Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Recurrence

Glioma

Brain Neoplasms

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Channel Blockers

Bone Density Conservation Agents

Bevacizumab

Lomustine

Carboxyamido-triazole

Antineoplastic Agents, Alkylating

Alkylating Agents

Calcium

Calcium Channel Blockers

Calcium, Dietary

Hormones

The combination of CTO with the standard dosing of 100 mg/m2 of lomustine among patients with recurrent malignant glioma (World Health Organization (WHO) grade III or IV) that have not previously received bevacizumab as treatment for their disease

CTO alone at the MTD established in the Phase 1 portion of this study

CTO at the same daily dose of as in the CTO alone arm in combination with 110 mg/m2 oral lomustine every 6 weeks

Oral lomustine alone at 110 mg/m2 every 6 weeks

Annick Desjardins, MD, FRCPC

This is a Phase 1/2 study of the combination of CTO with lomustine in patients with recurrent malignant glioma to be treated at the Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke. The Primary Objectives are:

* Phase 1: To determine the maximum tolerated dose (MTD) of CTO when combined with lomustine among patients with recurrent malignant glioma (World Health Organization (WHO) grade III or IV) who have not been previously treated with bevacizumab.
* Phase 2: To assess the efficacy of CTO (either in monotherapy or in combination with lomustine) compared to lomustine alone in patients with recurrent WHO grade IV malignant gliomas that have not been previously treated with bevacizumab based upon 6-month progression free survival (PFS6).

Note: This study was terminated early due to funding issues. At the time of termination, the study was still in Phase 1 and no MTD for the combination of CTO and lomustine had been determined for this population. Phase 2 will not proceed.

In the Phase 1 component of the study, we will conduct a dose-escalation study of the combination of CTO with lomustine among patients with recurrent malignant glioma (WHO grade III or IV). All patients will be bevacizumab-naïve. The dose escalation will be a standard "3+3" design to determine the MTD of CTO in combination with lomustine. The Phase 2 portion of this study will be a randomized screening study comparing CTO alone (Arm A) versus CTO with lomustine (Arm B) versus lomustine alone (Arm C) in patients with recurrent WHO grade IV malignant glioma who are bevacizumab-naïve. Subjects will be randomized with a treatment arm allocation ratio of 2:2:1.

Based on the results of patients who have already taken part in Phase 1 of the study, the Principal Investigator has decided to reduce the dose of lomustine used in combination with CTO in this study by 25% of the FDA-approved dose, due to hematologic side effects (side effects related to lower than expected blood counts). Therefore, the dose of lomustine received in combination with CTO is approximately 75% of the standard recommended dose.

Note: This study was terminated early due to funding issues. At the time of termination, the study was still in Phase 1 and no MTD for the combination of CTO and lomustine had been determined for this population. Phase 2 will not proceed.

Ph 1/2 CTO With Lomustine for Bevacizumab-Naive Recurrent Glioma

A Phase 1/2 Unblinded Trial of Carboxyamidotriazole Orotate (CTO) Alone or in Combination With Lomustine for Bevacizumab-Naïve Adult Patients With Recurrent Malignant Glioma

A standard "3+3" design to determine the MTD of CTO in combination with lomustine. Subjects will be administered CTO orally on a continuous daily dosing schedule, while subjects will receive oral lomustine (110 mg/m2) every 6 weeks. Cohorts of 3-6 subjects will accrue at each dose level of CTO, beginning with 225 mg/m2, until MTD is defined. The MTD is the highest dose level at which ≤ 1 out of 6 experienced a dose limiting toxicity (DLT).

MTD is defined as the highest dose level at which ≤ 1 out of 6 experienced DLT.

Percentage of participants surviving six months from date of randomization without progression of disease. Progression-free survival (PFS) was defined as the time from date of randomization to the date of the first documented progression according to the Response Assessment in Neuro-Oncology (RANO) criteria, or to death due to any cause.

All toxicities will be collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. DLTs will be defined as any of the following events that are possibly, probably, or definitely attributable to CTO or lomustine:

Non-hematologic:

* Nausea/vomiting of Grade 3 or greater despite maximal antiemetic therapy
* Diarrhea of Grade 3 or greater despite maximal antidiarrheal therapy
* Any other Grade 3 or 4 non-hematologic toxicity

Hematologic:

* Any Grade 4 neutropenia
* Grade 3 neutropenia associated with fever of any duration or where significant sepsis results
* Grade 4 thrombocytopenia

Time in months from date of randomization 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.

