scholarly journals CLRM-07. INCREASING EFFICIENCY IN EARLY PHASE MULTICENTER IMAGING BIOMARKER TRIALS: EMERGING STRATEGIES FROM THE GABLE (GLIOBLASTOMA ACCELERATED BIOMARKER LEARNING ENVIRONMENT) TRIAL

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv2-iv2
Author(s):  
Daniel Barboriak ◽  
Jon Steingrimsson ◽  
Constantine Gatsonis ◽  
David Schiff ◽  
Lawrence Kleinberg
Keyword(s):  
Learning Environment ◽  
Planning Process ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Multicenter Trial ◽  
Phase Iii ◽  
Imaging Biomarker ◽  
Imaging Biomarkers ◽  
Evaluation Strategy ◽  
Multicenter Trials

Abstract Validated biomarkers that more accurately predict prognosis and/or measure disease burden in patients with high-grade gliomas would help triage which treatment strategies are most promising for evaluation in Phase III multicenter trials. Multicenter trials to evaluate imaging biomarkers in this group face particular challenges; these trials have historically been slow to accrue and have not recently succeeded in validating new imaging biomarkers useful in treatment development. Due to variability in image acquisition protocols, scanner hardware, image analysis, and interpretive schemes, promising results obtained in single centers are poor predictors of success in the multicenter setting. Multicenter preliminary data to support further evaluation of imaging biomarkers is rarely available. The need for more efficient trial designs that bring multicenter data earlier into the process of biomarker development has become increasingly clear. In this presentation, the planning process within ECOG-ACRIN’s Brain Tumor Working Group for a platform multicenter trial called GABLE (Glioblastoma Accelerated Biomarker Learning Environment trial) designed to evaluate biomarkers for distinguishing pseudoprogression from true progression in patients with newly diagnosed GBM is described. In our planning process, it was determined that efficiencies can be gained from evaluating multiple biomarker types in parallel rather than serially; in the context of the proposed trial, not only conventional imaging biomarkers but plasma biomarkers and radiomic biomarkers can be evaluated simultaneously. Patient tolerance limits the feasibility of evaluating multiple non-standard-of-care imaging biomarkers in parallel. For this group of biomarkers, a “fast-switching” serial evaluation strategy using multiple interim analyses was developed to triage out biomarkers unlikely to succeed in identifying patient groups with clinically significant differences in median survival. For biomarker triage, an endpoint of event-free survival (events of either death or NANO progression) was proposed. Simulations were used to evaluate alpha and beta error using this evaluation strategy.

Use of First-Line PARP Inhibitors in Ovarian Cancer

2019 ◽  
pp. 26-29
Author(s):  
Ursula Hasler-Strub
Keyword(s):  
Ovarian Cancer ◽  
Treatment Strategies ◽  
Advanced Ovarian Cancer ◽  
Standard Of Care ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Line Treatment ◽  
Front Line ◽  
First Line ◽  
Platinum Based Chemotherapy

Platinum-based chemotherapy regimens are the mainstay of advanced ovarian cancer treatment. However, up to 85% of the patients experience recurrence under these settings. To fill this gap, novel front-line treatment strategies have been established, leading to unprecedented clinical benefits. For example, first-line bevacizumab, an anti-angiogenic agent, plus chemotherapy followed by bevacizumab maintenance, has emerged as a new standard of care for newly diagnosed high risk ovarian cancer patients. This was based on the results of the phase III GOG 0218 and ICON-7 trials. More recently, poly(ADP)-ribose polymerase (PARP) inhibitors, including niraparib, olaparib and veliparib, have offered a new treatment option as part of the front-line treatment in ovarian cancer. Here we provide an overview of three recent studies that may lead to a paradigm shift in the first-line treatment for advanced ovarian cancer.

