ACTR-22. RESULTS OF PHASE I OF THE PARADIGM TRIAL: A PHASE I DOSE ESCALATION STUDY OF OLAPARIB IN COMBINATION WITH SHORT COURSE RADIOTHERAPY IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)

Abstract Background The current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy with temozolomide. In recent studies, 40 Gy in 15 fractions vs. 60 Gy in 30 fractions, 34 Gy in 10 fractions vs. 60 Gy in 30 fractions, and 40 Gy in 15 fractions vs. 25 Gy in 5 fractions have been reported as non-inferior. The addition of temozolomide increased the survival benefit of radiotherapy with 40 Gy in 15 fractions. However, the optimal regimen for radiotherapy plus concomitant temozolomide remains unresolved. Methods This multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant (150 mg/m2/day, 5 days) and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant (75 mg/m2/day, every day from first to last day of radiation) and adjuvant temozolomide in terms of overall survival (OS) in elderly patients with newly diagnosed glioblastoma. A total of 270 patients will be accrued from 51 Japanese institutions in 4 years and follow-up will last 2 years. Patients 71 years of age or older, or 71–75 years old with resection of less than 90% of the contrast-enhanced region, will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, and proportion of health-related quality of life preservation. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in April 2020. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in August 2020. Discussion If the primary endpoint is met, short-course radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma. Trial registration Registry number: jRCTs031200099. Date of Registration: 27/Aug/2020. Date of First Participant Enrollment: 4/Sep/2020.

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A Phase I Dose Escalation Study of IMRT Field-in-field Boost for Newly Diagnosed Glioblastoma Multiforme (GBM)

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2008.06.694 ◽

2008 ◽

Vol 72 (1) ◽

pp. S227

Author(s):

A.M. Monjazeb ◽

J.D. Bourland ◽

L.D. Case ◽

T.L. Ellis ◽

G.J. Lesser ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Phase I ◽

Dose Escalation ◽

Newly Diagnosed ◽

Dose Escalation Study ◽

Newly Diagnosed Glioblastoma

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Phase I dose escalation study of pemetrexed and concurrent thoracic radiation in elderly patients with non-squamous non–small-cell lung cancer

Journal of Radiation Research ◽

10.1093/jrr/rry058 ◽

2018 ◽

Vol 60 (2) ◽

pp. 228-233

Author(s):

Kyoichi Kaira ◽

Akihiro Ono ◽

Yosuke Kamide ◽

Noriaki Sunaga ◽

Yasuhiko Koga ◽

...

Keyword(s):

Lung Cancer ◽

Elderly Patients ◽

Phase I ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Dose Escalation ◽

Small Cell ◽

Small Cell Lung ◽

Dose Escalation Study ◽

Thoracic Radiation

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Phase 1 TITE-CRM Dose Escalation Study of Concurrent Temozolomide and Intensity Modulated Radiation Therapy in Newly Diagnosed Glioblastoma Multiforme

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2009.07.298 ◽

2009 ◽

Vol 75 (3) ◽

pp. S124 ◽

Cited By ~ 1

Author(s):

D.R. Brown ◽

D. Normolle ◽

L.R. Junck ◽

T.S. Lawrence ◽

J.A. Heth ◽

...

Keyword(s):

Radiation Therapy ◽

Glioblastoma Multiforme ◽

Dose Escalation ◽

Phase 1 ◽

Intensity Modulated Radiation Therapy ◽

Newly Diagnosed ◽

Dose Escalation Study ◽

Intensity Modulated ◽

Newly Diagnosed Glioblastoma

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Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma (INTRAGO): An Open-Label, Dose-Escalation Phase I/II Trial

Neurosurgery ◽

10.1093/neuros/nyy018 ◽

2018 ◽

Vol 84 (1) ◽

pp. 41-49 ◽

Cited By ~ 10

Author(s):

Frank A Giordano ◽

Stefanie Brehmer ◽

Bettina Mürle ◽

Grit Welzel ◽

Elena Sperk ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Intraoperative Radiotherapy ◽

Newly Diagnosed ◽

Open Label ◽

Label Dose ◽

Newly Diagnosed Glioblastoma

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A Multicenter Phase I/II Dose Escalation Study of Lenalidomide in Combination with Melphalan and Dexamethasone in Subjects with Newly-Diagnosed Light-Chain (AL)-Amyloidosis.

