Neoplasms

All Conditions

Rare Diseases

Glioblastoma

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

Anaplastic Astrocytoma

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Natriuretic Agents

Bevacizumab

Mannitol

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Experimental portion of this proposal:

This trial will have two experimental arms that will be open labeled and non-randomized.

ARM 1 (If the patient has multifocal disease or leptomeningeal disease)

Day 0: Intraarterial Bevacizumab single dose (15mg/kg) after Mannitol to open the blood brain barrier Day 28: Intravenous Bevacizumab (10mg/kg) every two weeks thereafter until disease progression on MRI scan.

If progression occurs, repeat Intraarterial Bevacizumab single dose (15mg/kg) to area of progression and wait 28 days and then restart Intravenous Bevacizumab (10mg/kg) every two weeks thereafter until progression on MRI scan.

Repeat Cycle

ARM 2 (If the patient has no multifocal disease or leptomeningeal disease)

Day 0: Intraarterial Bevacizumab single dose (15mg/kg) after Mannitol to open the blood brain barrier Day 28: No biweekly IV Bevacizumab treatment

If MRI shows progression then repeat Intraarterial Bevacizumab single dose (15mg/kg) to area of progression Repeat Cycle

John Boockvar, MD

Tamika Wong, MPH

David Langer, MD

Rafael Ortiz, MD

Alexis Demopolous, MD

Ashley Ray, NP

Sherese Fralin, NP

The high-grade malignant brain tumors, glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), comprise the majority of all primary brain tumors in adults. This group of tumors also exhibits the most aggressive behavior, resulting in median overall survival durations of only 9-12 months for GBM, and 3-4 years for AA. Initial therapy consists of either surgical resection, external beam radiation or both. All patients experience a recurrence after first-line therapy, so improvements in both first-line and salvage therapy are critical to enhancing quality-of-life and prolonging survival. It is unknown if currently used intravenous (IV) therapies even cross the blood brain barrier (BBB). The investigators have shown in a previous phase I trial that a single Super-selective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab (up to 15mg/kg) is safe and effective in the treatment of recurrent GBM. Therefore, this phase I/II clinical research trial is an extension of that trial in that the investigators seek to test the hypothesis that repeated dosing of intraarterial Bevacizumab is safe and effective in the treatment of recurrent malignant glioma. By achieving the aims of this study the investigators will also determine if IV therapy with Bevacizumab should be combined with repeated selected intraarterial Bevacizumab to improve progression free and overall survival. The investigators expect that this project will provide important information regarding the utility of repeated SIACI Bevacizumab therapy for malignant glioma, and may alter the way these drugs are delivered to the patients in the near future.

The current standard of care for recurring GBM is for patients to receive Bevacizumab (Avastin) intravenously (IV) at 10mg/kg every two weeks until their tumor grows more than 25%. At that point, these patients are deemed treatment failures and are given another treatment. Because of the blood brain barrier (BBB) where IV drugs do not penetrate the blood vessel walls well to get into the brain, no one knows for sure if these IV drugs actually get into the brain after infusion. We have recently completed a Phase I clinical trial that has shown that SIACI of Bevacizumab is safe and effective up to a dose of 15mg/kg in patients with recurrent malignant glioma. This two arm open-label, non-randomized trial is a follow up study to that trial and will ask two simple questions: Is it safe to deliver repeated doses of Bevacizumab intraarterially using these super selective intraarterial delivery techniques? Is it necessary to combine this IA regimen of treatment with biweekly IV Bevacizumab in order to improve progression free survival (PFS) and overall survival (OS)? Information from this trial will yield important answers to the durability and efficacy of this delivery technique and may radically change the way chemotherapy is given to our patients with brain tumors.

Current Standard of Care:

Day 0: Intravenous Bevacizumab (10mg/kg) Day 14, 28 (and every two weeks thereafter): Intravenous Bevacizumab

Therefore the experimental aspects of this treatment plan will include:

1. Subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol 20%; 12.5 mL/s over 2 minutes) in order to disrupt the blood brain barrier. This technique has been used in several thousand patients in previous studies for the IA delivery of chemotherapy for malignant glioma. We have used this without complication in the 30 patients from our Phase I protocol as well.
2. To treat patients with one of two arms with repeated intraarterial delivery (SIACI) of Bevacizumab for patients with recurring or relapsing high grade glioma. Each arm gets IA delivery with one arm getting IV Bevacizumab biweekly as well and the other arm not getting intervening IV therapy. In each arm, IA therapy is repeated when MRI shows progression. Persistent progression after three intraarterial chemotherapies would remove the patient from the trial.