ATALANTE-1 randomized phase III trial, OSE 2101 versus standard treatment as second- or third-line in HLA-A2 positive advanced non-small cell lung cancer (NSCLC) patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS9121-TPS9121 ◽  
Author(s):  
Enriqueta Felip ◽  
Giuseppe Giaccone ◽  
Rafal Dziadziuszko ◽  
Fabrice Denis ◽  
Teresa Moran ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Advanced Nsclc ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Phase Iii ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Third Line ◽  
Nsclc Patients

TPS9121 Background: New treatment strategies are needed for advanced NSCLC patients who progress on treatment with immune checkpoint inhibitors (ICI). Tedopi (OSE2101) is a neoepitope vaccine restricted to HLA-A2 positive patients (45%) targeting five tumor-associated antigens frequently expressed in lung cancer cells, ACE, HER2, MAGE2, MAGE3 and P53. Previously, in a phase II trial (Barve et al. JCO 2008), Tedopi showed a median overall survival (OS) of 17.3 months with a manageable safety profile in advanced NSCLC patients. ATALANTE-1 (NCT02654587) is a randomized, open-label, phase 3 study comparing the efficacy and safety of TEDOPI with standard of care (SoC) treatment in HLA-A2 positive patients with advanced NSCLC, as second- or third-line therapy. Methods: Patients with advanced NSCLC without EGFR-sensitizing mutations or ALK rearrangements; progressive disease to platinum-based chemotherapy (ChT) with sequential or concurrent ICI; HLA-A2 positivity (blood test); ECOG PS 0-1; with treated and asymptomatic brain metastases,, are randomized 2:1 to receive 5mg Tedopi subcutaneously Q3W for 6 cycles, then Q8W for the reminder of the year and finally Q12W, or SoC treatment with: docetaxel 75 mg/m2 Q3W or pemetrexed 500 mg/m2 Q3W (in non-squamous and pemetrexed-naïve patients). Treatment continues until progression, intolerable toxicity or consent withdrawal, in both arms. Patients are stratified by histology, best response to first line, and line rank of ICI. Tumor assessment is performed every 6 weeks (RECIST 1.1). Primary endpoint is OS. Secondary end points are PFS, ORR, DCR, and duration of response, quality of life and safety. This is a superiority study with a hazard ratio of 0.7, two-sided alpha 5% and power 80%, after 278 events are observed. An independent analysis (1year OS rate) is planned in the first 84 patients treated with Tedopi. Last trial review by the DMC in June 18 suggested that the trial continues as planned. Translational research will be performed evaluating pharmacodynamic markers of efficacy such as immunogenicity response against Tedopi vaccine neoantigens, as well as parameters in liquid and tissue biopsies. End January 19, 87 patients (51 Tedopi, 36 Soc) have been enrolled. Clinical trial information: NCT02654587.

A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5103-TPS5103
Author(s):  
Marit Ahrens ◽  
Bernard Escudier ◽  
Ekaterini Boleti ◽  
Marc-Oliver Grimm ◽  
Marine Gross-Goupil ◽  
...  
Keyword(s):  
Phase Ii ◽  
Renal Cell ◽  
Clear Cell ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Phase Iii ◽  
Fixed Dose ◽  
Cell Renal Cell Carcinoma ◽  
Randomized Phase Ii ◽  
Prior Systemic Therapy

TPS5103 Background: Non-clear cell renal cell carcinomas (nccRCC) are a heterogeneous group of tumors accounting for approximately 25% of RCC patients (pts.). Since most clinical trials focus on clear-cell RCC (ccRCC) only, data on treatment strategies for nccRCC are limited. The combination of Nivolumab and Ipilimumab (IO/IO) has recently been approved for treatment in RCC showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) in intermediate and high-risk pts. compared to sunitinib in a phase-III trial. Furthermore retrospective analysis in nccRCC patients have shown promising results for IO/IO as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky > 70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ~306 pts. stratified for papillary or non-papillary non-clear cell histology and by the International Metastatic RCC Database Consortium (IMDC) risk score. Pts. will be randomized 1:1 to either i) Nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by Nivolumab fixed dose 240mg IV every 2 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 122 patients (78 pts with papillary, 37 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423 .

