Details

Details

Title Randomized Phase II trial of hypofractionated dose-escalated photon IMRT or proton beam therapy versus conventional photon irradiation with concomitant and adjuvant Temozolomide in patients with newly diagnosed Glioblastoma

IRB NRG-BN001

CC 15-470

Hospital Main Campus

Phase Phase 2

Disease Brain, Glioblastoma

Drug Temozolomide

Description

Description

Primary Objective
  • To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and adjuvant temozolomide improves overall survival, as compared to standard-dose photon irradiation with concomitant and adjuvant temozolomide.
Secondary Objectives
  • To indirectly compare dose-escalated and -intensified photon IMRT to dose-escalated and -intensified proton beam therapy in terms of overall survival.
  • To indirectly compare and record toxicities of dose-escalated and -intensified photon IMRT versus dose-escalated and -intensified proton beam therapy and directly compare the toxicities of these approaches versus standard-dose photon irradiation on the backbone of concomitant and adjuvant temozolomide
  • To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and adjuvant temozolomide improves perceived cognitive symptom severity, as compared to standard-dose photon irradiation with concomitant and adjuvant temozolomide.
  • To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and adjuvant temozolomide improves neurocognitive function, as compared to standard-dose photon irradiation with concomitant and adjuvant temozolomide.
  • To indirectly determine if dose-escalated and -intensified proton beam therapy with concomitant and adjuvant temozolomide improves perceived cognitive symptom severity, as compared to dose-escalated and -intensified photon IMRT, and to directly compare symptom burden with these approaches versus standard-dose photon irradiation on the backbone of concomitant and adjuvant temozolomide
  • To indirectly determine if dose-escalated and -intensified proton beam therapy with concomitant and adjuvant temozolomide improves neurocognitive function, as compared to dose-escalated and -intensified photon IMRT, and to directly compare neurocognitive function with these approaches versus standard-dose photon irradiation on the backbone of concomitant and adjuvant temozolomide
Exploratory Objectives
  • Tissue banking for future translational science projects that will be determined based on the state of the science at the time the primary endpoint is reported and will be submitted to NCI for review and approval.
  • To prospectively compare CD4 lymphopenia between dose-escalated and intensified proton beam therapy, dose-escalated and -intensified photon IMRT, and standard-dose photon irradiation and determine whether CD4 lymphopenia impacts overall survival.
  • To explore the most appropriate and clinically relevant technological parameters to ensure quality and effectiveness throughout radiation therapy processes, including imaging, simulation, patient immobilization, target and critical structure definition, treatment planning, image guidance and delivery.
    • To establish feasibility and clinical relevancy of quality assurance guidelines
    • To evaluate efficacy of quality assurance tools
  • To explore the most appropriate and clinically relevant advanced and standard MRI imaging parameters
    • To evaluate the feasibility of differentiating pseudo-progression and true progression in a multi institutional setting using MR diffusion and perfusion imaging.
    • To evaluate for early, imaging biomarkers of response and overall survival.
Inclusion Criteria