Repeated Super-selective Intraarterial Cerebral Infusion of Bevacizumab (Avastin) for Treatment of Relapsed GBM and AA

Phase I/II Trial Of Repeated Super-selective Intraarterial Cerebral Infusion Of Bevacizumab (Avastin) for Treatment of Relapsed/Refractory Glioblastoma Multiforme and Anaplastic Astrocytoma.

We will determine this composite overall response rate (CORR) through the Response Assessment in Neuro-Oncology (RANO) criteria

Six-month progression-free survival (PFS) and overall survival (OS) will be assessed by Kaplan-Meier survival analysis, assuming adequate follow-up time

The descriptive frequency of subjects experiencing toxicities will also be tabulated.

Feinstein Institute for Medical Research

Northwell Health

Professor

This phase I clinical research trial will test the hypothesis that Bevacizumab can be safely used by direct intracranial superselective intraarterial infusion up to a dose of 10mg/kg to ultimately enhance survival of patients with relapsed/refractory GBM/AA.

Day 0: Intraarterial Avastin single dose (starting at 2mg/kg and up to 10mg/kg) after Mannitol to open the blood brain barrier.

Super-Selective Intraarterial Intracranial Infusion of BEVACIZUMAB

The high-grade malignant brain tumors, glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), comprise the majority of all primary brain tumors in adults. This group of tumors also exhibits the most aggressive behavior, resulting in median overall survival durations of only 9-12 months for GBM, and 3-4 years for AA. Initial therapy consists of either surgical resection, external beam radiation or both. All patients experience a recurrence after first-line therapy, so improvements in both first-line and salvage therapy are critical to enhancing quality-of-life and prolonging survival. It is unknown if currently used intravenous (IV) therapies even cross the blood brain barrier (BBB). Superselective Intraarterial Cerebral Infusion (SIACI) is a technique that can effectively increase the concentration of drug delivered to the brain while sparing the body of systemic side effects. One currently used drug called, Bevacizumab (Avastin) has been shown to be active in human brain tumors but its actual CNS penetration is unknown. This phase I clinical research trial will test the hypothesis that Bevacizumab can be safely used by direct intracranial superselective intraarterial infusion up to a dose of 10mg/kg to ultimately enhance survival of patients with relapsed/refractory GBM/AA. By achieving the aims of this study we will determine the toxicity profile and maximum tolerated dose (MTD of SIACI Bevacizumab. We expect that this project will provide important information regarding the utility of SIACI Bevacizumab therapy for malignant glioma, and may alter the way these drugs are delivered to our patients in the near future.

The current standard of care for recurring GBM is for patients to receive Bevacizumab (Avastin) intravenously (IV) at 10mg/kg with CPT-11 (Irinotecan) every two weeks until their tumor grows more than 25%. At that point, these patients are deemed treatment failures and are given another treatment. Because of the blood brain barrier (BBB) where IV drugs do not penetrate the blood vessel walls well to get into the brain, no one knows for sure if these IV drugs actually get into the brain after infusion. Previous studies have shown that if you want to increase your penetration of drug to the brain, that intra-carotid artery (intraarterial) delivery is superior to standard intravenous delivery. Previous techniques using intra arterial (intracarotid) infusion still were non-selective as drug delivery still went to all blood vessels in the brain, so patients still had significant adverse events, such as blindness. Newer techniques in interventional neuroradiology have allowed for a more selective delivery of catheters higher up into the arterial tree where agents such as chemotherapies, can be delivered without the risk of adverse affects such as blindness. In fact, studies here at Cornell and MSKCC have developed very new and exciting super selective intraarterial delivery treatment for Pediatric Eye Tumors with little toxicity. Therefore, this trial will ask one simple question: Is it safe to delivery a patient's first dose of Avastin intraarterially using these super selective delivery techniques instead of the standard intravenous route of administration? This should not only increase the amount of drug that gets to the tumor but also spare the patient any adverse effects from a less selective delivery. During that single dose of intraarterial Avastin, the patient will also receive a dose of mannitol that opens up the blood brain barrier to improve delivery of the agent to the brain. After that single dose of Mannitol and Avastin intraarterially, the patient will be evaluated for 4 weeks to assess for toxicity. If no toxicity, then the patient will go on and get the standard chemotherapy (Avastin and CPT-11) every two weeks as is routine unless they fail. After this you are done with the "experimental" aspects of the protocol. This is a Phase I trial that is designed to test the safety of the single dose intraarterial delivery of Avastin and Mannitol, prior to starting standard IV Avastin and CPT-11.

