Patient survival on the dose escalation phase of the Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG) clinical trial compared to historical controls.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 2061-2061 ◽  
Author(s):  
Annick Desjardins ◽  
John H. Sampson ◽  
Katherine B. Peters ◽  
Gordana Vlahovic ◽  
Dina Randazzo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Malignant Glioma ◽  
Dose Escalation ◽  
Patient Survival ◽  
Who Grade ◽  
Historical Controls

A phase 1, multicenter, open-label study of marizomib (MRZ) with temozolomide (TMZ) and radiotherapy (RT) in newly diagnosed WHO grade IV malignant glioma (glioblastoma, ndGBM): Dose-escalation results.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e14083-e14083 ◽  
Author(s):  
Daniela Annenelie Bota ◽  
Santosh Kesari ◽  
David Eric Piccioni ◽  
Dawit Gebremichael Aregawi ◽  
Patrick Roth ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Newly Diagnosed ◽  
Open Label ◽  
Who Grade ◽  
Open Label Study ◽  
Label Study

scholarly journals Phase 1, multicenter, open-label, dose-escalation, study of marizomib (MRZ) and bevacizumab (BEV) in WHO grade IV malignant glioma (G4 MG).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 2037-2037 ◽  
Author(s):  
Daniela Annenelie Bota ◽  
Annick Desjardins ◽  
Warren P. Mason ◽  
Howard Alan Fine ◽  
Steven D. Reich ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Who Grade ◽  
Label Dose

scholarly journals A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with IDH1-Mutated Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2474
Author(s):  
Mohammed Khurshed ◽  
Remco J. Molenaar ◽  
Myra E. van Linde ◽  
Ron A. Mathôt ◽  
Eduard A. Struys ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Intrahepatic Cholangiocarcinoma ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Idh1 Mutation ◽  
Resonance Spectroscopy ◽  
Isocitrate Dehydrogenase 1 ◽  
Who Grade ◽  
Phase Ib

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial.

scholarly journals RTID-05. INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF VORASIDENIB (AG-881) VS PLACEBO IN PATIENTS WITH RESIDUAL/RECURRENT GRADE II GLIOMA WITH AN ISOCITRATE DEHYDROGENASE 1/2 (IDH1/2) MUTATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii194-ii194
Author(s):  
Ingo Mellinghoff ◽  
Martin van den Bent ◽  
Jennifer Clarke ◽  
Elizabeth Maher ◽  
Katherine Peters ◽  
...  
Keyword(s):  
High Risk ◽  
Dose Escalation ◽  
Objective Response ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
High Risk Population ◽  
Low Grade ◽  
Who Grade ◽  
Free Survival ◽  
Grade Ii

Abstract BACKGROUND Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options are surgery followed by observation (“watch and wait”) for patients with lower risk for disease progression or postoperative chemoradiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 80% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate. Vorasidenib, an oral, potent, reversible, brain-penetrant pan-inhibitor of mIDH1/2, was evaluated in 76 patients with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at daily doses below 100 mg. Preliminary clinical activity was observed in non-enhancing glioma patients in both studies, with an objective response rate (ORR) of 18.2% and median progression-free survival of 31.4 months in the dose escalation study. METHODS Approximately 366 patients will be randomized 1:1 to vorasidenib (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria: age ≥ 12 years; grade II oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥ 1 surgery for glioma with most recent ≥ 1 year but ≤ 5 years before randomization, and no other anticancer therapy; Karnofsky performance status ≥ 80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the vorasidenib arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint: progression-free survival assessed by independent review. Secondary endpoints: safety and tolerability, tumor growth rate assessed by volume, ORR, overall survival, and quality of life. Clinical data will be reviewed regularly by an independent data monitoring committee. The study is currently enrolling patients in the US, with additional countries planned (NCT04164901).

scholarly journals Double-targeting CDCA8 and E2F1 inhibits the growth and migration of malignant glioma

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Xiaoxiong Wang ◽  
Heping Wang ◽  
Jiajun Xu ◽  
Xu Hou ◽  
Haoqiang Zhan ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Malignant Tumors ◽  
Disease Free Survival ◽  
High Grade Glioma ◽  
Poor Overall Survival ◽  
Survival Prognosis ◽  
Who Grade ◽  
And Migration

AbstractHigh-grade glioma is the most common and aggressive primary brain tumor in adults with poor therapeutic efficiency and survival prognosis. Cell division cycle associated 8 (CDCA8) has been well known as a cell cycle regulator and tumor promotor in various malignant tumors. However, its biological role in glioma still remains unclear. Our results showed that high level of CDCA8 was significantly correlated with advanced WHO grade and poor overall survival and disease-free survival prognosis. In vitro and in vivo investigations demonstrated that CDCA8 promoted the glioma malignancy by promoting cell proliferation, cell migration, and inhibiting cell apoptosis. Moreover, we found its synergetic biological protein—E2F1 by the gene microarray chip. In this study, we revealed that CDCA8 synergized with E2F1 facilitated the proliferation and migration of glioma. In conclusion, our study provides a novel promising therapeutic targets and prognostic biomarkers for malignant glioma treatment.

