Neoplasms

All Conditions

Symptoms and General Pathology

Rare Diseases

Glioblastoma

Disease Progression

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

33% of the patients will be randomized to reirradiation (RT) alone. They will receive 36 Gy (2 Gy per fraction)

66% of the patients will be randomized to reirradiation (RT) + 400 mg APG101 weekly. They will receive 36 Gy (2 Gy per fraction) and 400 mg APG101 weekly as an intravenous infusion

APG101

Blood drawings, e.g. for safety labs, abdominal ultrasound, ECG. Re-Irradiation is not considered a study procedure, but standard of care (inclusion criterion)

Blood drawing

Wolfgang Wick, MD

This is a phase II study of APG101 + reirradiation (RT) versus reirradiation. Patients suffering from a malignant brain tumor called glioblastoma having a first or second progression can be included. They will be randomized to RT or RT + APG101.

APG101 is a fusion protein (similar to an antibody) and will be administered as a weekly infusion. Patients can stay in this study as long as they benefit from the participation (no fixed end).

In this trial, 30-35 sites in Germany, Austria and Russia take part.

In this phase II trial, patients with a recurrence / progression of glioblastoma (first or second progression) either not being eligible for tumour resection or having macroscopic residual tumour after resection of the recurrence can be included (tumor size must 1-4 cm in T1-weighted MRI). They must be candidates for a re-irradiation and will then be randomized in a 1:2 ratio to re-irradiation alone or re-irradiation + 400mg APG101 as a weekly intravenous infusion.

Radiotherapy (RT) is considered standard of care and not a study procedure. As prior therapies, a first radiotherapy (maximal dose of 60 Gy; at least 8 months since the end of preirradiation), a prior surgery (at least for histology) and at least one Temozolomide-containing chemotherapy are mandatory; patients with prior treatment with bevacizumab, iodine seeds and/or brachytherapy are not eligible. The patients' steroid dose must be stable or decreasing upon inclusion.

The number of patients to be included in this study is up to 83 (depending on the statistical 2-step SIMON design).

Primary objective: 6 months rate of progression free survival (PFS6). Subjects can participate in this study as long as a clinical benefit is considered by the treating physician.

MRI tumour imaging will be carried out every 6 weeks.

APG101 in Glioblastoma

A Phase II, Randomized, Open-label, Multi-centre Study of Weekly APG101 + Reirradiation Versus Reirradiation in the Treatment of Patients With First or Second Progression of Glioblastoma

Apogenix GmbH

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Amino Acids

Atezolizumab

Sirolimus

Palbociclib

Alectinib

Temsirolimus

MTOR Inhibitors

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Tyrosine Kinase Inhibitors

Tyrosine

* weekly application of 800 mg i.v. for 6 months or until progression
* in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks

* 600 mg orally twice daily (bid) for 6 months or until progression
* in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks

* at escalating doses from 100 mg until maximum tolerated dose daily administered (orally) on five consecutive days of a 28-day cycle for 6 months or until progression
* in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks

* application of 1200 mg i.v. every three weeks for 6 months or until progression
* in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks

* daily application of 150 mg orally for 6 months or until progression
* in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks

* 75/100/125 mg orally once daily on 21/28 days
* in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks
* followed by a 4 weeks break (after last dose of 2nd cycle)
* and with maintenance therapy with palbociclib at 125 mg daily for 6 months or until progression

* weekly application of 25 mg i.v. for 6 months or until progression
* in conjunction with radiotherapy (at 60 Gy in 2 Gy fractions) for the first 6 weeks

Idasanutlin

Vismodegib

Wolfgang Wick, Prof. Dr.

The objective of N²M² is the improvement of overall survival of patients with glioblastoma with an unmethylated MGMT promoter based on molecular characterization and use of targeted compounds in a modern trial design. The progression-free survival rate at six months (PFS-6) will be used to make decisions.

Advances in the understanding of glioblastoma at a molecular level along with technological progress have led to the identification of key genetic alterations, not only in scientific projects but also in every-day clinical practice. These alterations increasingly refine the sub-classification of glioblastoma and the introduction of molecular markers in this classification, which ultimately may allow defining subset specific treatments.

The present umbrella concept for multiple biomarker-driven subtrials anchors at the Heidelberg-based INFORM registry trial in recurrent pediatric malignancies, where in analogy to NCT Neuro Master Match (N²M²) whole-exome, low-coverage whole-genome and transcriptome sequencing is used to identify targeted agents, single or in combinations according to a dedicated algorithm. It also shares conceptual similarities with international projects currently developed for lung and breast cancer. Finally, approaches to use molecular information in glioblastoma for the definition of a therapy at progression are also planned by the "Defeat Glioma" Consortium in the US and a group of excellence centers also in the US.

The N²M² concept excels the aforementioned initiatives in the strict focus on newly diagnosed patients, the option to cross-validate molecular biomarkers in an already analyzed contemporary cohort of glioblastoma patients analyzed in the German Consortium for Translational Cancer Research (DKTK) and the use of a parallel group treated with standard-of-care (SOC). Further restriction is made by the inclusion of patients only with a low likelihood to benefit from the SOC, temozolomide (TMZ) chemotherapy on the basis of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, allowing to replace TMZ with a molecularly targeted agent in combination with radiotherapy (RT) in each of the experimental subtrials. Replacing TMZ by an experimental agent in the primary chemo-radiotherapy has been done in at least four completed trials, albeit without pre-selection of a targeted therapy but the more opportunistic use of an available drug with no known MGMT interaction. Focusing on newly diagnosed patients not only harbors the greater likelihood of impact on the disease, but also allows addressing questions on acquired resistance in the more likely obtained tumor tissue at recurrence.