In summary:

Current Standard of Care:

Day 0: Intravenous Avastin (10mg/kg) and CPT-11 Day 14, 28 (and every two weeks thereafter): Intravenous Avastin and CPT-11

Experimental portion of this proposal:

Day 0: Intraarterial Avastin single dose (starting at 2mg/kg and up to 10mg/kg) after Mannitol to open the blood brain barrier Day 28 (and every two weeks thereafter): Intravenous Avastin and CPT-11

1. Subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol 25%; 3-10 mL/s for 30seconds) in order to disrupt the blood brain barrier. This technique has been used in several thousand patients in previous studies for the IA delivery of chemotherapy for malignant glioma.
2. To add a single intraarterial delivery (SIACI) of the Avastin prior to beginning the standard IV Avastin and CPT-11 therapy for patients with recurring or relapsing high grade glioma. After a one cycle observation period assess for toxicity from the IA infusion, the subject will receive Intravenous (IV) bevacizumab 10 mg/kg and irinotecan (CPT-11) 125mg/m2 every 14 days as is standard therapy for relapsing recurring GBM.

The dose escalation algorithm is as follows: We will use a single intracranial superselective intraarterial infusion of Avastin, starting at a dose of 2mg/kg in the first three patients. Assuming no dose limiting toxicity during the first 28 days after IA infusion, the patient will then begin their standard chemotherapy regimen which is Avastin and CPT-11 every two weeks. The doses will be escalated to 4,6,8 and finally 10mg/kg in this Phase I trial.

Inclusion criteria Include: Males or females, ≥18 years of age, with documented histologic diagnosis of relapsed or refractory glioblastoma multiforme (GBM), anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma (AOA).

Both hematologic and non-hematologic toxicity will be determined and scored according to the NCI Common Toxicity Criteria (version 3.0). Monitoring will be conducted by post procedure CT scan (at 6-12 hours post procedure), serial history, neurological and physical examinations together with serial blood counts, prothrombin time (PT), partial thromboplastin time (PTT) and chemistries. MRI will be performed every two cycles or approximately every two months.

Response will be evaluated after two cycles of chemotherapy via a MRI with the injection of contrast. Subjects who show an objective response (reduction in tumor size) or stable disease after 2 cycles of treatment will be able to continue on study. Progressive disease will require that subjects be taken off the research protocol. The following will be evaluated every cycle, and then during follow-up: neurological examination, physical examination, performance status, laboratory parameters and review of adverse reactions. Contrast enhanced MRI (MRI with gadolinium is the preferable imaging study except in case where MRI is contraindicated i.e., in those with pacemakers or metallic implants. In these subjects, CT with contrast is acceptable) will be performed every two-treatment cycles under this research protocol. The following subjects will be taken off protocol: those with progressive disease; those who experience dose-limiting toxicity (DLT). Follow-up will continue until disease progression or death. Survival will be measured from the time of the first dose of IA Avastin® (given at the start of each treatment cycle).

The patient will not be responsible for any additional costs associated with enrollment in the trial. All costs of the IA delivery will be submitted to the patient's insurance provider. WCMC will not be named as a sponsor of the study nor will it cover the cost of the experimental procedure.

Super-Selective Intraarterial Intracranial Infusion of Avastin (Bevacizumab)

Phase I Trial of Super-Selective Intraarterial Intracranial Infusion of Avastin (Bevacizumab) For Treatment of Relapsed/Refractory Glioblastoma Multiforme and Anaplastic Astrocytoma

Associate Professor

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Symptoms and General Pathology

Carcinoma

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Adenocarcinoma

Recurrence

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Ovarian Cancer

Ovarian Epithelial Cancer

Dianhydrogalactitol

Antineoplastic Agents, Alkylating

Alkylating Agents

VAL-083 given by intravenous infusion with a starting dose of 60 mg/m2 once weekly. If this regimen is well tolerated for at least three sequential weekly treatments the patient's dose may be escalated to 67 mg/m2 i.v. If the 67 mg/m2 dose is well tolerated for at least three sequential weekly treatments the patient's dose may be escalated to 75 mg/m2 i.v. once weekly for the remainder of the study. Dosing will be conducted once per week for a total of 16 weeks.

VAL-083, Dianhydrogalactitol

Bradley J Monk, M.D.