Dose-dependent interleukin-3 stimulation of thrombopoiesis and neutropoiesis in patients with small-cell lung carcinoma before and following chemotherapy: a placebo-controlled randomized phase Ib study.

1993 ◽  
Vol 11 (11) ◽  
pp. 2063-2071 ◽  
Author(s):  
V D'Hondt ◽  
P Weynants ◽  
Y Humblet ◽  
T Guillaume ◽  
J L Canon ◽  
...  
Keyword(s):  
Patient Survival ◽  
Survival Rates ◽  
Small Cell ◽  
World Health ◽  
Small Cell Lung ◽  
Who Grade ◽  
Cell Lung Carcinoma ◽  
Interleukin 3 ◽  
Platelet Counts ◽  
Dose Dependent

PURPOSE To evaluate the safety, tolerance, and hematologic effects of recombinant human interleukin-3 (IL-3) in patients with small-cell lung cancer (SCLC) before and following multiagent antineoplastic therapy in a placebo-controlled, randomized, double-blind study. PATIENTS AND METHODS Twenty-eight patients (22 men and six women; median age, 60 years) with previously untreated SCLC entered the study. Patients were assigned to six groups of escalating-dose IL-3 ranging from 0.25 to 10 micrograms/kg/d administered by continuous infusion for 7 days, with one patient in each group receiving placebo. After a 1-week interval, the first of three cycles of carboplatin, etoposide (VP16), and epirubicin (CVE) given every 3 weeks was administered. The second cycle of CVE was followed by 7 days of IL-3 administered at the same daily dose as administered during the first infusion. RESULTS The maximum-tolerated dose was not encountered in this study. Fever was the most frequently observed side effect. Before any chemotherapy, World Health Organization (WHO) grade II fever only appeared at doses > or = 2.5 micrograms/kg/d. Other side effects included rash, headache, and myalgia. During the first infusion of IL-3, before administration of chemotherapy, dose-dependent increases in peripheral-platelet counts (r = .613; P < .001) and neutrophil counts (r = .505; P = .007) were observed. Following the second cycle of CVE, recovery of peripheral platelet counts was faster as compared with the first cycle of CVE for patients treated with 7.5 and 10 micrograms/kg of IL-3 (P = .021). Chemotherapy postponements due to myelotoxicity were also less frequent following the second cycle of CVE as compared with the first for patients treated with > or = 2.5 micrograms/kg of IL-3 (P = .036). Compared with an age-matched historical group receiving identical chemotherapy (n = 191), administration of IL-3 did not modify either disease-free survival or overall patient survival rates. CONCLUSION IL-3 is well tolerated at doses up to 10 micrograms/kg/d. In the absence of chemotherapy, biologic effects on both neutrophils and platelets were seen at doses > or = 2.5 micrograms/kg/d. IL-3 infusion following the second cycle of CVE appears to reduce chemotherapy-induced myelosuppression, but does not alter tumor response or patient survival rates.

CTNI-01. A PHASE 1-2 CLINICAL TRIAL OF EO1001 (APL-122), A NOVEL IRREVERSIBLE PAN-ERBB INHIBITOR WITH PROMISING BRAIN PENETRATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi58-vi58
Author(s):  
Sophia Frentzas ◽  
Gary Richardson ◽  
Jeffrey Bacha ◽  
Sarath Kanekal ◽  
Neil Sankar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Escalation ◽  
Phase 1 ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Cns Metastases ◽  
Once Daily ◽  
Adult Participants ◽  
Xenograft Models ◽  
Cns Penetration

Abstract CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive crosstalk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models. We report on a first-in-human Phase 1-2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, with adequate bone marrow, renal and liver function are eligible. ESCALATION: One subject per dose cohort is enrolled in an accelerated dose-escalation design until drug-related toxicity (≥G2) is observed in the first cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Cycle 1: Patients receive a single oral dose of EO1001 on day 1; single-dose pharmacokinetics are measured. Beginning on day 8, EO1001 is administered once daily for 21 days; multi-dose pharmacokinetics are measured. Cycles 2-6: EO1001 is administered once daily in continuous 28-day cycles for up to 20 weeks. EXPANSION: EO1001 will be administered once daily to 20 patients at the MTD in continuous 28-day cycles for up to 6 cycles to determine a recommended Phase 2 dose (RP2D) for further study. Toxicity is assessed based on NCI CTCAEv5 and tumor response is assessed by RECIST 1.1. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.

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