scholarly journals NIMG-17. VALIDATION OF DIFFUSION MRI AS AN IMAGING BIOMARKER FOR BEVACIZUMAB THERAPY IN RECURRENT GLIOBLASTOMA IN A RANDOMIZED PHASE III TRIAL OF BEVACIZUMAB WITH OR WITHOUT VB-111 (GLOBE)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii150-ii150
Author(s):  
Benjamin Ellingson ◽  
Timothy Cloughesy ◽  
Chencai Wang ◽  
Kunal Patel ◽  
Catalina Raymond ◽  
...  
Keyword(s):  
Diffusion Mri ◽  
Tumor Volume ◽  
Univariate Analysis ◽  
Gaussian Model ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Imaging Biomarker ◽  
Imaging Biomarkers ◽  
Phase Ii Trials ◽  
Anti Vegf

Abstract BACKGROUND Evidence from independent single center as well as multicenter phase II trials have suggested diffusion MRI is a strong predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF monotherapy, but not systemic chemotherapies or combination therapies with anti-VEGF agents. The current study builds on this body of evidence by evaluating these diffusion MR phenotypes in a large randomized phase III clinical trial. METHODS Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus bevacizumab in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pre-treatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 um2/ms) or low (< 1.24 um2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor. RESULTS Baseline tumor volume (P=0.3460) and ADCL (P=0.2143) did not differ between treatment arms. Univariate analysis showed that patients with high ADCL had a significant survival advantage when pooling all patients (P=0.0006), as well as when examining the BV (P=0.0159) and BV+VB-111 individually (P=0.0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume and ADCL identified continuous measures of tumor volume (P< 0.0001; HR=1.0212) and ADCL phenotypes (P=0.0012; HR=0.5574) as independent predictors of OS. CONCLUSION Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111. Since ADCL was predictive of OS in combination BV+VB-111, results support the working hypothesis that co-administration of VB-111 with BV may block any VB-111 anti-tumor effect, whereas VB-111 monotherapy or priming may result in higher efficacy of VB-111.

Equivalence Randomized Trial to Compare Treatment on the Basis of Sentinel Node Biopsy Versus Neck Node Dissection in Operable T1-T2N0 Oral and Oropharyngeal Cancer

2020 ◽  
Vol 38 (34) ◽  
pp. 4010-4018 ◽  
Author(s):  
Renaud Garrel ◽  
Gilles Poissonnet ◽  
Antoine Moyà Plana ◽  
Nicolas Fakhry ◽  
Gilles Dolivet ◽  
...  
Keyword(s):  
Sentinel Node ◽  
Hospital Stay ◽  
Standard Of Care ◽  
Multicenter Trial ◽  
Phase Iii ◽  
Node Dissection ◽  
Neck Node ◽  
Neck Lymph Node ◽  
Median Hospital Stay ◽  
Oral And Oropharyngeal Cancer

PURPOSE Sentinel node (SN) biopsy is accurate in operable oral and oropharyngeal cT1-T2N0 cancer (OC), but, to our knowledge, the oncologic equivalence of SN biopsy and neck lymph node dissection (ND; standard treatment) has never been evaluated. METHODS In this phase III multicenter trial, 307 patients with OC were randomly assigned to (1) the ND arm or (2) the SN arm (experimental arm: biopsy alone if negative, or followed by ND if positive, during primary tumor surgery). The primary outcome was neck node recurrence-free survival (RFS) at 2 years. Secondary outcomes were 5-year neck node RFS, 2- and 5-year disease-specific survival (DSS), and overall survival (OS). Other outcomes were hospital stay length, neck and shoulder morbidity, and number of physiotherapy prescriptions during the 2 years after surgery. RESULTS Data on 279 patients (139 ND and 140 SN) could be analyzed. Neck node RFS was 89.6% (95% CI, 0.83% to 0.94%) at 2 years in the ND arm and 90.7% (95% CI, 0.84% to 0.95%) in the SN arm, confirming the equivalence with P < .01. The 5-year RFS and the 2- and 5-year DSS and OS were not significantly different between arms. The median hospital stay length was 8 days in the ND arm and 7 days in the SN arm ( P < .01). The functional outcomes were significantly worse in the ND arm until 6 months after surgery. CONCLUSION This study demonstrated the oncologic equivalence of the SN and ND approaches, with lower morbidity in the SN arm during the first 6 months after surgery, thus establishing SN as the standard of care in OC.