This is an open label, multi-center, Phase 1/2 clinical trial in subjects with recurrent adenocarcinoma of the ovary who have been previously treated with a minimum of two courses of platinum-based chemotherapy, and up to two additional cytotoxic regimens that may also have included platinum (no more than four total lines of prior therapy), with or without bevacizumab, whose cancer has recurred within six months of the most recent platinum-based chemotherapy. All eligible subjects will receive VAL 083 i.v. in a once weekly cycle until disease progression, development of other unacceptable toxicity, death, withdrawal of consent, loss to follow-up, or Sponsor ending the study, whichever occurs first.

The basis of drug treatment for advanced-stage ovarian cancer in the first-line setting is platinum (cisplatin or carboplatin) plus taxane (paclitaxel or docetaxel), with or without bevacizumab. First line treatment regimens often result in high response rates, but most tumors will recur within 2 years and patients die within 3 to 4 years of diagnosis. If a patient progresses after 2 consecutive regimens without a response (refractory) or has recurrent ovarian cancer within 6 months from their last platinum-based regimen (platinum-resistant), prognosis is poor. The absence of an approved treatment or standard of care in the recurrent setting represents an unmet need.

Early NCI studies in the 1970s and 1980s support VAL-083 activity in ovarian cancer. Interest in this agent for ovarian cancer has recently re-emerged. The unique functional groups and cytotoxic mechanisms are hoped to provide a viable novel treatment option in patients with recurrent ovarian cancer that was resistant to platinum chemotherapies.

This is an open label, multi-center, Phase 1/2 clinical trial in subjects with recurrent adenocarcinoma of the ovary who have been previously treated with a minimum of two courses of platinum-based chemotherapy, and up to two additional cytotoxic regimens that may also have included platinum (no more than four total lines of prior therapy), with or without bevacizumab, whose cancer has recurred within six months of the most recent platinum-based chemotherapy.

Study subjects will initially receive VAL-083 60 mg/m2 i.v. once weekly. If this regimen is well tolerated for at least three sequential weekly treatments, the patient's dose may be escalated to 67 mg/m2 i.v. If the 67 mg/m2 dose is well tolerated for at least three sequential weekly treatments, the patient's dose may be escalated to 75 mg/m2 i.v. once weekly for the remainder of the study. Dosing will continue once weekly for 16 weeks or until disease progression, development of other unacceptable toxicity, death, withdrawal of consent, loss to follow-up, or Sponsor ending the study, whichever occurs first. The treatment plan is to enroll a minimum number of 20 subjects in Phase 1, followed by expansion of enrollment in Phase 2 using the optimal dosing regimen determined in Phase 1.

Hematological safety assessments will be conducted at Screening and weekly before each treatment. Clinical evaluations for physical examination, vital signs, disease symptoms, quality of life measures (FOSI and opioid pain medication use), adverse events and concomitant medications will be completed while the subject remains on study treatment. Radiographic assessments (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) to obtain tumor measurements and CA-125 concentration will be conducted at Screening and every 8 weeks while on study treatment, independent of dose delays and/or dose interruptions, until progression of disease is suspected.

Pharmacokinetics will be evaluated in each of the first 10 subjects who have plasma samples drawn on Day 1 of study treatment: pre-dose, then 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of i.v. infusion with VAL-083.

A post-treatment safety assessment is to be scheduled 28 ±7 days after the last dose of study treatment.

Follow-up for subjects terminating from study for any reason other than withdrawal of consent will be done to allow an exploratory assessment of survival. All anti-tumor treatments received after discontinuing treatment with VAL-083 will be collected, if available, and survival status will also be reported to the Sponsor, on a monthly basis, when survival data are available. In addition to survival, this assessment includes outcomes for subsequent anticancer therapies including any new malignancy information. Date and cause of death will be recorded.

The primary reason for study completion and discontinuation from monthly follow-up will be captured for each study subject.

A Multi-center Study of VAL-083 in Patients With Recurrent Platinum Resistant Ovarian Cancer

A Phase 1/2, Open Label, Multi-center Study of VAL-083 in Patients With Recurrent Platinum Resistant Ovarian Cancer

The Clinical Study Report for this trial will be prepared and provided to the U.S. FDA as required by applicable regulatory requirement(s). Each participating trial investigator will be provided a copy of their patient data captured in the database for this trial.

