RTOG 0825 - "Phase III Double-Blind Placebo-Controlled Trial of Conventional Concurrent Chemoradiation and Adjuvant Temozolomide Plus Bevacizumab versus Conventional Concurrent Chemoradiation and Adjuvant Temozolomide in Patients with Newly Diagnosed Glioblastoma"

NOTE: 

Institutions must meet IMRT &/or 3D-CRT and Neurocognitive Function Testing requirements per protocol.

Treatment Plan    (Supplied Drug:  Bevacizumab/placebo)

STEP 1 REGISTRATION

Central Path Tissue Screening

• Histology confirmation

• Confirmation of adequacy of tissue for MGMT analysis & molecular profile

• Tissue must be received & central review confirmation completed b/f STEP 2 REGISTRATION can occur

STEP 2 REGISTRATION

Initial 3 Wks of Chemoradiation

RT:  30Gy in 2Gy fx

Temozolomide (concurrent w/RT):  75mg/m2, PO, QD x 21 days

Analysis for MGMT methylation & molecular profile

STEP 3 REGISTRATION  

RANDOMIZATION STEP - Must occur by Day 10 after start of RT (Stratification by MGMT Methylation Status & Molecular Profile)

Arm 1 (Final 3 Wks of Chemoradiation)
RT:  30Gy in 2Gy fx

Temozolomide (concurrent w/RT):  75mg/m2, PO, QD x 21 days

Placebo:  IV, Q 2 wks (continues w/o stop)

(4 wks after completion of Chemoradiation)

Temozolomide:  150mg/m2/day, PO, Days 1-5 of 28 day cycle

Placebo:  Q 2 wks, 12 cycle max**

Arm 2 (Final 3 Wks of Chemoradiation)
RT:  30Gy in 2Gy fx

Temozolomide (concurrent w/RT):  75mg/m2, PO, QD x 21 days

Bevacizumab:  IV, Q 2 wks (continues w/o stop)

(4 wks after completion of Chemoradiation)

Temozolomide:  150mg/m2/day, PO, Days 1-5 of 28 day cycle

Bevacizumab:  Q 2 wks, 12 cycle max**

**  Bevacizumab at progression at physician's discretion.

Eligibility

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

• Tumor tissue determined by central path review prior to Step 2 Regist of sufficient size for MGMT status analysis & determination of molecular profile.

  • Must have >1 block of tumor tissue; submission of 2 blocks is strongly encouraged.  >1 cubic cm composed primarily of tumor must be present.

  • CUSA-derived material not allowed; fresh frozen tumor tissue acquisition is encouraged.

  • Dx by surgical excision - either partial or complete.  Stereotactic bx NOT allowed.

  • Send tumor tissue ASAP to maximize chance of eligibility.  Submit by 4 wks after surg procedure to study regist & tx can start by mandatory 5 wk post-surgery outer limit.

  • MUST submit tissue directly to Dr. Aldape in order to obtain MGMT analysis.  Pts from sites not doing this will be ineligible.

• Must have supratentorial component.

• Recovered from effects of surgery, post-op infection, & other complications b/f regist.

• Diagnostic contrast-enhanced brain MRI performed pre-op & post-op prior to start of RT.  Post-op scan must be done w/i 28 days prior to Step 1 regist.

  • MRI or CT (potentially in addition to the post-op scan) must be obtained w/i 1 wk pre-regist & must not show significant post-op hemorrhage (>1cm diameter of blood).  If >1cm acute blood is detected, pt will be ineligible.  RT planning MRI or CT may be used to determine presence of hemorrhage.

  • Pts unable to undergo MRI (due to non-compatible devices) can be enrolled if pre- & post-op contrast-enhanced CTs are obtained & are of sufficient quality.  Pre- & post-op scans must be same type. 

• Karnofsky PS >70.

• Age >18.

• Within 14 days pre-regist:   ANC >1800 cells/mm3; platelets >100,000 cells/mm3; Hgb >10.0g/dl (transfusion or other intervention to achieve this is acceptable); BUN <30mg/dl; creat <1.7mg/dl; UPC ratio (if >0.5, a 24-hr urine protein should be obtained & level must be <1000mg); bili <2.0mg/dl; SGOT/SGPT <3x normal range; systolic BP <160 mg Hg or diastolic BP <90 mg Hg; EKG w/o evidence of acute cardiac ischemia; PT/INR <1.4 for pts not on Warfarin. 

• Pts on full-dose anticoagulation must meet both of following:

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

  • In-range INR (between 2 & 3) on stable dose of oral anticoagulant or on stable dose of low molecular weight heparin.

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

• Negative serum pregnancy test w/i 14 days pre-regist (if applicable).  No nursing women.

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

• No recur or multifocal malignant gliomas.

• No mets below tentorium or beyond cranial vault.

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

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

• No severe, active co-morbidity:

  • Unstable angina &/or CHF w/i last 6 mos

  • Transmural MI w/i last 6 mos

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

  • NYHA >Grade II CHF requiring hospitalization w/i 12 mos pre-regist

  • Hx of stroke, CVA, or TIA w/i 6 mos

  • 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 pre-regist (except craniotomy for tumor resection).

  • Acute bacterial or fungal infection requiring IV antibiotics at regist

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

  • Hepatic insufficiency resulting in clinical jaundice &/or coagulation defects.  NOTE:  LFTs & coagulation parameters are NOT required for study entry.

  • AIDS based on current CDC definition.  NOTE:  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 or psychiatric impairment to preclude study completion & followup (investigator's opinion)

• No other therapeutic clinical trial participation w/i 30 days pre-study entry or during participation in this study.

• PRESTUDY REQUIREMENTS:

  • Tissue eval for histology & sample adequacy (ASAP post-surgery)#

  • H&P*

  • Standard Imaging:  Contrast-enhanced MRI**

  • MRI/CT (blood detection)***

  • Steroid dose documentation*

  • Perf status*

  • CBC/diff/platelets, ANC, Hgb*

  • BUN*

  • Creat*

  • Urine protein*

  • Bili*

  • SGOT/SGPT*

  • PT/INR (pts not on Warfarin)*

  • PT/INR (pts on full-dose anticoagulants)*

  • EKG*

  • Serum pregnancy test (if applicable)*

  • Tissue for banking (ASAP post-surg)##&

  • Blood for banking $##&

  • Urine for banking$##&

  • QOL Questionnaires***##

  • Neurocognitive Function Tests***##

  *       <14 days pre-regist

  **     <28 days pre-regist

  ***   <1 wk pre-regist

  $      <28 days pre-tx

  #       MANDATORY:  Paraffin-embedded block from pre-study open bx or surg resection.  Send by overnight mail directly to:  Ken Aldape, MD; UT MD Anderson Cancer Ctr; Houston, TX.  STRONGLY ENCOURAGED:  1 or more additional blocks & 1 H&E stained slide.

  ##    With pt's consent

  &      Contact KCCOP for kit.

• Signed informed consent.