dose dense TMZ 125 mg/m2 x 7 days on / 7days off plus Zotiraciclib (TG02) dose escatlation

metronomic TMZ 50 mg/ m2 daily plus Zotiraciclib (TG02) doseescalation

MTD of Zotiraciclib (TG02) from phase I plus and "winner" of dd vs metronomic TMZ from phase I

"winner" of dd vs metronomic TMZ from phase I alone

Brain Tumor

Astrocytoma

Astroglioma

Glioblastoma

Gliosarcoma

Phase I: Two treatment arms and several dose levels are planned; In the MTD finding part, TMZ with two alternate schedules (dd and mn) in combination with Zotiraciclib (TG02) will be administered;
--A cohort extension of both arms will be performed at each MTD and the treatment arm with a better progression free survival at 4 months (PFS4) will be selected for the combination treatment arm for Phase II; Patients will be randomized between two competing treatment arms: ( winner of dd vs mn) TMZ + Zotiraciclib (TG02) versus dd/mn TMZ alone using a Bayesian clinical trial design. The dosage for the combination arm will be derived from the MTD determined in the Phase I component of the study.

Zotiraciclib (TG02)

Phase I: In the MTD finding part, TMZ with two alternate schedules (dd and mn) in combination with Zotiraciclib (TG02) will be administered; A cohort extension of both arms will be performed at each MTD and the treatment arm with a better progression free survival at 4 months (PFS4) will be selected for the combination treatment arm for Phase II; Patients will be randomized between two competing treatment arms: ("winner" of dd vs mn) TMZ + Zotiraciclib (TG02) versus dd/mn TMZ alone using a Bayesian clinical trial design.

National Institutes of Health Clinical Center

Zotiraciclib (TG02) Plus Dose-Dense or Metronomic Temozolomide Followed by Randomized Phase II Trial of Zotiraciclib (TG02) Plus Temozolomide Versus Temozolomide Alone in Adults With Recurrent Anaplastic Astrocytoma and Glioblastoma

Phase I Trial of Zotiraciclib (TG02) Plus Dose-Dense or Metronomic Temozolomide Followed by Randomized Phase II Trial of Zotiraciclib (TG02) Plus Temozolomide Versus Temozolomide Alone in Adults With Recurrent Anaplastic Astrocytoma and Glioblastoma

maximum tolerated dose of Zotiraciclib (TG02)

Median amount of time subject survives without disease progression after treatment

National Cancer Institute (NCI)

Panitumumab in Combination with Irinotecan : Panitumumab, 6mg/kg, as an intravenous infusion every other week in combination with Irinotecan (dose dependent upon whether the patient is taking an enzyme-inducing anti-epileptic drug [EIAED]). On an enzyme-inducing anti-epileptic drug (EIAED), irinotecan will be dosed at 340 mg/m2 every other week. Not on an EIAED, irinotecan will be dosed at 125 mg/m2. Treatment will continue until tumor progression or unacceptable toxicity.

Panitumumab and Irinotecan

Sex: Female, Male

Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. Macdonald criteria are standard criteria in neuro-oncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of: 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), and 3) concomitant steroid use (as reported by the investigator).

6-month Progression-free Survival (PFS)

Percentage of participants surviving 12 months from the start of study treatment. OS was defined as the time from the date of study treatment initiation to the date of the death due to any cause.

One-Year Overall Survival

Number of participants experiencing a toxicity ≥ grade 3 as graded per CTCAE v.3.0

Safety of Panitumumab in Combination With Irinotecan

Average change in corticosteroid dose from baseline to the end of cycle 1.

Effect of Panitumumab in Combination With Irinotecan on Corticosteroid Dose

Number of participants with an abnormal fluorescence in situ hybridization (FISH) interpretation that 1) survived < 6 months and 2) experienced a ≥ grade 3 toxicity as graded per CTCAE v.3.0

Relationship Between Epidermal Growth Factor Receptor (EGF-R) Mutational Analysis and Efficacy or Toxicity

Number of participants with an objective response (complete response or partial response) based on modified Macdonald criteria. A complete response is defined as the disappearance of all enhancing rumor and mass effect, off all corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. A partial response is defined as greater than or equal to 50% reduction in tumor size on MR (magnetic resonance) / CT(computed tomography) by bi-dimensional measurement on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks.