Blood ◽

10.1182/blood.v112.11.1732.1732 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1732-1732

Author(s):

Philippe Moreau ◽

Arnaud Jaccard ◽

Lotfi Benboubker ◽

Bruno Royer ◽

Valerie Coiteux ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Response Rate ◽

Standard Dose ◽

High Dose ◽

Al Amyloidosis ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Open Label ◽

Dose Escalation Study

Abstract A recent prospective randomized trial comparing standard-dose to high-dose melphalan in patients presenting with newly diagnosed AL-amyloidosis showed that oral melphalan-dexamethasone (M-dex) given monthly could be considered the current standard of care, with a median survival of 56 months (Jaccard, N Engl J Med 2007). The use of a combination of lenalidomide and dexamethasone has also been tested in patients with symptomatic AL-amyloidosis. The initial dose of lenalidomide at 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide (M-dex-rev) could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1–4 of each 28 day cycle and dexamethasone 40mg/day from day 1– 4 of each 28 day cycle, 3 cohorts of 3 subjects were successively exposed to escalating doses of lenalidomide (5, 10 and 15mg once daily on days 1–21 of a 28 day cycle). DLT was defined using National Cancer Institute (NCI) common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. No DLT was observed among the first 3 patients treated at 5, 10 and 15 mg lenalidomide/day. 9 additional subjects will be enrolled at 15 mg/day to better define the safety profile and estimate the hematologic and organ response rate. Final results regarding both toxicity and efficacy will be presented during the meeting.

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A phase II study of dasatinib therapy in children and adolescents with newly diagnosed chronic phase chronic myelogenous leukemia (CML-CP) or Philadelphia chromosome-positive (Ph+) leukemias resistant or intolerant to imatinib.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.tps9594 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. TPS9594-TPS9594

Author(s):

Michel Zwaan ◽

Linda C. Stork ◽

Yves Bertrand ◽

Lia Gore ◽

Nobuko Hijiya ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Dose Escalation ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Newly Diagnosed ◽

Dose Escalation Study

TPS9594 Background: Dasatinib is a BCR-ABL inhibitor approved for treatment in adult patients (pts) with newly diagnosed Ph+ CML-CP; CML resistant/intolerant to prior therapy, including imatinib; and Ph+ acute lymphoblastic leukemia (ALL). There are no established dasatinib treatment regimens for children/adolescents with relapsed/refractory leukemia, but pediatric trials are underway. A phase I dose-escalation study of dasatinib in pediatric pts with refractory solid tumors (n=28) and imatinib-refractory, Ph+ leukemia (n=11) reported a maximum tolerated dose of 85 mg/m2 twice daily in solid-tumor pts and at least a partial cytogenetic response (CyR) in all evaluable CML pts (n=9) (Aplenc, J Clin Oncol 2011). Preliminary results from a phase I dose-escalation study in pediatric pts with subtypes of relapsed/refractory leukemia (NCT00306202) indicate that dasatinib was well tolerated up to 120 mg/m2 (Zwaan, Blood 2010 [abstr 2265]). Further study of dasatinib in pediatric pts is warranted. Methods: To evaluate the safety and efficacy of dasatinib monotherapy in children/adolescents with newly diagnosed CML-CP or Ph+ leukemias resistant/intolerant to imatinib, a phase II nonrandomized, global study of dasatinib in pts birth to <18 y is ongoing (NCT00777036): Cohort 1 (C1), Ph+ CML-CP pts resistant/intolerant to imatinib; Cohort 2 (C2), Ph+ ALL, accelerated or blast phase CML pts resistant/intolerant to or relapsed after imatinib therapy; or Cohort 3 (C3), newly diagnosed, treatment-naïve Ph+ CML-CP pts. Treatments are once daily with dasatinib 60 mg/m2 (C1/C3) or 80 mg/m2 (C2) for ≥24 months. Primary endpoints are major CyR (C1), complete hematologic response (C2), and complete CyR (C3). Secondary endpoints include safety, tolerability, best response, time to/duration of response, survival, and molecular response rates. BCR-ABL mutations are evaluated. First patient first visit was March 2009; estimated trial completion is September 2016. As of January 2012, 63 pts (n=27 aged <12 y; n=36 aged ≥12 y) have been treated in C1/C2 (n=41) and C3 (n=22). Enrollment is ongoing at 79 sites.