Overall number of tumor complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria or GCIG criteria using computed tomography (CT) or magnetic resonance imaging (MRI)

Using NCI CTCAE version 4 criteria to assess frequency, severity and study drug relationship of clinically significant changes in vital signs, lab test results, EKGs or any other adverse events reported while patients are receiving treatment with VAL-083

To measure the changes in concentration of CA-125 antigen levels in blood

Time from start of treatment until first occurrence of progression or patient death, whichever occurs first

Progression-free Survival for VAL-083 compared to Progression-free Survival for patient's last treatment regimen received

Time from start of treatment to achievement of either complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria or GCIG criteria using computed tomography (CT) or magnetic resonance imaging (MRI)

Length of time from start of treatment until patient death

Maximum observed plasma concentration of VAL-083 in the first 10 study subjects receiving VAL-083

Time of maximum observed plasma concentration of VAL-083 in the first 10 study subjects receiving VAL-083

Area under the concentration-time curve from pre-dose (time 0) to the time of the last quantifiable concentration of VAL-083 in plasma for the first 10 study subjects receiving VAL-083

Area under the concentration-time curve extrapolated to infinity for VAL-083 in plasma of the first 10 study subjects receiving VAL-083

Terminal elimination rate constant determined by selection of at least 3 decreasing data points on the terminal phase of the concentration-time curve for VAL-083 in plasma of the first 10 study subjects receiving VAL-083

Terminal elimination half-life of VAL-083 in plasma of the first 10 study subjects receiving VAL-083

Functional Assessment of Cancer Therapy - Ovarian Symptom Index (FOSI)

DelMar Pharmaceuticals, Inc.

Temozolomide

A single dose of Intraarterial Mannitol to open the blood brain barrier followed by Intra-arterial Temozolomide single dose (starting at 75mg/m2 and up to 250mg/m2)

Super-Selective Intraarterial Intracranial Infusion of Temozolomide

The high-grade malignant brain tumors, glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), comprise the majority of all primary brain tumors in adults. This group of tumors also exhibits the most aggressive behavior, resulting in median overall survival durations of only 9-12 months for GBM, and 3-4 years for AA. Initial therapy has consisted of surgical resection, external beam radiation or both. More recently, a Phase 3 clinical published by Stupp et al in 2005 showed a benefit for using radiotherapy plus concomitant and adjuvant Temozolomide. Still, all patients experience a recurrence after first-line therapy, so improvements in both first-line and salvage therapy are critical to enhancing quality-of-life and prolonging survival. It is unknown if currently used intravenous (IV) therapies even cross the blood brain barrier (BBB). Superselective Intra-arterial Cerebral Infusion (SIACI) is a technique that can effectively increase the concentration of drug delivered to the brain while sparing the body of systemic side effects. One currently used drug called Temozolomide (Temodar) has been shown to be active in human brain tumors but its actual central nervous system (CNS) penetration is unknown. This phase I clinical research trial will test the hypothesis that following the standard 42 day Temozolomide/radiotherapy regimen, Temozolomide can be safely used by direct intracranial superselective intra-arterial cerebral infusion (SIACI) up to a dose of 250mg/m2, followed by the standard maintenance cycle of temozolomide to ultimately enhance survival of patients with newly diagnosed GBM/AA. The investigators will determine the toxicity profile and maximum tolerated dose (MTD) of SIACI Temozolomide. The investigators expect that this project will provide important information regarding the utility of SIACI Temozolomide therapy for malignant gliomas, and may alter the way these drugs are delivered to our patients in the near future.

The current standard of care for newly diagnosed GBM is radiation therapy plus concomitant oral Temozolomide of doses of 75mg/m2 up to 150mg/m2. Because of the blood brain barrier (BBB) where drugs do not penetrate the blood vessel walls well to get into the brain, no one knows for sure if these oral drugs actually get into the brain after infusion. Previous studies have shown that intra-carotid artery (intra-arterial) delivery is superior to standard intravenous or oral delivery for increasing the penetration of drug to the brain. Previous techniques using intra arterial (intracarotid) infusion still were non-selective as drug delivery still went to all blood vessels in the brain, so patients still had significant adverse events, such as blindness. Newer techniques in interventional neuroradiology have allowed for a more selective delivery of catheters into the arterial tree where chemotherapies can be delivered without the risk of adverse affects such as blindness. Therefore, this trial will ask one simple question: Is it safe to deliver a dose of Temozolomide intraarterially using these super selective delivery techniques in addition to the standard oral route of administration? This should not only increase the amount of drug that gets to the tumor but also spare the patient many of the adverse effects from a less selective delivery. Prior to this single dose of intra-arterial Temozolomide, the patient will also receive a dose of mannitol that will increase the permeability of the blood brain barrier to improve delivery of the agent to the brain. After this single dose of mannitol and Temozolomide, the patient will be evaluated for 4 weeks to assess for toxicity. If there is no toxicity at this point, then the patient will proceed with oral maintenance Temozolomide chemotherapy. In summary, this is a Phase I trial that is designed to test the safety of a single dose of intra-arterial delivery of Temozolomide immediately following 42 days of radiotherapy/oral temozolomide and prior to starting oral maintenance Temozolomide.

