Abstract 5759
Background
Treatment of glioblastoma (GBM) xenografts with chloroquine (CQ) has been shown to inhibit autophagy, thereby reducing the hypoxic fraction and sensitizing tumours to radiation. Preclinical evidence shows that EGFRvIII+ GBM may benefit most from CQ because of autophagy dependency. This study explores the safety, pharmacokinetics and maximum tolerated dose (MTD) of CQ in combination with radiotherapy (RT) and concurrent daily temozolomide (TMZ) in patients with a newly diagnosed GBM.
Methods
This study is a single-centre, open label, dose-finding phase I trial (3 + 3 design). Patients received oral CQ once daily one week before the course of concurrent chemoradiation (TMZ 75 mg/m2/day) until the end of RT. Toxicity was scored according to the CTCAE 4.0. Molecular markers were identified on paraffin embedded tissue.
Results
Thirteen patients were included in the study (n = 6:200mg, n = 3:300mg, n = 4:400mg CQ). Tumour characteristics: 7/13 MGMT promotor hypermethylation, 12/13 IDH wildtype, 0/13 1p/19q co-deletion and 7/13 EGFRvIII expression. A total of 44 adverse events possibly/likely related to CQ were registered. Serious adverse events are presented in Table. In the 400mg cohort 2 patients developed ECG QTc prolongation and 1 patient developed irreversible blurred vision. Three patients developed grade III nausea/vomiting (n = 2 300mg, n = 1 200mg) resulting in cessation of TMZ or delay of adjuvant TMZ cycles. Median overall survival is 8,1 months for EGFRvIII – and 13,4 months for EGFRvIII + patients; with 7 patients currently still alive at a median follow-up of 9 months (range 2 – 21).Table: 425P
Serious adverse events grade I - V - Adverse events possibly/likely related to chloroquine are presented with an *.
Toxicity | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 |
---|---|---|---|---|---|
Blurred Vision* | 1 | ||||
Confusion | 1 | ||||
Electrocardiogram (ECG) QT corrected interval prolonged* | 1 | 1 | |||
Fall (trauma capitis)* | 1 | ||||
Hypercalcemia | 1 | ||||
Nausea/vomiting* | 3 | 3 | |||
Seizure | 1 | ||||
Thromboembolic event | 1 | 1 |
Conclusions
A daily dose of 200mg CQ was established as the MTD when combined with RT and concurrent TMZ for newly diagnosed GBM. Favorable tolerability and extensive pre-clinical evidence on anti-tumour activity support further clinical phase II and III studies.
Clinical trial identification
The study was approved by the Medical Review Ethics Committee Maastricht UMC+: #NL52723.068.15/METC153051. (NCT02378532).
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Stichting StopHersentumoren.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
4883 - A New Population Model Validated Pharmacokinetic Similarity of HLX01 and Rituximab in B-Cell Lymphoma
Presenter: Yuankai Shi
Session: Poster Display session 1
Resources:
Abstract
4908 - Efficacy of salvage therapy in the treatment of Helicobacter pylori-positive gastric low-grade mucosa-associated lymphoid tissue lymphoma
Presenter: Sung-Nam Lim
Session: Poster Display session 1
Resources:
Abstract
2360 - Mutational analysis of extranodal marginal zone lymphoma using next generation sequencing
Presenter: Seok Jae Huh
Session: Poster Display session 1
Resources:
Abstract
2430 - Clinical features, treatment and outcomes of colon and rectum mucosa-associated lymphoid tissue (MALT) lymphoma: Literature reviews published in English between 1993 and 2017
Presenter: Jeong Yeon Kim
Session: Poster Display session 1
Resources:
Abstract
4654 - Splenic marginal zone lymphoma: clinical characteristics and prognostic factors in a series of 52 patients
Presenter: Guldane Cengiz Seval
Session: Poster Display session 1
Resources:
Abstract
1732 - Safety and efficacy of Bendamustine and Rituximab (BR) regimen in Indian Chronic Lymphocytic Leukemia patients
Presenter: Ajay Gogia
Session: Poster Display session 1
Resources:
Abstract
5784 - N-terminal B-type natriuretic peptide (NT-proBNP) as an independed prognostic marker for patients with newly diagnosed multiple myeloma complicated by dialysis-dependent renal failure
Presenter: Sergey Semochkin
Session: Poster Display session 1
Resources:
Abstract
836 - The first-line effect of Bortezomib-based Therapy on Clinical Outcomes for Taiwanese Patients with multiple myeloma
Presenter: Ching-Liang Ho
Session: Poster Display session 1
Resources:
Abstract
2085 - Impact of Donor Lymphocyte Infusion in Relapsing Myeloid Neoplasms Post Allogeneic Hematopoietic Stem Cell Transplantation
Presenter: Hanafy Hafez
Session: Poster Display session 1
Resources:
Abstract
6079 - Invasive fungal diseases in patients with Hodgkin’s lymphoma before and after allogeneic hematopoietic stem cell transplantation
Presenter: Marina Popova
Session: Poster Display session 1
Resources:
Abstract