Objective Response Rate

Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.

Median Overall Survival (OS)

Overall Study

Annick Desjardins

Malignant Glioma of Brain

Irinotecan: for those patients on an enzyme-inducing anti-epileptic drug (EIAED), irinotecan will be dosed at 340 mg/m2 every other week. For those not on an EIAED, irinotecan will be dosed at 125 mg/m2. Treatment on both drugs will continue until tumor progression or unacceptable toxicity.

Irinotecan

Panitumumab, 6 mg/kg, as an intravenous infusion every other week. Treatment on both drugs will continue until tumor progression or unacceptable toxicity.

Panitumumab

The Preston Robert Tisch Brain Tumor Center at Duke

The Preston Robert Tisch Brain Tumor Center at Duke University Medical Center

Panitumumab and Irinotecan for Malignant Gliomas

Phase II Study of Panitumumab in Combination With Irinotecan for Malignant Gliomas

Assist Professor of Medicine-Neurology

Amgen

Patients are treated with standard radiation therapy and daily temozolomide at 75 mg/ m2 daily for 6.5 weeks of radiation. Following completion of radiation therapy, patients have a MRI and, if there is no evidence of disease progression, patients receive 12 cycles of Avastin, temozolomide, and topotecan. Beginning a minimum of 14 days after the last radiation treatment, the Avastin is dosed at 10 mg/kg every other week; temozolomide is given at 150 mg/m2 daily the first 5 days in combination with topotecan on days 2 through 6 at 1.5 mg/ m2 for patient not taking EIAEDs and 2.0 mg/ m2 for patients taking EIAEDs on days 2-6 of each 28-day.

Avastin, XRT, Temodar followed by Avastin, Temodar, Topotecan : Standard radiation therapy and daily temozolomide at 75 mg/ m2 daily for 6.5 weeks of radiation in combination with Avastin at 10 mg/kg every other week.
This will be followed by Avastin at 10 mg/kg every other week, temozolomide at 150 mg/m2 daily the first 5 days in combination with topotecan at 1.5 mg/m2 (patients not taking enzyme-inducing anti-epileptic drugs) or 2.0 mg/m2 (patients taking enzyme-inducing anti-epileptic drugs) on Days 2-6 of each 28-day cycle.

Avastin, XRT, Temodar Followed by Avastin, Temodar, Topotecan

Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause.

Bevacizumab, XRT, Temozolomide followed by Bevacizumab, Temozolomide, Topotecan : Standard radiation therapy and daily temozolomide at 75 mg/ m2 daily for 6.5 weeks of radiation in combination with Bevacizumab at 10 mg/kg every other week.
This will be followed by Bevacizumab at 10 mg/kg every other week, temozolomide at 150 mg/m2 daily the first 5 days in combination with topotecan at 1.5 mg/m2 (patients not taking enzyme-inducing anti-epileptic drugs) or 2.0 mg/m2 (patients taking enzyme-inducing anti-epileptic drugs) on Days 2-6 of each 28-day cycle.

Bevacizumab, XRT, Temozolomide, Topotecan

6-month Progression-free Survival

Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date.

One and Two Year Overall Survival

OS was defined as time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.

Median Overall Survival

Number of times a CNS hemorrhage or systemic hemorrhage was experienced

Number of Patients Experiencing a Central Nervous System (CNS) Hemorrhage or a Systemic Hemorrhage

Number of times a grade ≥4 hematologic or grade ≥3 non-hematologic toxicity was experienced

Number of Patients Experiencing a Greater Than or Equal to Grade 4 Hematologic or a Greater Than or Equal to Grade 3 Non-hematologic Toxicity

PFS was defined as time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.

Median Progression-free Survival

Dr. Annick Desjardins, MD, FRCPC

Malignant Glioma

Bevacizumab (Avastin) at 10 mg/kg every other week during standard radiation therapy (XRT). Following XRT, bevacizumab will remain at 10 mg/kg every other week.

