Clinical trial NCT00643097: Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
Official title: A Complementary Trial of an Immunotherapy Vaccine Against Tumor-Specific EGFRvIII
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malignant Neoplasms of Brain
Keywords: adult giant cell glioblastoma
adult gliosarcoma
adult glioblastoma
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2008-03-26
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Vaccines made from a peptide may help the body build an effective immune response to kill tumor cells. Colony-stimulating factors, such as GM-CSF, increase the number of white blood cells and platelets found in bone marrow or peripheral blood. Giving vaccine therapy after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase II trial is studying how well vaccine therapy works in treating patients with newly diagnosed glioblastoma multiforme.

Detailed description: OBJECTIVES:

Primary

* To assess humoral and cellular immune responses to adjuvant PEP-3-KLH conjugate vaccine in patients with newly diagnosed glioblastoma multiforme (GBM).
* To assess the clinical efficacy of the PEP-3-KLH conjugate vaccine, in terms of progression-free survival, in patients with newly diagnosed GBM.

Secondary

* To determine whether patients with GBM, who are known to be at least mildly immunosuppressed, can respond to standard and proven vaccine strategies.
* To assess for any potential toxicity to the PEP-3-KLH conjugate vaccine in patients with newly diagnosed GBM.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center.

At the time the study was initiated, standard of care temozolomide was not established, therefore, Arm I (ACTIVATE)was given without monthly cycles of temozolomide. At the point of interim analysis, monthly cycles of temozolomide had become standard of care. Arm II was then given the standard of care 5-day cycles of monthly temozolomide and during this time, dose-intensified temozolomide was in trials to compare with the 5-day temozolomide. Therefore, Arm III was initiated to determine the immunologic effects of 21-day monthly cycles of temozolomide with vaccine.

* Arm I (ACTIVATE): Patients receive PEP-3-KLH conjugate vaccine and sargramostim (GM-CSF) intradermally on days 1, 15, and 29 and then monthly in the absence of disease progression or unacceptable toxicity.
* Arm II (ACT II Standard (STD)): Patients first receive 3 initial vaccinations of an epidermal growth factor receptor variant III (EGRRvIII)- specific peptide (PEP-3) keyhole limpet hemocyanin (KLH) conjugate vaccine and sargramostim (GM-CSF) biweekly starting within 6 weeks of completing radiation. Additional vaccinations are given until clinical or radiographic evidence of progression or death. Patients subsequently receive temozolomide at a targeted dose of 200 mg/m2 for the first 5 days of a 28 day cycle.
* Arm III (ACT II Dose-intensified (DI)): Patients first receive 3 initial vaccinations of an epidermal growth factor receptor variant III (EGRRvIII)- specific peptide (PEP-3) keyhole limpet hemocyanin (KLH) conjugate vaccine and sargramostim (GM-CSF) biweekly starting within 6 weeks of completing radiation. Additional vaccinations are given until clinical or radiographic evidence of progression or death. Patients subsequently receive temozolomide at a targeted dose of 100 mg/m2 for the first 21 days of a 28 day cycle.

  * Patients undergo delayed-type hypersensitivity (DTH) skin testing\* at baseline, after the third vaccination, and then monthly thereafter. Patients also undergo leukapheresis to obtain sufficient peripheral blood lymphocytes for immunologic monitoring at baseline, after the third vaccination, and then, if applicable, at the time of positive DTH response, disease progression, or after the sixth course of post-radiotherapy temozolomide. Methods used for immunologic monitoring include Enzyme-linked Immunospot(ELISPOT) assays, cytotoxicity assays, fluorescence activated cell sorting (FACS), and ELISA.

NOTE: \*Patients with positive DTH skin testing, also undergo skin punch biopsies.

After completion of study therapy, patients are followed periodically.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed newly diagnosed glioblastoma multiforme
* Has undergone prior gross total resection (GTR) followed by conformal radiotherapy\* with or without concurrent chemotherapy

  * GTR is defined as ≥ 95% volumetric resection of the contrast-enhancing component on the preoperative MRI
  * Residual radiographic contrast enhancement on post-resection CT scan or MRI must be ≤ 1 cm in maximal diameter in any two perpendicular axial planes
  * No evidence of disease progression after completion of radiotherapy\* NOTE: \*Patients may enroll in part 2 of the study within 2 weeks after surgery; these patients will receive radiotherapy with concurrent chemotherapy during the study
* EGFRvIII-positive tumor by immunohistochemistry, polymerase chain reaction, or related molecular techniques
* Karnofsky performance status 80-100%
* Curran group status I-IV
* Signed informed consent form

Exclusion Criteria:

* Absolute Neutrophil Count (ANC) \< 1,000/mm³
* Platelet count \< 50,000/mm³
* Prothrombin Time/Partial Thromboplastin Time (PT/PTT) \> 1.5 times normal
* Positive hepatitis B (HB) surface antigen (HbsAg), antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc)
* Pregnant or nursing
* Positive pregnancy test
* Active infection requiring treatment
* Unexplained febrile illness (T max \> 101.5 F)
* Inflammatory bowel disease, lupus erythematosus, rheumatoid arthritis, or other autoimmune disease
* Known immunosuppressive disease
* Known HIV infection
* Diffuse leptomeningeal disease
* Unstable or severe concurrent medical condition, such as severe heart and lung disease or active hepatitis
* Demonstrated allergy to temozolomide or inability to tolerate temozolomide for reasons other than lymphopenia
* Concurrent corticosteroids (except for nasal or inhaled steroids) at a dose above physiologic levels (\> 2 mg of dexamethasone/day).

Primary outcomes:
measure: Humoral and Cellular Immune Response
timeFrame: 26 months
measure: Clinical Efficacy of Vaccination, in Terms of Progression-free Survival (PFS)
timeFrame: 58 months
Secondary outcomes:
measure: Response to Vaccination
timeFrame: 26 months
measure: Toxicity to PEP-3 Vaccine Immunization
timeFrame: 26 months
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Houston
country: United States
facility: M. D. Anderson Cancer Center at University of Texas
state: Texas
Study officials:
affiliation: Duke University
name: Gordana Vlahovic, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schmittling RJ, Archer GE, Mitchell DA, Heimberger A, Pegram C, Herndon JE 2nd, Friedman HS, Bigner DD, Sampson JH. Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines. J Immunol Methods. 2008 Nov 30;339(1):74-81. doi: 10.1016/j.jim.2008.08.004. Epub 2008 Sep 4.
citation: Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE 2nd, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010 Nov 1;28(31):4722-9. doi: 10.1200/JCO.2010.28.6963. Epub 2010 Oct 4.
citation: Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, Friedman HS, Gilbert MR, Herndon JE, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling R, Shi W, Vredenburgh JJ, Bigner DD, Heimberger AB. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011 Mar;13(3):324-33. doi: 10.1093/neuonc/noq157. Epub 2010 Dec 10.