N²M² is formally divided into a DISCOVERY and a TREATMENT aspect. DISCOVERY starts with an (epigenomewide) Illumina methylation array and a panel sequencing followed by an appropriate and accepted standard method (Sanger Sequencing or Immunohistochemistry) within the scope of these methods for target validation prior to any suggestion for patient allocation into one of the subtrials. Suggestions for patients' allocation to one of the subtrials will be based on results of accepted standard methods. These data will be generated from formaline-fixed paraffine embedded (FFPE) tissue within in 2-3 weeks after surgery. The Heidelberg site has already established the next generation gene panel sequencing (used for target discovery in case of N²M²) and genome wide DNA methylation analyses for aiding daily routine. To meet the criteria for a safe use of these data for decision-making the orthogonal, standard methods performed in the Institute of Pathology are supplemented.

DISCOVERY also includes the use of whole exome, low-coverage whole-genome, and transcriptome sequencing, the methylome analysis, and gene expression arrays to find new, unexpected targets and get a more comprehensive view on affected pathways. Discovery is also the driving force behind the work on resistant tumors. The latter may result in individual treatment decisions at recurrence, knowing there are no relevantly active treatments in this setting.

TREATMENT is driven by a match/no match decision rendered in an algorithm that will be subject to refinement in the process of the project, both by data generated in N²M², but also external evidence; i.e. there may be some linear relations between an alteration, e.g. BRAF V600E mutation and a distinct treatment or some others, but it is expected that these linear relations will be replaced in a learning system by relations that take upstream and downstream target alterations and also parallel signaling pathways into account and may therefore already predict a certain likelihood of resistance development.

In detail, FFPE tissue (and blood) from patients diagnosed with a glioblastoma harboring an unmethylated MGMT promoter after informed consent will be subjected to a (epigenomewide) methylation array and panel sequencing as well as the appropriate methods to validate any of the trial immanent targets, if they are present, with results available within a maximum of 3 weeks postoperatively. This allows for a timely decision at the molecular Neurooncology Tumor Board and a timely initiation (within 4 to 6 weeks) of the postoperative treatment. Further examinations on fresh tumor tissue (and blood) such as whole exome, low-coverage whole genome and transcriptome sequencing as well as expression arrays will be done to enhance the scientific background on the tumor tissue. These data will not be used for decision-making, Runs already done within the INFORM project with glioblastoma samples and also dry runs (n=43) for the N²M² project support the feasibility of the timelines and principal options for discovery.

Matching will be defined as a molecular situation, which makes treatment with RT and a matching targeted drug from a prespecified warehouse separated in subtrials meaningful. Patients will be informed about the identified treatment option within the "matching" open-label, parallel group Phase I/IIa trial. As for 2 of the experimental compounds (APG101 and Atezolizumab) no specific biomarker is validated at the moment, the nonmatching patients will be equally allocated to receive either APG101, Atezolizumab or the current SOC (radiochemotherapy with TMZ, TMZ-group). Patients allocated to the TMZ-group will serve as a meaningful control group with basic efficacy parameters documented, if consent has been obtained.

The objective of N²M² is the improvement of overall survival of patients with glioblastoma with an unmethylated MGMT promoter based on molecular characterization and use of targeted compounds in a modern trial design. The progression-free survival rate at six months (PFS-6) will be used to make decisions.

Parallel and ongoing translational projects within the DKTK will examine prognostic properties of the biomarkers identified to drive therapy decisions in this trial. Trial accrual will be asymmetric into the different subtrials. It is expected that 75-100 patients will be accrued into this trial per year at about 14 sites in Germany (mainly Deutsches Konsortium für Translationale Krebsforschung, DKTK and Neuroonkologische Arbeitsgemeinschaft, NOA). Importantly, the parallel SPECTAbrain initiative of the European Organization for the Research and Treatment of Cancer (EORTC) is synergistic and not competitive to our study proposal since it is focused on the treatment at recurrence, using paraffin-embedded tissues, panels/arrays only and it would be desirable that data from these initiatives are looked at in a joined manner.

NCT Neuro Master Match - N²M² (NOA-20)

Umbrella Protocol for Phase I/IIa Trials of Molecularly Matched Targeted Therapies Plus Radiotherapy in Patients With Newly Diagnosed Glioblastoma Without MGMT Promoter Methylation: NCT Neuro Master Match - N²M² (NOA-20)

defined as the proportion of patients free of progression at 6 months after study entry. PFS will be calculated from study entry until clinical or radiographic progression or death, whichever comes first.Progression will be evaluated according to Response Assessment in Neurooncology (RANO) criteria or Immunotherapy Response Assessment in Neurooncology (iRANO) criteria.

Toxic effects will be graded according to CTCAE v5.0.

defined as the time from first administration of the investigational medicinal product (IMP) to time of death from any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
APG101 in Glioblastoma	NCT01071837	Glioblastoma Mu...	APG101 Blood drawing	18 Years -	Apogenix AG
NCT Neuro Master Match - N²M² (NOA-20)	NCT03158389	Glioblastoma, A...	APG101 Alectinib Idasanutlin Atezolizumab Vismodegib Temsirolimus Palbociclib	18 Years -	University Hospital Heidelberg

Spots Global Cancer Trial Database for apg101

Every month we try and update this database with for apg101 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for apg101

Every month we try and update this database with for apg101 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for apg101 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.