Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

NCT ID: NCT00643097

Last Updated: 2017-02-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-09-30
• Study Completion Date: 2016-11-30

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.

Conditions

Malignant Neoplasms of Brain

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm I (ACTIVATE)

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), referred to as PEP-3 vaccine, every 2 weeks starting 4 weeks after the completion of radiation. Subsequent vaccinations were given once a month until clinical or radiographic evidence of progression or death.

Group Type: EXPERIMENTAL

PEP-3 vaccine

Intervention Type: BIOLOGICAL

Given intradermally

sargramostim

Intervention Type: BIOLOGICAL

Given intradermally

Temozolomide

Intervention Type: DRUG

Standard of care chemotherapy

Arm II (ACT II 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), referred to as PEP-3 vaccine, biweekly starting within 6 weeks of completing radiation. Additional vaccinations were 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.

Group Type: EXPERIMENTAL

PEP-3 vaccine

Intervention Type: BIOLOGICAL

Given intradermally

sargramostim

Intervention Type: BIOLOGICAL

Given intradermally

Temozolomide

Intervention Type: DRUG

Standard of care chemotherapy

Arm III (ACT II 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), referred to as PEP-3 vaccine, biweekly starting within 6 weeks of completing radiation. Additional vaccinations were 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.

Group Type: EXPERIMENTAL

PEP-3 vaccine

Intervention Type: BIOLOGICAL

Given intradermally

sargramostim

Intervention Type: BIOLOGICAL

Given intradermally

Temozolomide

Intervention Type: DRUG

Standard of care chemotherapy

Interventions

PEP-3 vaccine

Given intradermally

Intervention Type: BIOLOGICAL

sargramostim

Given intradermally

Intervention Type: BIOLOGICAL

Temozolomide

Standard of care chemotherapy

Intervention Type: DRUG

Other Intervention Names

TMZ; Temodar

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

John Sampson

OTHER

Sponsor Role: lead

Responsible Party

John Sampson

Professor of Neurology

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Gordana Vlahovic, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University

Locations

Duke University Medical Center

Durham, North Carolina, United States

M. D. Anderson Cancer Center at University of Texas

Houston, Texas, United States

Countries

United States

References

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.

Reference Type: RESULT

PMID: 18775433 (View on PubMed)

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.

Reference Type: RESULT

PMID: 20921459 (View on PubMed)

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.

Reference Type: RESULT

PMID: 21149254 (View on PubMed)

Other Identifiers

P50NS020023

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CDR0000589632

Identifier Type: OTHER

Identifier Source: secondary_id

DUMC-5421

Identifier Type: REGISTRY

Identifier Source: secondary_id

Pro00004040

Identifier Type: -

Identifier Source: org_study_id

NCT00090597

Identifier Type: -

Identifier Source: nct_alias