Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme (ACTIVATe)
A Complementary Trial of an Immunotherapy Vaccine Against Tumor-Specific EGFRvIII
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.
調査の概要
詳細な説明
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.
研究の種類
入学 (実際)
段階
- フェーズ2
連絡先と場所
研究場所
-
-
North Carolina
-
Durham、North Carolina、アメリカ、27710
- Duke University Medical Center
-
-
Texas
-
Houston、Texas、アメリカ、77030-4009
- M. D. Anderson Cancer Center at University of Texas
-
-
参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
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).
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：非ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
実験的：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.
|
皮内投与
Given intradermally
Standard of care chemotherapy
他の名前：
|
|
実験的：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.
|
皮内投与
Given intradermally
Standard of care chemotherapy
他の名前：
|
|
実験的：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.
|
皮内投与
Given intradermally
Standard of care chemotherapy
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Humoral and Cellular Immune Response
時間枠：26 months
|
Number of patients that developed a delayed-type hypersensitivity (DTH) response at following vaccination.
Any skin reaction in response to the intradermal injection of the antigen was measured and recorded.
A positive skin test was defined as > 5 mm induration (swelling).
|
26 months
|
|
Clinical Efficacy of Vaccination, in Terms of Progression-free Survival (PFS)
時間枠：58 months
|
Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve. Macdonald criteria are standard criteria in neuro-oncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of: 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), 3) concomitant steroid use (as reported by the investigator). |
58 months
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Response to Vaccination
時間枠：26 months
|
The objective is to assess the duration of immunosuppressive cytokine secretion and to identify a receptive interval for active immunotherapy.
Immunosuppression will determined by monitoring a panel of immunosuppressive serum/plasma cytokines longitudinally and by determining the response of each patient to Recombivax Hepatitis B (HB) vaccination.
Response is defined as seropositive or seronegative to the Hepatitis B surface antigen.
|
26 months
|
|
Toxicity to PEP-3 Vaccine Immunization
時間枠：26 months
|
To assess for any potential toxicity to the PEP-3 vaccine immunization in patients with newly diagnosed glioblastoma, Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used to tabulate any toxicities attributable to PEP-3.
The number of patients with toxicity attributable to vaccine while on study are tabulated.
|
26 months
|
協力者と研究者
スポンサー
捜査官
- 主任研究者：Gordana Vlahovic, MD、Duke University
出版物と役立つリンク
一般刊行物
- 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.
- 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.
- 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.
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (見積もり)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- Pro00004040
- P50NS020023 (米国 NIH グラント/契約)
- CDR0000589632 (その他の識別子：National Cancer Institute)
- DUMC-5421 (レジストリ識別子：DUMC IRB)
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。