scholarly journals P14.124 EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with standard temozolomide-based radiochemotherapy versus standard temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii98-iii98 ◽  
Author(s):  
P Roth ◽  
J Reijneveld ◽  
T Gorlia ◽  
F Dhermain ◽  
F De Vos ◽  
...  
Keyword(s):  
Performance Status ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Primary Objective ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Open Label ◽  
Newly Diagnosed Glioblastoma

Abstract BACKGROUND The standard of care for patients with newly diagnosed glioblastoma includes maximal debulking surgery followed by radiotherapy (RT), and concomitant as well as maintenance therapy with the alkylating agent, temozolomide (TMZ). However, the prognosis remains poor and novel treatment strategies are urgently needed. Targeting the proteasome has been considered a promising anti-cancer approach for several years. Marizomib is a novel, irreversible and pan-proteasome inhibitor, which crosses the blood-brain barrier and has been assessed in phase I trials in patients with newly diagnosed or recurrent glioblastoma. MATERIAL AND METHODS EORTC 1709/CCTG CE.8 is a randomized, controlled, open label phase III superiority trial. Patients with histologically confirmed newly diagnosed glioblastoma and a performance status >70 are eligible. Patients are randomized in a 1:1 ratio to receive standard of care (TMZ/RT→TMZ) alone or TMZ/RT→TMZ plus marizomib. The study aims at enrolling 750 patients. Stratification factors include study site, age, performance status and extent of resection. The primary objective of this trial is to compare overall survival in patients receiving marizomib in addition to standard of care with those receiving standard treatment only. The testing strategy specifies the determination of this objective in the intent-to-treat population as well as the subgroup of patients with MGMT-unmethylated tumors. Secondary endpoints include progression-free survival, safety, neurocognitive function and quality of life. A translational research program has been set up. The study will be activated at approximately 50 EORTC sites across Europe, 25 sites in Canada and additional sites in the US. Patient recruitment started in June 2018 and as of April 29, 2019, a total of 164 patients have been randomized. An update on the enrolment status will be provided at the EANO meeting. ClinicalTrials.gov Identifier: NCT03345095

scholarly journals Validation of diffusion MRI as a biomarker for efficacy using randomized phase III trial of bevacizumab with or without VB-111 in recurrent glioblastoma

2021 ◽  
Author(s):  
Benjamin M Ellingson ◽  
Kunal Patel ◽  
Chencai Wang ◽  
Catalina Raymond ◽  
Andrew Brenner ◽  
...  
Keyword(s):  
Diffusion Mri ◽  
Tumor Volume ◽  
Cox Regression ◽  
Controlled Trial ◽  
Univariate Analysis ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Imaging Biomarker ◽  
Imaging Biomarkers ◽  
Phase Ii Trials

Abstract Background Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial. Methods Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pre-treatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (&gt;1.24 um 2/ms) or low (&lt; 1.24 um 2/ms) ADCL, the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor. Results Baseline tumor volume (P=0.3460) and ADCL (P=0.2143) did not differ between treatment arms. Univariate analysis showed patients with high ADCL had a significant survival advantage in all patients (P=0.0006), as well as BV (P=0.0159) and BV+VB-111 individually (P=0.0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume and ADCL identified continuous measures of tumor volume (P&lt;0.0001; HR=1.0212) and ADCL phenotypes (P=0.0012; HR=0.5574) as independent predictors of OS. Conclusion Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111.

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