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Axitinib

Sunitinib

Angiogenesis Inhibitors

Growth Inhibitors

Protein Kinase Inhibitors

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A single dose of Axitinib - 1 mg in a liquid form in the composition (Axitinib+Sunitinib+Pazopanib) of the nasal spray.

A single dose of Sunitinib- 5 mg in a liquid form in the composition (Axitinib+Sunitinib+Pazopanib) of the nasal spray.

A single dose of Pazopanib-5 mg in a liquid form in the composition (Axitinib+Sunitinib+Pazopanib) of the nasal spray.

Pharmaceutical composition of Axitinib 5MG +Sunitinib 5MG + Pazopanib 5MG in the liquid form of a nasal spray NST-4-G.

Subjects take a nasal spray BID at a single dose in each nostril (approximately at the same time of day) for 7 weeks or unacceptable toxicity or other adverse events.

Axitinib 1 MG

Pharmaceutical composition of Axitinib 5MG +Sunitinib 5MG + Pazopanib 5MG in the liquid form of a nasal spray NST-4-G.

Sunitinib 5 MG

Pazopanib 5 MG

Ivo Reznic, PhD

Oliever R Kolb

This is a study to determine the efficacy, safety and clinical benefit (how well the drugs works), of the pharmaceutical compositions in Nasal Spray NST-4G for the treatment of brain tumors( Recurrent Glioblastoma, Gliosarcoma,Anaplastic Gliomas, Previously Treated).

All drugs target the inhibition of the growth factors and neo-angiogenesis as one the main reasons for the growth of the tumor.

The purpose of the Nasal Spray NST-4G study is to determine the safety and tolerability in order to establish the best dose level to be used in future studies.

This is an open-label study, Phase 1 study evaluating the preliminary safety, efficacy, tolerability and clinical benefit of Nasal Spray NST-4G in patients with Recurrent Glioblastoma, Gliosarcoma,Anaplastic Gliomas.

Acceptable subjects included in the study will receive Nasal Spray NST-4G, administered twice daily for 7 weeks intranasally.

Every 8th day, a blood function (hematopoiesis) is examined . Patients may continue to receive subsequent nasal spray cycles if the subject is not intolerant of the test product, does not withdraw consent or the individual no longer receives clinical benefit (the factors taken for consideration will be the progression of the disease, expressed in increasing neuropathy, hemiparesis, pain intensification ,DLT events, Clinical signs of deteriorating quality of life (QOL).

The evaluation of the tumor size will be repeated using the MRI method with a contrast agent after each 7-week nasal spray cycle.

The use of nasal spray is a non-invasive method of treatment that does not require specialized conditions for therapy

Clinical Trial of the Use of the Nasal Spray of Patients With Recurrence of Glioblastoma

Phase I Clinical Trial of Nasal Spray in Treating Patients With Recurrent Glioblastoma, Gliosarcoma, Glioma

The definition of survival without progression of disease is estimated as time of the disease-free period / absence of continued tumor growth (in weeks) by objective methods of control (MRI or CT)

The determine overall survival from the date of commencement of participation in the study until date of death from any cause.

To determine late toxicity for the maximum tolerated dose is estimated a function of hematopoiesis of patients by blood sampling every 8th day The MTD is based upon dose-limiting toxicities (DLTs) experienced during Cycle 1 of treatment. The MTD is the dose level at which 0/6 or 1/6 patients experience DLT with at least two patients experiencing DLT at the next higher dose level. Using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, DLTs are defined as: Grade 4 neutropenia lasting greater than 5 days; Grade 3 thrombocytopenia; the occurrence of non-hematologic Grade 3 or greater drug-related adverse events excluding Grade ≥ 3 elevation in alkaline phosphatase, Grade ≥ 3 nausea or vomiting unless occurring despite the use of standard anti-emetics or Grade 3 diarrhea unless occurring despite standard anti-diarrheal therapy; \> 14 day delay to re-treat due to failure to resolve drug-related toxicity to re-treatment criteria or pre-treatment baseline.

Center Trials & Treatment

Nervous System Diseases

Brain Neoplasms

Bevacizumab

Patients who had tumor progression while treated with bevacizumab.

Patients with progressive tumor who have not been treated with bevacizumab.

Oral dose 37.5 mg daily on a continuous 4 week cycle

Sutent (sunitinib)

Teri N Kreisl, M.D.

Background:

One way tumors are able to grow is by forming new blood vessels that supply them with nutrients and oxygen.

Sunitinib blocks certain proteins on the surface of tumor and blood vessel cells that are involved with the formation of new blood vessels.

Blocking these proteins may prevent the tumor cells or blood vessels from continuing to grow.

Objectives:

To determine whether sunitinib can cause tumors to shrink or stabilize in patients with recurrent brain cancer.

Eligibility:

Patients 18 years of age or older with brain cancer whose disease has worsened after standard treatment with surgery, radiation.

Design:

Patients take a sunitinib pill once a day in 4-week treatment cycles. Treatment may continue as long as the tumor remains stable or decreases in size and the side effects of treatment are tolerated.

Routine blood tests are done every 2 weeks during the first 8 weeks of treatment and then every 4 weeks after that.

