Malignant Glioma (WHO Grade III or IV)
Conditions
Keywords
Carboxyamidotriazole Orotate, CTO, Bevacizumab, Avastin, Malignant Glioma, Pro00044274, Desjardins, Duke, The Preston Robert Tisch Brain Tumor Center
Brief summary
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.
Detailed description
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.
Interventions
DRUGCTO and Bevacizumab
DRUGCTO alone
Sponsors
Tactical Therapeutics, Inc.
Annick Desjardins
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Phase 1 portion: Patients must have recurrent histologically confirmed diagnosis of World Health Organization (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. * Must have had a least 1 prior progression on a bevacizumab-containing regimen * Age greater than or equal to 18 years * Karnofsky ≥ 70% * Bi-dimensionally measurable disease, as assessed by magnetic resonance imaging based on The Revised Assessment in Neuro-Oncology (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 (ULN) or calculated creatinine clearance ≥ 50 ml/min; Urine dipstick for proteinuria \< 2+ unless a 24-hour urine protein \<1 g of protein is demonstrated * Prothrombin time (PT) ≤ 1.5 x 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 * Signed informed consent approved by the Institutional Review Board * No evidence of \> grade 1 active central nervous system (CNS) hemorrhage on the baseline magnetic resonance imaging (MRI) or computed tomography (CT) scan * Female patients must not be pregnant or breast-feeding. Female patients of childbearing potential (defined as \< 2 years after last menstruation or not surgically sterile) must use a highly effective contraceptive method (allowed methods of birth control, \[i.e. with a failure rate of \< 1% per year\] are implants, injectables, combined oral contraceptives, intra-uterine device (IUD) (only hormonal), sexual abstinence or vasectomized partner) during the trial and for a period of \> 6 months following the last administration of trial drug(s). Female patients with an intact uterus (unless amenorrhea for the last 24 months) must have a negative serum pregnancy test within 48 hours prior to first study treatment. * Fertile male patients must agree to use a highly effective contraceptive method (allowed methods of birth control \[i.e. with a failure rate of \< 1% per year\] include a female partner using implants, injectables, combined oral contraceptives, IUDs \[only hormonal\], sexual abstinence or prior vasectomy) during the trial and for a period of \> 6 months following the last administration of trial drugs.
Exclusion criteria
* Pregnancy or breast-feeding * Co-medication that may interfere with study results, for example, immuno-suppressive agents other than corticosteroids * Active infection requiring intravenous (IV) antibiotics within 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 * Taking cytochrome P450 3A4 (CYP3A4) inducers and moderate or strong inhibitors (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) * Less than 12 weeks from radiation therapy, unless progressive disease outside of the radiation field or progression on 2 consecutive scans or histopathologic confirmation * Treated with immunotherapeutic agents or vaccines 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 with daily or metronomic chemotherapy within 1 week before enrollment, unless the patient has recovered from the expected toxic effects of such therapy * Prior chemotherapy (non-alkylating agents) within 2 weeks before enrollment, unless the patient has recovered from the expected toxic effects of such therapy * Current, recent (within 4 weeks of the first infusion of this study) use of an experimental drug, unless the patient has recovered from the expected toxic effects of study therapy Vascular endothelial growth factor (VEGF) Inhibitor-Specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Determine the Maximum Tolerated Dose (MTD) of CTO when combined with standard dosing of bevacizumab | 1 year | 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). |
| Phase 2: Percentage of subjects who remain alive and progression-free at 6 months | 2 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Median Overall Survival (OS) | 2 years | 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. |
| Phase 2: 6 and 12 month Overall Survival (OS) | 2 years | 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. |
| Phase 1: Number of subjects who experience a dose-limiting toxicity (DLT) during cycle 1 | 1 year | 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 |
| Phase 2: Median PFS | 2 years | 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. |
| Phase 2: 12 month PFS | 2 years | 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. |
| Phase 2: Percentage of subjects with best overall response (BOR) of complete response (CR) or partial response (PR) | 2 years | 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. |
| Phase 2: Percentage of subjects who experience a dose-limiting toxicity (DLT) during any cycle of protocol treatment | 2 years | 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 |
Countries
United States
Outcome results
None listed