Bevacizumab

Daily temozolomide at 75 mg/ m2 daily for 6.5 weeks of radiation therapy (XRT). Following XRT, temozolomide will be dosed at 150 mg/m2 daily the first 5 days of each 28-day cycle.

Temozolomide

Standard radiation therapy for approximately 6.5 weeks

Radiation Therapy (XRT)

Following standard radiation therapy, patients will receive topotecan on days 2 through 6 of each 28-day cycle at a dose of 1.5 mg/m2 for patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs) and 2.0 mg/m2 for patients taking EIAEDs.

Topotecan

The Preston Robert Tisch Brain Tumor Center

Avastin/Radiation (XRT)/Temozolomide (Temodar) Followed by Avastin/Temodar/Topotecan for Glioblastoma

Avastin in Combination With Radiation and Temozolomide Followed by Avastin, Temozolomide, and Topotecan for Glioblastoma Multiformes and Gliosarcomas

Duke University

Genentech, Inc.

GlaxoSmithKline

Gliadel/Avastin/CPT-11

The percentage of participants surviving 24 weeks from the start of study treatment

24-week Overall Survival

The percentage of participants surviving 24 weeks from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to modified Macdonald criteria, or to death due to any cause.

24-week Progression-free Survival (PFS)

Time in months from the start of study treatment to the date of first progression according to modified Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.

Gliadel wafers (1-8) inserted at time of gross total resection. CPT-11 (Irinotecan): 125 mg/m2 (no enzyme-inducing anticonvulsant drugs) or 340 mg/m2 (enzyme-inducing anticonvulsant drugs) given every two weeks on days 1, 15, 29 of each 42 day cycle, up to 12 cycles. If the patient has the UGT 1A1 polymorphism (7/7), they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. For patients on an EIAED, the starting dose will be 275 mg/M2, and for patients not on an EIAED, the starting dose will be 75 mg/M2. Avastin: 10 mg/kg immediately after the irinotecan given every 2 weeks on days 1, 15, 29 of each 42 day cycle.

Median Progression-free Survival (PFS)

Time in months from the start of study treatment to date of death due to any cause. Patients alive at last follow-up are censored as of that follow-up date. Median OS was estimated using a Kaplan-Meier curve.

Incidence and Severity of Central Nervous System (CNS) Hemorrhage

Incidence of grade ≥ 4 hematologic and ≥ grade 3 non-hematologic toxicities

Incidence of Grade ≥ 4 Hematologic and ≥ Grade 3 Non-hematologic Toxicities

Gliadel wafers (1-8) inserted at time of gross total resection. CPT-11 (Irinotecan): 125 mg/m2 (no enzyme-inducing anticonvulsant drugs) or 340 mg/m2 (enzyme-inducing anticonvulsant drugs) given every two weeks on days 1, 15, 29 of each 42 day cycle, up to 12 cycles. If the patient has the uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) polymorphism (7/7), they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. For patients on an enzyme-inducing anti-epileptic drugs (EIAED), the starting dose will be 275 mg/M2, and for patients not on an EIAED, the starting dose will be 75 mg/M2. Avastin: 10 mg/kg immediately after the irinotecan given every 2 weeks on days 1, 15, 29 of each 42 day cycle.

Annick Desjardins, MD, FRCPC

Glioblastoma Multiforme

Duke University Medical Center Clinical Trials

gliosarcoma/viduriavimas

Zotiraciclib (TG02) Plus Dose-Dense or Metronomic Temozolomide Followed by Randomized Phase II Trial of Zotiraciclib (TG02) Plus Temozolomide Versus Temozolomide Alone in Adults With Recurrent Anaplastic Astrocytoma and Glioblastoma

Panitumumab and Irinotecan for Malignant Gliomas

Avastin/Radiation (XRT)/Temozolomide (Temodar) Followed by Avastin/Temodar/Topotecan for Glioblastoma

A Study of Gliadel Followed by Avastin + Irinotecan for Glioblastoma Multiforme (GBM)

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