To summarize:

Current Standard of Care Therapy:

Days 1-42: Adjuvant dose of Temozolomide 75mg/m2 for 42 days concomitant with focal radiotherapy Day 42: 4 week rest period Day 70: Maintenance dose of Temozolomide 150mg/m2 once daily for Days 1-5 of a 28 day cycle for 6 cycles

Experimental portion of this proposal:

Days 1-42: Adjuvant dose of Temozolomide 75mg/m2 for 42 days concomitant with focal radiotherapy Day 42: Single Intra-arterial Mannitol to increase the permeability of the blood brain barrier followed by Intra-arterial Temozolomide single dose (starting at 75mg/m2 and up to 250mg/m2) followed by 4 week rest period Day 70: Maintenance dose of Temozolomide 150mg/m2 once daily for Days 1-5 of a 28 day cycle for 6 cycles

Therefore the experimental aspects of this treatment plan will include:

1. On day 42, subjects will first be treated with Mannitol prior to chemotherapy infusion (Mannitol 25%; 3-10 mLs for 30seconds) in order to disrupt the blood brain barrier. This technique has been used in several thousand patients in previous studies for the intraarterial (IA) delivery of chemotherapy for malignant glioma.
2. Following the addition of mannitol, the investigators will deliver a single SIACI dose of Temozolomide for patients with high-grade glioma. After a one-cycle observation period to assess for toxicity from the IA infusion, the subject will receive the standard oral maintenance regimen of Temozolomide chemotherapy. The Intra-Arterial Infusion Procedure will be done under general anesthesia and standard monitoring will occur.

The dose escalation algorithm is as follows: The investigators will use a single intracranial superselective intra-arterial infusion of Temozolomide, starting at a dose of 75mg/m2 in the first three patients. Assuming no dose limiting toxicity during the next 28 days after the infusion, the patient will then begin standard maintenance oral Temozolomide chemotherapy regimen. The doses will be escalated from 75 to 100, to 150, 200, and finally 250mg/m2 in this Phase I trial.

Most patients with GBM are also monitored every two months with serial history, neurological and physical examinations together with serial blood counts, prothrombin time (PT), partial thromboplastin time (PTT) and chemistries. In addition, most patients with GBM have an MRI performed every two cycles or approximately every two months to assess for tumor progression. .

Since this is a Phase I trial, response is not a primary endpoint. However, the investigators will evaluate response to the one time IA Temozolomide therapy with a MRI with the injection of contrast approximately 4 weeks after infusion. Follow-up of all patients in the trial after the IA Temozolomide therapy will continue until disease progression or death. Survival will be measured from the time of the dose of IA Temozolomide®. The investigators expect patients in the trial to be monitored for 12 months.

Super-Selective Intraarterial Cerebral Infusion Of Temozolomide (Temodar) For Treatment Of Newly Diagnosed GBM And AA

Phase I Trial of Super-Selective Intraarterial Cerebral Infusion of Temozolomide (Temodar) for Treatment of Newly Diagnosed Glioblastoma Multiforme and Anaplastic Astrocytoma

Hofstra North Shore

Carboplatin

Day 0: Intraarterial Bevacizumab single dose (15mg/kg) plus Intraarterial Carboplatin (150mg/m2) after Mannitol to open the blood brain barrier

Day 28: Intravenous Bevacizumab (10mg/kg) plus Carboplatin (AUG5) every two weeks thereafter until disease progression on MRI scan.

If progression occurs, repeat intraarterial Bevacizumab single dose (15mg/kg) plus intraarterial Carboplatin (150mg/m2) to area of progression and wait 28 days and then restart Intravenous Bevacizumab (10mg/kg) plus Carboplatin (AUG5) every two weeks thereafter until progression on MRI scan.