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A phase III randomized controlled trial of short-course radiotherapy with or without concomitant and adjuvant temozolomide in elderly patients with glioblastoma (CCTG CE.6, EORTC 26062-22061, TROG 08.02, NCT00482677).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.18_suppl.lba2 ◽

2016 ◽

Vol 34 (18_suppl) ◽

pp. LBA2-LBA2 ◽

Cited By ~ 21

Author(s):

James R. Perry ◽

Normand Laperriere ◽

Christopher J. O'Callaghan ◽

Alba Ariela Brandes ◽

Johan Menten ◽

...

Keyword(s):

Clinical Trial ◽

Controlled Trial ◽

Phase Iii ◽

Newly Diagnosed ◽

Adjuvant Temozolomide ◽

Short Course ◽

Newly Diagnosed Glioblastoma ◽

To Receive ◽

Short Course Radiotherapy ◽

Clinical Trial Information

LBA2 Background: The EORTC (26981-22981)/NCIC CTG (CE.3) RCT in newly diagnosed glioblastoma (GB) showed increased overall survival (OS) with concomitant and adjuvant temozolomide (TMZ) added to radiotherapy (RT). Pts were 18-71 (median 56) years; however, a trend of decreasing benefit from the addition of TMZ with increasing age was noted. Recent RCTs in elderly GB detected non-inferiority of 40 Gy/15 v 60 Gy/30 RT and superior survival was noted for MGMT-methylated pts treated with TMZ alone. However, whether the addition of TMZ to RT improves survival in elderly pts remained unanswered. Methods: We conducted a global randomized phase III clinical trial for patients ≥ 65 yrs with histologically confirmed newly diagnosed GB, ECOG 0-2, randomized 1:1 to receive 40Gy/15 RT v 40Gy/15 RT with 3 weeks of concomitant TMZ plus monthly adjuvant TMZ until progression or 12 cycles. Stratification was by centre, age (65-70, 71-75, or 76+), ECOG 0,1 vs 2, and biopsy vs resection. Results: 562 pts were randomized, 281 on each arm; median age 73 yrs (range 65-90), male 61%, PS 0/1 77%, resection 68%. RT+TMZ significantly improved OS over RT alone (median 9.3m v 7.6m, HR 0.67, 95%CI 0.56-0.80, p < 0.0001) and significantly improved PFS (median 5.3m v 3.9m, HR 0.50, 95%CI 0.41 – 0.60, p < 0.0001). Tissue from 462 pts was provided and adequate for MGMT analysis in 354 to date. In MGMT methylated patients (n = 165) OS for RT+TMZ v RT was 13.5 m and 7.7m respectively (HR: 0.53 (95% C.I. 0.38, 0.73, p = 0.0001). In MGMT unmethylated patients (n = 189) OS for RT + TMZ v RT was 10.0m vs 7.9m respectively (HR 0.75 (95% C.I. 0.56 – 1.01, p = 0.055). QoL analyses showed no differences in functional domains of QLQC30 and BN20 but were worse in the RT/TMZ arm for nausea, vomiting, and constipation. Systemic therapy after PD was reported in 39% on RT+TMZ v 41% on RT. Conclusions: The addition of concomitant and adjuvant TMZ to hypofractionated RT for elderly pts with GB significantly improves OS and PFS in all patients and is well tolerated. Patients with MGMT methylated tumors benefit the most from the addition of TMZ to RT where median OS is nearly doubled. Clinical trial information: NCT00482677.

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