prior to Step 2 regist

  **    Within 28 days prior to Step 2 regist

  #     >1 PE block (2 encouraged) + 1 H&E stained slide (encouraged) from pre-study open bx or surgical resection.  Overnight delivery to:  Ken Aldape, MD; Dept of Pathology; UT MD Anderson Cancer Ctr; Houston, TX.  Must occur as soon as STEP 1 regist is complete.

  ##   Contact KCCOP for kits.  Process per protocol.  Store in -80^oC freezer (see protocol for other freezing options).  Mail via overnight delivery to:  RTOG Biospecimen Resource; San Francisco, CA.

• Signed informed consent (prior to Step 1 regist).