Repeat Cycle

Bevacizumab and Carboplatin

Day 0: Intraarterial Bevacizumab single dose (15mg/kg) plus Intraarterial Carboplatin (150mg/m2) after Mannitol to open the blood brain barrier

Day 28: No biweekly IV Bevacizumab plus Carboplatin treatment

If MRI shows progression then repeat intraarterial Bevacizumab single dose (15mg/kg) plus intraarterial Carboplatin (150mg/m2) to area of progression Repeat Cycle

The high-grade malignant brain tumors, glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), comprise the majority of all primary brain tumors in adults. This group of tumors also exhibits the most aggressive behavior, resulting in median overall survival durations of only 9-12 months for GBM, and 3-4 years for AA. Initial therapy consists of either surgical resection, external beam radiation or both. All patients experience a recurrence after first-line therapy, so improvements in both first-line and salvage therapy are critical to enhancing quality-of-life and prolonging survival. It is unknown if currently used intravenous (IV) therapies even cross the blood brain barrier (BBB). The investigators have shown in a previous phase I trial that a single Superselective Intraarterial Cerebral Infusion (SIACI) of Bevacizumab (up to 15mg/kg) is safe and effective in the treatment of recurrent GBM. Therefore, this phase I/II clinical research trial is an extension of that trial in that the investigators seek to test the hypothesis that repeated dosing of intra-arterial Bevacizumab is safe and effective in the treatment of recurrent malignant glioma. Additionally the investigators will analyze if a combination with IA Carboplatin will further improve the treatment response. By achieving the aims of this study the investigators will also determine if IV therapy with Bevacizumab with IV Carboplatin should be combined with repeated selected intra-arterial Bevacizumab plus Carboplatin to improve progression free and overall survival. The investigators expect that this project will provide important information regarding the utility of repeated SIACI Bevacizumab therapy for malignant glioma, and may alter the way these drugs are delivered to the investigators patients in the near future.

Repeated Super-selective Intraarterial Cerebral Infusion Of Bevacizumab Plus Carboplatin For Treatment Of Relapsed/Refractory GBM And Anaplastic Astrocytoma

Phase I/II Trial Of Repeated Super-selective Intraarterial Cerebral Infusion Of Bevacizumab Plus Carboplatin For Treatment Of Relapsed/Refractory Glioblastoma Multiforme And Anaplastic Astrocytoma

The composite overall response rate (CORR) will be examined. The overall response proportion along with a 95% confidence interval will be estimated via binomial proportions.

PFS will be measured from the date of the first dose of SIACI Bevacizumab plus Carboplatin to the date of progression. OS will be measured from the date of the first dose of SIACI Bevacizumab plus Carboplatin to the date of death.

The descriptive frequency of subjects experiencing toxicities will also be tabulated. Toxicities will be assessed and graded according to the NCI Common Toxicity Criteria, version 3.0.

Heart and Blood Diseases

Oligodendroglioma

Mitral Valve Insufficiency

Anaplastic Oligodendroglioma

Carmustine

MRS to study epilepsy, Alzheimer's disease, brain tumors, and the effects of drugs on brain growth and metabolism.

Magnetic Resonance Spectroscopy uses a continuous band of radio wave frequencies to excite hydrogen atoms in a variety of chemical compounds other than water. These compounds absorb and emit radio energy at characteristic frequencies, or spectra, that can be used to identify them. Generally, a color image is created by assigning a hue to each distinctive spectral emission. This comprises the "spectroscopy" part of MRS. MRS is still experimental, and is available in only a few research centers.

Physicians mainly use MRS to study the brain and disorders such as epilepsy, Alzheimer's disease, brain tumors, and the effects of drugs on brain growth and metabolism. The technique is also useful in evaluating metabolic disorders of the muscles and nervous system. MRS is a noninvasive scan similar to an MRI that may be done at the same time as an MRI.

MRS Spectroscopy

Susan C. Pannullo, MD

Subjects with newly diagnosed brain tumors who undergo surgical resection and whose pathology in the operating room shows a high grade glioma will be eligible.

During a screening visit, the study will be discussed, inform consent discussed and signed, a medical history will be taken and a physical examination and laboratory tests will be performed. If these tests are all within acceptable ranges, the subject will be considered for inclusion on this treatment protocol. If the results of any tests are extremely different from normal expected values, she/he may not be able to participate.