Inclusion Criteria

Prior to STEP 1 REGISTRATION
  1. A diagnostic contrast-enhanced MRI (no other scan type allowed) of the brain must be performed postoperatively. The residual enhancing tumor and/or resection cavity must have a maximal diameter of 5 cm or less (as specified in the aforementioned University of Michigan phase I/II trial of dose-intensification with temozolomide). The tumor diameter will be the greatest diameter as measured on the contrast-enhanced postoperative MRI and will include residual disease and/or the postoperative surgical cavity as appropriate.
    • The postoperative brain MRI should be obtained within 72 hours of resection. If it is not obtained within 72 hours post-resection, then an MRI obtained 2 weeks or longer after surgery is required and can be utilized to ensure maximal diameter of residual tumor and/or resection cavity is 5cm or less.
    • For cases where a gross total resection of enhancing tumor is performed, but postoperative surgical cavity is NOT identifiable (e.g., polar lobectomy is performed), the patient will be excluded from the trial.
  2. Tumor tissue must be available for submission for central pathology review.
    • Timing Requirements:
      • Sites able to submit tissue for central pathology review on or before postoperative calendar day 30: MGMT analysis will be performed centrally for stratification and randomization. Tumor tissue must be sent by overnight courier (FedEx/UPS) on or before postoperative calendar day 30. Sites must submit all tissue requirements to the NRG Oncology Biospecimen Bank per Section 10.2
      • Sites able to submit tissue for central pathology review on or before postoperative calendar day 40 but after postoperative calendar day 30: MGMT must be assessed by LabCorp and the official LabCorp result must be submitted to the NRG Oncology Biospecimen Bank per Section 10.2 on or before postoperative day 40 at the time of tissue submission. The site�s MGMT report from LabCorp will be used to stratify the patient, and a post-stratification MGMT central review will be performed.
      • Sites not able to submit tissue for central pathology review (A) on or before 30 calendar days after surgery with no prior LabCorp MGMT assessment, or (B) on or before 40 calendar days after surgery with completed LabCorp MGMT result may NOT enroll patients on this trial, as central pathology review will not be complete in time for the patient to start treatment within 49 calendar days following surgery.
    • Tissue Requirements:
      • Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility. In total, at least 1 cubic centimeter of tissue composed primarily of tumor must be present.
      • Submission of an accompanying H&E slide is MANDATORY.
      • Diagnosis must be made by surgical excision, either partial or complete. Stereotactic biopsy and cavitronic ultrasonic surgical (CUSA) techniques are not allowed.
  3. The tumor must be located in the supratentorial compartment only (any component involving the brain stem or cerebellum is not allowed).
  4. Patients must provide study-specific informed consent prior to step 1 registration.
Prior to STEP 2 REGISTRATION
  1. Histologically proven diagnosis of glioblastoma (WHO grade IV) confirmed by central review prior to step 2 registration (See Section 10 for details)
  2. Tumor tissue that is determined by central pathology review prior to step 2 registration to be of sufficient quantity for analysis of MGMT status (See Section 10).
  3. History/physical examination within 28 days prior to step 2 registration.
  4. The patient must have recovered from effects of surgery, postoperative infection, and other complications within 28 days prior to step 2 registration.
  5. Documentation of steroid doses within 28 days prior to step 2 registration.
  6. Karnofsky performance status ≥ 70 within 28 days prior to step 2 registration.
  7. Age ≥ 18.
  8. CBC/differential obtained within 28 days prior to step 2 registration, with adequate bone marrow function defined as follows:
    • Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3;
    • Platelets ≥ 100,000 cells/mm3;
    • Hemoglobin ≥ 10.0 g/dl (Note: the use of transfusion or other intervention to achieve Hgb ≥10.0 g/dl is acceptable);
  9. Adequate hepatic function within 28 days prior to step 2 registration, as defined below:
    • Bilirubin ≤ 1.5 ULN
    • ALT and AST ≤ 3 x ULN
  10. Negative serum pregnancy test obtained for females of child-bearing potential within 28 days prior to step 2 registration
Exclusion Criteria

Exclusion Criteria

  1. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease-free for a minimum of 3 years. (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
  2. Recurrent or multifocal malignant gliomas.
  3. Any site of distant disease (for example, drop metastases from the GBM tumor site).
  4. Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable (except temozolomide).
  5. Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted. See Section 3.2.1.
  6. Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields
  7. Severe, active co-morbidity, defined as follows:
    • Unstable angina at step 2 registration
    • Transmural myocardial infarction within the last 6 months prior to step 2 registration
    • Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of ≥ 2 mm using the analysis of an EKG performed within 28 days prior to step 2 registration. (Note: EKG to be performed only if clinical suspicion of cardiac issue.)
    • New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration.
    • Serious and inadequately controlled arrhythmia at step 2 registration
    • Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for surgical resection
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration
    • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol.
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
    • Acquired immune deficiency syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is because the treatments involved in this protocol may be significantly immunosuppressive with potentially fatal outcomes in patients already immunosuppressed.
    • Any other severe immunocompromised condition.
    • Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity.
    • End-stage renal disease (ie, on dialysis or dialysis has been recommended).
    • Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy.
  8. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
  9. Patents treated on any other therapeutic clinical protocols within 30 days prior to step 2 registration.
  10. Inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker, or severe claustrophobia).
  11. Postoperative tumor plus surgical bed size exceeds 5 cm in maximum diameter.