AT-51 * PHASE I STUDY OF PANOBINOSTAT AND FRACTIONATED STEREOTACTIC RE-IRRADIATION THERAPY (FSRT) FOR RECURRENT HIGH GRADE GLIOMAS

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

Download Full-text

A phase I study of temozolomide and lapatinib combination in patients with recurrent high-grade gliomas

Journal of Neurology ◽

10.1007/s00415-012-6812-z ◽

2013 ◽

Vol 260 (6) ◽

pp. 1469-1480 ◽

Cited By ~ 16

Author(s):

Vasilios Karavasilis ◽

Vassiliki Kotoula ◽

George Pentheroudakis ◽

Despina Televantou ◽

Sofia Lambaki ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

High Grade ◽

High Grade Gliomas

Download Full-text

ACTR-67. A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN (ONIVYDE) USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS: RESULTS THUS FAR

Neuro-Oncology ◽

10.1093/neuonc/noy148.097 ◽

2018 ◽

Vol 20 (suppl_6) ◽

pp. vi26-vi27 ◽

Cited By ~ 1

Author(s):

Karishma Kumar ◽

Susan Chang ◽

Nancy Ann Oberheim-Bush ◽

Jennifer Clarke ◽

Jennie Taylor ◽

...

Keyword(s):

Phase I ◽

Real Time ◽

Phase I Study ◽

High Grade ◽

Convection Enhanced Delivery ◽

Real Time Imaging ◽

High Grade Gliomas ◽

Liposomal Irinotecan

Download Full-text

Phase I trial of panobinostat and fractionated stereotactic re-irradiation therapy for recurrent high grade gliomas

Journal of Neuro-Oncology ◽

10.1007/s11060-016-2059-3 ◽

2016 ◽

Vol 127 (3) ◽

pp. 535-539 ◽

Cited By ~ 16

Author(s):

Wenyin Shi ◽

Joshua D. Palmer ◽

Maria Werner-Wasik ◽

David W. Andrews ◽

James J. Evans ◽

...

Keyword(s):

Phase I ◽

Phase I Trial ◽

High Grade ◽

Irradiation Therapy ◽

High Grade Gliomas

Download Full-text

Sequential therapy with the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas: An Adult Brain Tumor Consortium phase I study (ABTC1101).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.tps2105 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. TPS2105-TPS2105 ◽

Cited By ~ 2

Author(s):

Matthias Holdhoff ◽

Stuart A. Grossman ◽

Jeffrey G. Supko ◽

Xiaobu Ye ◽

Joy D. Fisher ◽

...

Keyword(s):

Phase I ◽

Calcium Channel ◽

Calcium Channel Blocker ◽

Phase I Study ◽

Channel Blocker ◽

Standard Dose ◽

S Phase ◽

Adult Brain ◽

High Grade ◽

High Grade Gliomas

TPS2105 Background: Despite recent advances in their treatment, high-grade gliomas (HGG) carry a dismal prognosis. Treatment options at recurrence are particularly limited and a re-challenge with temozolomide (TMZ) frequently appears as the most appropriate systemic treatment option in patients whose progression occurred off TMZ. This study investigates the sequential treatment of mibefradil (MIB), a selective Cav3 calcium channel blocker, and standard dose TMZ. Preclinical data showed that Cav3 inhibitors such as MIB can slow tumor growth without significant effect on normal tissues and can induce cell cycle arrest in cancer cells at the G1/S-phase checkpoint. We hypothesize that withdrawal of MIB could synchronize and release cells into S-phase, thereby potentiating the cytotoxic effect of TMZ. Methods: This trial is an open-label, multicenter phase I study, structured into a dose escalation phase to determine the maximum tolerated dose of MIB (MTD; Primary Objective) and an expansion cohort of 10 patients at the MTD level. Adults with recurrent HGG (WHO grade 3 or 4) who have previously received standard adjuvant therapy with radiation (RT) and TMZ (last dose ≥ 3 months prior to enrollment) and who have not received other cytotoxic therapy (except for carmustine wafers) are eligible. Patients receive oral MIB for 7 days on a 4 x/day (QID) schedule, followed by standard dose TMZ at 150-200 mg/m2 for 5 days each 28-day cycle. Dose finding uses a modified 3+3 design, starting at MIB 25 mg po QID (100 mg/day) with dose increases of 25 mg/dose per dose level. The target dose-limiting toxicity (DLT) rate is ≤ 33%. Secondary Objectives: (1) safety and adverse event analysis (incl. cardiac monitoring during cycle 1), (2) pharmacokinetic profile of MIB, (3) response assessment (RANO criteria), and (4) assessment of the potential effect of MIB on tumor DNA synthesis as determined by fluorothymidine positron emission tomography (FLT PET; extension cohort). Enrollment status as of January 2013: cohort 1 completed without DLT; cohort 2 enrolling at MIB 200 mg/day. Clinical trial information: NCT01480050.

