Erratum: Phase I/IIa trial of autologous formalin-fixed tumor vaccine concomitant with fractionated radiotherapy for newly diagnosed glioblastoma

Object The objective of the present study was analysis of results of the prospective clinical trial directed toward the evaluation of therapeutic efficacy of the administration of autologous formalin-fixed tumor vaccine (AFTV) concomitant with fractionated radiotherapy in cases of newly diagnosed glioblastoma multiforme. Methods Twenty-four patients were enrolled into the clinical trial, while 2 cases were excluded from the final analysis of results. The treatment protocol included aggressive tumor resection, fractionated radiotherapy up to a total dose of 60 Gy, and 3 concomitant courses of AFTV administered with an interval of one week at the late stage of irradiation. Two delayed-type hypersensitivity (DTH) tests were done—one 48 hours before the initial course of vaccination (DTH-1) and one 2 weeks after the third (DTH-2). All but one of the patients received salvage therapy at the time of tumor progression. The defined primary end point was overall survival; secondary end points were progression-free survival and safety of concomitant treatment. Results The median duration of overall survival was 19.8 months (95% CI 13.8–31.3 months). The actuarial 2-year survival rate was 40%. The median duration of progression-free survival was 7.6 months (95% CI 4.3–13.6 months). Overall survival showed a statistically significant association with recursive partitioning analysis class (p < 0.05); progression-free survival showed a statistically significant association with p53 staining index (p < 0.05) and size of DTH-2 response (p < 0.001). AFTV injection concomitant with fractionated radiotherapy was well tolerated by all patients and in no case did treatment-related adverse effects exceed Grade 1 toxicity; adverse effects were limited to local erythema, induration, and swelling at the site of injection. Conclusions The results of this study demonstrate that AFTV treatment concomitant with fractionated radiotherapy may be effective in patients with newly diagnosed glioblastoma. Further clinical testing is warranted.

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Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma

Journal of Neurosurgery ◽

10.3171/2014.5.jns132392 ◽

2014 ◽

Vol 121 (3) ◽

pp. 543-553 ◽

Cited By ~ 26

Author(s):

Eiichi Ishikawa ◽

Yoshihiro Muragaki ◽

Tetsuya Yamamoto ◽

Takashi Maruyama ◽

Koji Tsuboi ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Treatment Regimen ◽

Tumor Vaccine ◽

Delayed Type Hypersensitivity ◽

Karnofsky Performance Scale ◽

Newly Diagnosed ◽

Fractionated Radiotherapy ◽

Formalin Fixed ◽

Fixed Tumor

Object Temozolomide (TMZ) may enhance antitumor immunity in patients with glioblastoma multiforme (GBM). In this paper the authors report on a prospective Phase I/IIa clinical trial of fractionated radiotherapy (FRT) concomitant with TMZ therapy, followed by treatment with autologous formalin-fixed tumor vaccine (AFTV) and TMZ maintenance in patients with newly diagnosed GBM. Methods Twenty-four patients (age 16–75 years, Karnofsky Performance Scale score ≥ 60% before initiation of FRT) with newly diagnosed GBM received a total dose of 60 Gy of FRT with daily concurrent TMZ. After a 4-week interval, the patients received 3 AFTV injections and the first course of TMZ maintenance chemotherapy for 5 days, followed by multiple courses of TMZ for 5 days in each 28-day cycle. Results This treatment regimen was well tolerated by all patients. The percentage of patients with progression-free survival (PFS) ≥ 24 months was 33%. The median PFS, median overall survival (OS), and the actuarial 2- and 3-year survival rates of the 24 patients were 8.2 months, 22.2 months, 47%, and 38%, respectively. The median PFS in patients with a delayed-type hypersensitivity (DTH) response after the third AFTV injection (DTH-2) of 10 mm or larger surpassed the median length of follow-up for progression-free patients (29.5 months), which was significantly greater than the median PFS in patients with a smaller DTH-2 response. Conclusions The treatment regimen was well tolerated and resulted in favorable PFS and OS for newly diagnosed GBM patients. Clinical trial registration no.: UMIN000001426 (UMIN clinical trials registry, Japan).

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OS09.8 Randomized placebo-controlled trial of autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma

Neuro-Oncology ◽

10.1093/neuonc/nox036.067 ◽

2017 ◽

Vol 19 (suppl_3) ◽

pp. iii20-iii20 ◽

Cited By ~ 1

Author(s):

Y. Muragaki ◽

T. Maruyama ◽

E. Ishikawa ◽

M. Nitta ◽

S. Ikuta ◽

...

Keyword(s):

Tumor Vaccine ◽

Controlled Trial ◽

Newly Diagnosed ◽

Newly Diagnosed Glioblastoma ◽

Formalin Fixed ◽

Fixed Tumor

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ATIM-22. PLACEBO CONTROLLED DOUBLE BLIND PHASE IIB/III TRIAL OF AUTOLOGOUS FORMALIN-FIXED TUMOR VACCINE (AFTV-GBM) FOR NEWLY DIAGNOSED GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/now212.087 ◽

2016 ◽

Vol 18 (suppl_6) ◽

pp. vi22-vi22

Author(s):

Takashi Maruyama

Keyword(s):

Tumor Vaccine ◽

Newly Diagnosed ◽

Double Blind ◽

Newly Diagnosed Glioblastoma ◽

Formalin Fixed ◽

Fixed Tumor

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IMPS-23RETROSPECTIVE ANALYSIS CLINICAL RESULTS OF AUTOLOGOUS FORMALIN-FIXED TUMOR VACCINE FOR NEWLY DIAGNOSED GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/nov217.23 ◽

2015 ◽

Vol 17 (suppl 5) ◽

pp. v118.2-v118

Author(s):

Takashi Maruyama ◽

Yoshihiro Muragaki ◽

Masayuki Nitta ◽

Hiroshi Iseki ◽

Tadao Ohno ◽

...