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

Response is based on Response Assessment in Neuro-Oncology (RANO) criteria as determined by investigator assessment. A confirmation of response was not required. Complete Response was defined as complete disappearance on MRI/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. Partial Response was defined as greater than or equal to 50% reduction in tumor size on MRI/CT 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.

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

Tactical Therapeutics, Inc.

Annick Desjardins

Associate Professor of Medicine

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

The combination of CTO with the standard dosing of bevacizumab of 10 mg/kg every 2 weeks among patients with recurrent malignant glioma (World Health Organization (WHO) grade III or IV) that have previously failed bevacizumab

The first 25 patients will be treated with CTO alone at the maximum tolerated dose (MTD) established in the Phase 1 portion of the study.

The second group of 25 patients will be treated with the combination of CTO at the MTD established in the Phase 1 portion of this study and standard dosing of bevacizumab.

CTO and Bevacizumab

CTO alone

The primary objectives of the study are to determine the maximum tolerated dose (MTD) of Carboxyamidotriazole Orotate (CTO) when combined with standard dosing of bevacizumab among patients with recurrent malignant glioma (WHO grade III or IV) that have previously failed bevacizumab (Phase 1); to determine the activity of CTO alone in bevacizumab-failure WHO grade IV malignant glioma patients (Phase 2, Arm 1); to determine the activity of CTO plus bevacizumab in bevacizumab-failure WHO grade IV malignant glioma patients (Phase 2, Arm 2).

This study was terminated early due to funding issues. At the time of termination, the study was still in Phase 1 and no MTD for the combination of CTO and bevacizumab had been determined for this population. Phase 2 will not proceed.

In Phase 1 of the study, we will conduct a dose-escalation study of the combination of CTO with the standard dosing of bevacizumab among patients with recurrent malignant glioma (WHO Grade III or IV) that have previously failed bevacizumab. All patients will have also received standard treatment with radiation therapy and temozolomide prior to enrollment on study.

The Phase 2 portion of this study will investigate two novel treatment regimens sequentially. Each regimen will include 25 patients with recurrent WHO grade IV malignant glioma who have been treated in the past with standard radiation therapy, temozolomide, and bevacizumab. All patients must have failed therapy while on bevacizumab. Subjects in the first treatment regimen will receive CTO alone and subjects in the second treatment regimen will receive the combination of CTO and bevacizumab together.

Note: This study was terminated early due to funding issues. At the time of termination, the study was still in Phase 1 and no MTD for the combination of CTO and bevacizumab had been determined for this population. Phase 2 will not proceed.

Phase 1/2 CTO + Bevacizumab for Recurrent Glioma Post-Bevacizumab Failure

A Phase 1/2 Trial of Carboxyamidotriazole Orotate (CTO) Alone or in Combination With Bevacizumab for Adult Patients With Recurrent Malignant Glioma Post-Bevacizumab Failure

A standard "3+3" design to determine the MTD of CTO in combination with bevacizumab. Subjects will be administered CTO orally on a continuous daily dosing schedule, while subjects will receive bevacizumab (10 mg/kg) every 2 weeks. Cohorts of 3-6 subjects will accrue at each dose level of CTO, beginning with 225 mg/m2, until MTD is defined. The MTD is the highest dose level at which ≤ 1 out of 6 experienced a dose limiting toxicity (DLT).

Percentage of participants surviving six months from start of study treatment without progression of disease. Progression-free survival (PFS) was defined as the time from start of study treatment to the date of the first documented progression according to the Response Assessment in Neuro-Oncology (RANO) criteria, or to death due to any cause.

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

Percentage of participants surviving 6 and 12 months from start of study treatment. OS is defined as time from start of study treatment to the date of death due to any cause.

Response is based on Response Assessment in Neuro-Oncology (RANO) criteria as determined by investigator assessment. A confirmation of response was not required. Complete Response was defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. Partial Response was defined as greater than or equal to 50% reduction in tumor size on MR/CT 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.

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

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Ph 1/2 CTO With Lomustine for Bevacizumab-Naive Recurrent Glioma	NCT01989052	Malignant Gliom...	CTO Lomustine	18 Years -	Duke University
Phase 1/2 CTO + Bevacizumab for Recurrent Glioma Post-Bevacizumab Failure	NCT01954030	Malignant Gliom...	CTO and Bevaciz... CTO alone	18 Years -	Duke University
Phase 1/2 CTO + Bevacizumab for Recurrent Glioma Post-Bevacizumab Failure	NCT01954030	Malignant Gliom...	CTO and Bevaciz... CTO alone	18 Years -	Duke University

Spots Global Cancer Trial Database for malignant glioma (who grade iii or iv)