Magnetic resonance imaging (MRI) scans are done before starting treatment (at baseline) and at the end of every 4-week cycle to monitor tumor growth.

Positron emission tomography (PET) scans are done at baseline and at the end of the first cycle.

Neurological and physical examinations are done at baseline, at week 2 of treatment and at the end of every treatment cycle.

Health-related quality of life is assessed every 4 weeks.

Pregnancy tests, electrocardiograms and echocardiograms are repeated as needed.

Background:

Solid tumors have multiple mechanisms for stimulating angiogenesis with the vascular endothelial growth factor (VEGF)-kinase insert domain receptor (KDR) axis being only one of them. Sunitinib, through its multiple tyrosine kinase receptor targets, represents an attempt to capitalize on the concept of targeting multiple mechanisms responsible for glioma-associated angiogenesis. Sunitinib inhibits platelet derived growth factor receptor (PDGFR) and c-kit (stem cell factor (SCF) receptor) at nanomolar concentrations. The combination blocks all three known major glioma-mediated angiogenic mechanisms (VEGF, c-kit, PDGF). Based on this scientific rationale, the promising anti-glioma activity of sunitinib in preclinical models, and the promising clinical data in patients with gliomas treated with other VEGF inhibitors, we are now proposing a phase II trial of sunitinib in patients with recurrent malignant gliomas.

Objectives:

To evaluate the anti-glioma activity of sunitinib in patients with recurrent malignant gliomas who are either naive or resistant to prior bevacizumab therapy.

Eligibility:

Patients with recurrent malignant glioma are eligible for this study.

Design:

This is a phase II study with a target enrollment of 64 (32 with glioblastoma multiforme (GBM) and 32 with anaplastic glioma (AG)) patients who have not progressed on prior treatment with anti-VEGF therapy, and 64 (32 with GBM and 32 with AG)patients who have progressed on prior bevacizumab therapy.

Sunitinib will be self-administered orally at 37.5 mg daily, with dose adjustments allowed for toxicity and concomitant drug interactions.

The primary endpoint is six-month progression free survival for both arms of the study.

We performed an interim analysis (see below) and after consulting with the pharmaceutical company (Pfizer) we believe that ending the study is the most appropriate course of action to take.

In the original design of the trial, for the AG stratum, the agent will be considered effective if at least 14 patients have not progressed by 6 months. Now, we have observed one out 10 Bev-naïve who haven't progressed by 6 months. Then given one patient in the first 10 patients whose PFS \>=6, the conditional probability of observing at least 14 out of 32 patients who are 6 month-PFS is only 43% even if the true 6 months-PFS is 55%. Since in the first 10 patients, we only observed one patient with PFS\>=6 months, it is unlikely that the true 6 month-PFS is 55%. The conditional power would be close to zero, if the true 6 month-PFS close to 10% as observed so far. Based on the conditional probability, the chance of a positive study is small, and hence the trial should be considered stopped for futility.

For Bev-resistant patients, because in the first 12 patients none had PFS \>= 6 months the conditional probability of declaring the agent being effective is even lower and equals 12%, if the true PFS at 6 months is 55%. Essentially there is little chance that the agent can be declared effective.

Sunitinib to Treat Recurrent Brain Cancer

A Phase II Trial of Sunitinib in the Treatment of Recurrent Malignant Gliomas

Time between the start of treatment to progression. Progression is defined by the RANO(Response Assessment in Neuro-Oncology) criteria. Progression is defined by any of the following: 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration.

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

National Cancer Institute (NCI)

Principal Investigator

Bevacizumab Resistant Patients

Bevacizumab Naive Patients

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

The study was terminated based on results of an interim analysis for futility.

Dr. Teri Kreisl

63 patients enrolled with glioblastoma multiforme (GBM) (32 Bev naive, 31 Bev resistant) and were evaluated for this outcome measure.

6-month Progression-free Survival.

Number of Participants With Adverse Events

Patients who had tumor progression while treated with bevacizumab. Oral dose Sutent (sunitinib) 37.5 mg daily on a continuous 4 week cycle.

Patients with progressive tumor who have not been treated with bevacizumab.Oral dose Sutent (sunitinib) 37.5 mg daily on a continuous 4 week cycle.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Clinical Trial of the Use of the Nasal Spray of Patients With Recurrence of Glioblastoma	NCT03275558	Recurrent Gliob... Gliosarcoma Anaplastic Glio...	Axitinib 1 MG Sunitinib 5 MG Pazopanib 5 MG	18 Years - 80 Years	Center Trials & Treatment
Sunitinib to Treat Recurrent Brain Cancer	NCT00923117	Glioblastoma Mu... Malignant Gliom... Anaplastic Glio...	Sutent (sunitin...	18 Years -	National Institutes of Health Clinical Center (CC)
Clinical Trial of the Use of the Nasal Spray of Patients With Recurrence of Glioblastoma	NCT03275558	Recurrent Gliob... Gliosarcoma Anaplastic Glio...	Axitinib 1 MG Sunitinib 5 MG Pazopanib 5 MG	18 Years - 80 Years	Center Trials & Treatment

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