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

NCT01989052•Annick Desjardins

View on ClinicalTrials.gov

Summary

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.

Detailed Description

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.

Eligibility

Age

18 - No limit years

Sex

ALL

Healthy Volunteers

Inclusion Criteria

•Phase 1 portion: Patients must have recurrent histologically confirmed diagnosis of WHO grade III or IV malignant glioma with no more than 3 prior progressions
•Phase 2 portion: Patients must have recurrent histologically confirmed diagnosis of WHO grade IV malignant glioma (glioblastoma or gliosarcoma) with no more than 3 prior progressions
•Patients should have received optimal surgical management and radiotherapy prior to study enrollment
•Age ≥ 18 years
•Karnofsky Performance Status (KPS) ≥ 70%
•Bi-dimensionally measurable disease as assessed by magnetic resonance imaging based on RANO criteria
•Absolute Neutrophil Count (ANC) ≥ 1000 cells/µl, Platelets ≥ 100,000 cells/µl (without transfusion within 14 days before enrollment)
•Adequate renal function as indicated by the following: Serum creatinine \< 1.25 times upper limit of normal or calculated creatinine clearance ≥ 50 ml/minute and urine dipstick for proteinuria \< 2+ unless a 24-hour urine protein \<1 g of protein is demonstrated
•Prothrombin time (PT) ≤ 1.5 x upper limit of normal (ULN) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN within 14 days prior to first study treatment for patients not receiving anti-coagulation. The use of full-dose oral or parenteral anticoagulants is permitted as long as the PT or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the first study treatment.
•For patients on corticosteroids, they must be on a stable dose for 7 days prior to anticipated start of study drug, and the dose should not be escalated over entry dose level, if clinically possible.
+4 more criteria

Exclusion Criteria

•Pregnancy or breastfeeding
•Treated previously with vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) therapies, including antibodies and tyrosine kinase inhibitors
•Prior disease progression on lomustine
•Taking cytochrome P450 3A4 (CYP3A4) inducers and moderate or strong inhibitors. To note: Corticosteroids are allowed, as long as patients have been on a stable dose for 7 days prior to anticipated start of study drug, and the dose should not be escalated over entry dose level, if clinically possible.
•Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids
•Active infection requiring IV antibiotics 7 days before enrollment
•Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin
•Less than 12 weeks from radiation therapy, unless progressive disease outside of the radiation field or 2 consecutive scans or histopathologic confirmation
•Treated with immunotherapeutic agents, vaccines, or monoclonal antibody (MAb) therapy within 4 weeks before enrollment, unless the patient has recovered from the expected toxic effects of such therapy
•Treated with alkylating agents within 4 weeks before enrollment or treated within 1 week before enrollment with daily or metronomic chemotherapy, unless the patient has recovered from the expected toxic effects of such therapy
+17 more criteria

Locations (1)

The Preston Robert Tisch Brain Tumor Center at Duke

Durham, North Carolina, United States

Key Dates

Start Date

May 1, 2014

Primary Completion Date

March 1, 2015

Completion Date

February 1, 2016

Last Updated

August 4, 2016

Enrollment

ACTUAL participants

Conditions

Malignant Glioma (WHO Grade III or IV)

Interventions

CTO

DRUG

Lomustine

DRUG