Prior to surgery, the subject will have a contrast enhanced MRI and MRS. The neurosurgeon will attempt to remove the majority of the tumor in the operating room and will send a portion of the specimen removed to the pathologist immediately. This is called a "frozen section". If the pathologist believes that the tumor is a high-grade malignant brain tumor, then the surgeon will place up to 8 dime-sized chemotherapy wafers in the tumor cavity of the brain. The remainder of the tumor specimen will be given to the pathologist to review more closely in the laboratory. If the frozen section does not show that the tumor is a high-grade malignant brain tumor, the subject will not receive the Gliadel wafers and will be removed from the study. The surgeon will then discuss with the subject the appropriate treatment options for the disease he or she has.

During recovery in the hospital, another contrast enhanced MRI will be performed within the first 72 hours after surgery. This is a standard of care for patients who are not involved on this protocol as well. The subject will have another contrast enhanced MRI and MRS performed at the 21st Day after his or her surgery. After Day 21, He or she may begin other forms of treatment. The last contrast enhanced MRI and MRS assessment will be performed 12 weeks after the surgery and the implantation of the Gliadel wafers. Further MRI and MRS may be performed subsequently at the discretion of the doctor.

Throughout the course of treatment, clinical data will be collected.

Examination of Changes on Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) in Patients Who Receive Gliadel Wafers During Initial Surgery for Glioblastoma Multiforme. Response or Failure to Gliadel Wafers for Subjects With Glioblastoma Multiforme.

Treatment Of Newly Diagnosed, High-Grade, Malignant Glioma With Polifeprosan 20 Containing Carmustine Implant (Gliadel® Wafer) Using MR Spectroscopy Data As A Primary Indicator Of Therapeutic Response.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Repeated Super-selective Intraarterial Cerebral Infusion of Bevacizumab (Avastin) for Treatment of Relapsed GBM and AA	NCT01269853	Glioblastoma Mu... Anaplastic Astr...	Bevacizumab Bevacizumab	18 Years -	Northwell Health
Super-Selective Intraarterial Intracranial Infusion of Avastin (Bevacizumab)	NCT00968240	Glioblastoma Mu... Anaplastic Astr...	Super-Selective...	18 Years -	Northwell Health
A Multi-center Study of VAL-083 in Patients With Recurrent Platinum Resistant Ovarian Cancer	NCT03281681	Ovarian Cancer	VAL-083, Dianhy...	18 Years -	Kintara Therapeutics, Inc.
A Multi-center Study of VAL-083 in Patients With Recurrent Platinum Resistant Ovarian Cancer	NCT03281681	Ovarian Cancer	VAL-083, Dianhy...	18 Years -	Kintara Therapeutics, Inc.
Super-Selective Intraarterial Intracranial Infusion of Avastin (Bevacizumab)	NCT00968240	Glioblastoma Mu... Anaplastic Astr...	Super-Selective...	18 Years -	Northwell Health
Super-Selective Intraarterial Cerebral Infusion Of Temozolomide (Temodar) For Treatment Of Newly Diagnosed GBM And AA	NCT01180816	Glioblastoma Mu... Anaplastic Astr...	Super-Selective...	18 Years -	Northwell Health
Repeated Super-selective Intraarterial Cerebral Infusion Of Bevacizumab Plus Carboplatin For Treatment Of Relapsed/Refractory GBM And Anaplastic Astrocytoma	NCT01386710	Glioblastoma Mu... Anaplastic Astr...	Bevacizumab and... Bevacizumab and...	18 Years -	Northwell Health
A Multi-center Study of VAL-083 in Patients With Recurrent Platinum Resistant Ovarian Cancer	NCT03281681	Ovarian Cancer	VAL-083, Dianhy...	18 Years -	Kintara Therapeutics, Inc.
Super-Selective Intraarterial Intracranial Infusion of Avastin (Bevacizumab)	NCT00968240	Glioblastoma Mu... Anaplastic Astr...	Super-Selective...	18 Years -	Northwell Health
A Multi-center Study of VAL-083 in Patients With Recurrent Platinum Resistant Ovarian Cancer	NCT03281681	Ovarian Cancer	VAL-083, Dianhy...	18 Years -	Kintara Therapeutics, Inc.
Examination of Changes on Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) in Patients Who Receive Gliadel Wafers During Initial Surgery for Glioblastoma Multiforme. Response or Failure to Gliadel Wafers for Subjects With Glioblastoma Multiforme.	NCT00645385	Glioblastoma Mu... Anaplastic Astr... Anaplastic Olig...	MRS Spectroscop...	18 Years - 85 Years	Weill Medical College of Cornell University

Spots Global Cancer Trial Database for ao

Every month we try and update this database with for ao 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 ao

Every month we try and update this database with for ao 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 ao 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.