HGG-TCP (High Grade Glioma - Tumor Concentrations of Protein Kinase Inhibitors)

• Sponsor: Amsterdam UMC, location VUmc (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT02239952
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arms: 3
• Duration (Months): 84
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine intratumoral concentration of kinase inhibitors upon 2 weeks of treatment in tumor tissue (in the brain) of patients with high-grade gliomas (HGG).

Condition or Disease	Intervention/Treatment	Phase
Cancer; High-grade Glioma	Drug: Sunitinib; Drug: vandetanib; Drug: Erlotinib	N/A

Detailed Description

In clinical trials for HGG, multiple agents targeting various oncogenic signaling pathways that play an important role in the biology of HGG have been studied, but unfortunately only a small number of patients seem to benefit from these treatment strategies. Whether these disappointing results are due to a restricted drug delivery through the blood-brain barrier, or due to differential biological characteristics of these HGGs, remains unknown. To better understand these clinical observations and to find potential insight how to overcome them, we intend to measure tumor concentrations of PKIs after approximately two weeks treatment and to determine whether these tumor concentrations correlate with plasma- and CSF concentrations of PKIs. Subsequently, we intend to determine the (phospho)proteomic profiles and kinase inhibitory activity in tumor tissue from these HGG patients after approximately two weeks of treatment with a PKI.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Pilot Study on the Determination of Tumor Concentrations of Protein Kinase Inhibitors in Patients With Newly Diagnosed High-grade Glioma
• Study Start Date: Nov 1, 2014
• Anticipated Primary Completion Date: Nov 1, 2021
• Anticipated Study Completion Date: Nov 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: sunitinib	Drug: Sunitinib; 50 mg once daily, oral use for 14 days
Experimental: vandetanib	Drug: vandetanib; 300 mg, once daily, oral use for 14 days
Experimental: Erlotinib	Drug: Erlotinib; 150 mg, once daily, oral use for 14 days

Outcome Measures

Primary Outcome Measures

1. PKI and active metabolites concentrations in tumor tissue [2 weeks]

   PKI concentrations and active metabolites in tumor tissue after approximately two weeks of PKI treatment will be determined.

Secondary Outcome Measures

1. Correlation of PKI and active metabolites concentrations in tumor. [2 weeks]

   Venous blood sampling will be performed to determine plasma drug and active metabolites concentrations after approximately one and two weeks of PKI treatment and during surgery. CSF samples will be drawn during surgery. Plasma- and CSF drug concentrations will be correlated to tumor drug concentrations. Plasma samples for pharmacodynamics will be simultaneously drawn with the on- and after treatment hematology and chemistry analysis.

2. Feasibility of determining the (phospho)proteomic profiles and kinase activity profiles in tumor tissue and CSF. [2 weeks]

   Kinome wide and quantitative (phospho)proteomic profiles will be determined in tumor tissue of study patients and in tumor tissue of matched controled patients. We anticipate that these profiles will reveal information on the effect of treatment on kinase abundances, phosphopeptide levels and on phosphorylation sites. Differences in levels of phosphopeptides and fold-change of phosphorylation sites will be quantified. In an exploratory design, we will determine whether observed profile differences can be correlated to drug concentrations in tumor tissue. Kinase inhibition profiles will be measured according to standard methods as developed and modified in our laboratory.

3. Significant difference of the (phospho)proteomic profiles and kinase activities of tumor tissue in study patients and control group. [2 weeks]

   The (phospho)proteomic profiles and kinase activity profiles will be determined in tumor tissue of study patients and in tumor tissue of patients in a control group. Kinase inhibition profiles will be measured according to standard methods as developed and modified in our laboratory.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients without a history of brain tumor

2. Initial brain MR-scan suggesting a high grade glioma, according to the interpretation of an expert neuroradiologist

3. On initial MR-scan a tumor localisation that is deemed resectable without major neurological deficits

4. Patients must have a Karnofsky Performance Score ≥ 70%

5. Patients must have a RTOG Neurologic Function Status of 0-2

6. Patients need to have adequate hematological, renal and hepatic function as assessed by the following laboratory requirements to be conducted within seven days prior to start study treatment: - Hemoglobin > 7.0 mmol/l - Absolute neutrophil count (ANC)

1,5 x 109/l - Platelet count > 100 x 109/l - ALT and AST< 2.5 x ULN - Alkaline phosphatase < 4 x ULN - Serum creatinine eGFR > 50 ml/min

1. Patients are 18 years of older

2. Male and female patients with reproductive potential must use an approved contraceptive method during and for three months after discontinuation of study treatment

3. Patients need to give informed consent

4. Patients should be able to swallow oral medication

Exclusion Criteria:

1. Patients receiving prior chemotherapy, radiotherapy or anti-angiogenic therapy

2. Use of anti-coagulant therapy

3. Use of CYP3A4 enzyme-inducing drugs, other than dexamethasone (including Carbamazepine, Phenytoine, Phenobarbital)

4. Initial MR-scan of the brain showing tumor hemorrhage or intracerebral hemorrhage

5. Patients with progressive neurological symptoms despite dexamethasone

6. Inability to comply with protocol or study procedures

7. Pregnancy

8. Patients with uncontrolled arterial hypertension. Blood pressure must be ≤160/95 mmHg at the time of screening on a stable antihypertensive regimen.

9. Patients with a history of cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)

10. Patients with evidence or history of bleeding diathesis

11. Patients with a history of venous or arterial thrombo-embolic events or hemorrhagic disease during the past six months

12. Patients with a history of congestive heart failure (NYHA III, IV)

13. Patients with a history of peripheral vascular disease (Fontaine stage III and IV)

14. Patients with stroke or myocardial infarction during the past six months

15. Patients with a history of a recent peptic ulcer disease (endoscopically-proven gastric ulcer, duodenal ulcer of esophageal ulcer) during the past six months

16. Patients with uncontrolled infections (> grade 2 NCI-CTC version 4.0)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VU University Medical Center	Amsterdam	Noord-Holland	Netherlands	1081 HV

Sponsors and Collaborators

• Amsterdam UMC, location VUmc

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: M.E. van Linde, Medical Oncologist, Amsterdam UMC, location VUmc
• ClinicalTrials.gov Identifier: NCT02239952
• Other Study ID Numbers: 2013.465
• First Posted: Sep 15, 2014
• Last Update Posted: Oct 8, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Glioma; Erlotinib Hydrochloride; Sunitinib

Study Results

No Results Posted as of Oct 8, 2020