Download Full-text

A phase I study of 2-hydroxyoleic acid (2-OHOA), a novel sphingomyelin synthase activator in patients (pt) with advanced solid tumors (AST) including refractory high grade gliomas/glioblastomas (GBM): Updated results of the expansion.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e14086 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e14086-e14086

Author(s):

Mariane Sousa Fontes ◽

Nikolaos Diamantis ◽

Niamh Coleman ◽

Nina Tunariu ◽

L Rhoda Molife ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase I Study ◽

High Grade ◽

Advanced Solid Tumors ◽

Sphingomyelin Synthase ◽

High Grade Gliomas

Download Full-text

Phase I study of erlotinib administered concurrently with and after irradiation (RT) in the treatment of children, adolescents, and young adults with newly diagnosed intracerebral high-grade glioma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.9553 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 9553-9553

Author(s):

A. Broniscer ◽

S. J. Baker ◽

T. E. Merchant ◽

F. H. Laningham ◽

M. Kocak ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

High Grade Glioma ◽

Maximum Tolerated Dose ◽

Exclusion Criterion ◽

Pharmacokinetic Studies ◽

High Grade ◽

Newly Diagnosed ◽

High Grade Gliomas ◽

Grade 3

9553 Background: High-grade gliomas are uncommon neoplasms in childhood that portend a poor prognosis. Because of the promising activity of erlotinib in adults with high-grade glioma, we conducted this Phase I study to determine the maximum tolerated dose and dose limiting toxicity (DLT) of erlotinib administered concurrently with and after RT. Methods: Patients between 3 and 25 years of age with newly diagnosed high-grade glioma received erlotinib continuously once daily during and after RT for a maximum of 52 weeks. Pharmacokinetic studies of erlotinib and its metabolite OSI-420, and genotyping were performed during course 1 in consenting patients. Use of enzyme-inducing anticonvulsants was an exclusion criterion. Dose escalation followed a typical Phase I design (dosage levels of 70, 90, and 120 mg/m2 per day). The DLT-evaluation period comprised the first 8 weeks of erlotinib. Results: Seventeen patients (median age 10.4 yrs; 10 males) were enrolled. Diagnoses consisted of glioblastoma (n=9), anaplastic astrocytoma (n=4), and other high-grade gliomas (n=4). Two of seven patients experienced reversible grade 3 hypokalemia / hypophosphatemia at the 70 mg/m2 level. Once electrolyte abnormalities were excluded as DLT, only one of seven patients at the 120 mg/m2 level has experienced grade 3 diarrhea so far. Pharmacokinetic studies were obtained in 14/17 patients. At the 70 mg/m2 dosage level, the median (range) erlotinib and OSI-420 Cmax and Tmax were 1,405 ng/ml (937–2,180) and 4.1 hr (2.2–8.2) and 158.5 ng/ml (45–203) and 4.1 hr (2.2–7.9), respectively. Three patients have received erlotinib for more than 1 year with disease stabilization. Six patients have already experienced disease progression. Conclusions: Erlotinib administered concurrently with RT on this schedule has been well tolerated. Preliminary pharmacokinetic results are comparable to those observed in adults. Rather than continue to escalate erlotinib dosages, we plan to complete this study and open a phase II study of erlotinib and RT for this same patient population. No significant financial relationships to disclose.

Download Full-text