Keyword(s):

Tumor Vaccine ◽

Clinical Results ◽

Newly Diagnosed ◽

Newly Diagnosed Glioblastoma ◽

Formalin Fixed ◽

Fixed Tumor

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Abstract CT062: A Phase I study of the safety and immunogenicity of personalized mutation-derived tumor vaccine and treatment fields in patients with newly diagnosed glioblastoma

10.1158/1538-7445.sabcs18-ct062 ◽

2019 ◽

Author(s):

Adilia Hormigo ◽

Alex Rubinsteyn ◽

Julia Kodysh ◽

Ana Blazquez ◽

Nina Bhardwaj

Keyword(s):

Phase I ◽

Phase I Study ◽

Tumor Vaccine ◽

Newly Diagnosed ◽

Newly Diagnosed Glioblastoma

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CTNI-38. PriCoTTF TRIAL: A PHASE I/II TRIAL OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.263 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi68-vi68

Author(s):

Sied Kebir ◽

Daniela Pierscianek ◽

Martin Proescholdt ◽

Peter Hau ◽

Anca-Ligia Grosu ◽

...

Keyword(s):

Phase I ◽

Survival Rates ◽

Progression Free Survival ◽

The Elderly ◽

Phase Iii ◽

Newly Diagnosed ◽

Safety And Efficacy ◽

Fractionated Radiotherapy ◽

Tumor Treating Fields ◽

Newly Diagnosed Glioblastoma

Abstract TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In the phase 3 EF-14 trial, survival rates were significantly improved when adding tumor-treating fields (TTFields) to adjuvant temozolomide-based chemotherapy in patients with newly diagnosed glioblastoma (nGBM). Preclinical studies showed that combination of TTFields and radiotherapy synergistically impaired glioblastoma cell growth. Here, we present the PriCoTTF trial, which is enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy. Following surgery and wound-healing, TTFields therapy is initiated in adult nGBM patients. TTFields therapy continues throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. During radiotherapy, the arrays - through which TTFields is delivered - remain on the patients’ scalp. Totally, thirty-three patients are planned to be enrolled in two treatment arms. In arm A, 20 patients receive normo-fractionated radiotherapy, whereas in the elderly arm, arm B, 13 patients receive hypo-fractionated radiotherapy. The primary endpoint of this trial is safety and tolerance that will be gauged by a set of pre-specified treatment-limiting toxicities. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. At the time of abstract submission, 9 patients enrolled in Arm B. Patient recruitment for arm A has been completed with. We will present initial practical experiences as well as preliminary safety and tolerance data. There is a biological rationale for combining TTFields and radiotherapy to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in nGBM will be assessed. In addition, initial efficacy data (phase II) may serve as a rationale for a putative randomized phase III trial.

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IMT-05 PHASE III RANDOMIZED CLINICAL TRIAL OF AFTV FOR NEWLY DIAGNOSED GLIOBLASTOMA

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.079 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii17-ii18

Author(s):

Masayuki Nitta ◽

Yoshihiro Muragaki ◽

Eiichi Ishikawa ◽

Takashi Maruyama ◽

Soko Ikuta ◽

...

Keyword(s):

Placebo Group ◽

Local Treatment ◽

Phase Iii ◽

Newly Diagnosed ◽

Total Removal ◽

Double Blind ◽

Significant Difference ◽

Newly Diagnosed Glioblastoma ◽

Formalin Fixed ◽

Fixed Tumor

Abstract BACKGROUND The highly fatal glioblastoma has an extremely poor prognosis and development of a new treatment is desired. Local treatment is limited due to its high invasiveness, and immunotherapy utilizing self-immune mechanism is theoretically expected. An autologous formalin-fixed tumor vaccine (AFTV) is a vaccine that is prepared using formalin-fixed tumor tissue and recognizes tumor antigen peptides to induce cytotoxic T cells. We have previously conducted three clinical trials using AFTV for patients with newly diagnosed glioblastoma since 2004. The third trial was a double-blind multicenter phase IIb/III trial with 63 case registries, which did not make a significant difference in OS (study group 25 months, placebo group 31 months), the total removal group showed excellent clinical results (3-year survival rate; 65%, median survival; not reached). Since the study was designed to go to Phase III if the test group was not inferior to the placebo group, so it went on to go to Phase III. METHODS Target patients will be 80 patients with newly diagnosed glioblastoma undergoing pathologic diagnosis, who have undergone total removal of contrast-enhanced lesions and receive standard chemoradiation therapy. STUDY DESIGN Double-blind, 3-year enrollment period, 18-month observation period. Stratification factor: Photodynamic therapy (PDT), facility, age, KPS. Administration method: After standard chemoradiotherapy, in parallel with maintenance chemotherapy, a total of 9 times intradermal administration of vaccine. Primary endpoint: PFS of FAS patients, Secondary endpoints: 18 months PFS of the FAS patient, OS, PFS of the ITT analysis target case. Based on the results of the IIb trial, we limited the registered patients with total tumor removal, and in view of the fact that the prognosis of patients with combined PDT and AFTV were excellent, PDT was added to the stratification factor. We outline our efforts and problems aimed at clinical approval of AFTV for glioblastoma.

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