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

NCT01954030 | Terminated Phase 1

• 1 other identifier: Pro00044274
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

Malignant Glioma (WHO Grade III or IV)

Keywords

Carboxyamidotriazole Orotate; CTO; Bevacizumab; Avastin; Malignant Glioma; Pro00044274; Desjardins; Duke; The Preston Robert Tisch Brain Tumor Center

Outcome Measures

Primary Outcomes (2)

• Phase 1: Determine the Maximum Tolerated Dose (MTD) of CTO when combined with standard dosing of bevacizumab

  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).

  1 year

• Phase 2: Percentage of subjects who remain alive and progression-free at 6 months

  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.

  2 years

Secondary Outcomes (7)

• Phase 1: Number of subjects who experience a dose-limiting toxicity (DLT) during cycle 1

  1 year

• Phase 2: Percentage of subjects who experience a dose-limiting toxicity (DLT) during any cycle of protocol treatment

  2 years

• Phase 2: Median Overall Survival (OS)

  2 years

• Phase 2: 6 and 12 month Overall Survival (OS)

  2 years

• Phase 2: Percentage of subjects with best overall response (BOR) of complete response (CR) or partial response (PR)

  2 years

Study Arms (3)

CTO and Bevacizumab (Phase 1)

EXPERIMENTAL

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

Drug: CTO and Bevacizumab

Phase 2: CTO alone (Phase 2)

EXPERIMENTAL

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.

Drug: CTO alone

CTO and Bevacizumab (Phase 2)

EXPERIMENTAL

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.

Drug: CTO and Bevacizumab

Interventions

CTO and Bevacizumab DRUG

Also known as: CTO, Carboxyamidotriazole Orotate, Bevacizumab, Avastin

CTO and Bevacizumab (Phase 1); CTO and Bevacizumab (Phase 2)

CTO alone DRUG

Also known as: CTO, Carboxyamidotriazole Orotate

Phase 2: CTO alone (Phase 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• Inadequately controlled hypertension (defined as systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg) within 28 days of first study treatment
• Prior history of hypertensive crisis, hypertensive encephalopathy, reverse posterior leukoencephalopathy syndrome (RPLS)
• Prior history of gastrointestinal perforation or abscess
• Clinically significant (active) cardiovascular disease, for example cerebrovascular accidents ≤ 6 months prior to study enrollment, myocardial infarction ≤ 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade 2 or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment
• History or evidence upon physical/neurological examination of central nervous system disease (for example, seizures) unrelated to cancer unless adequately controlled by medication or potentially interfering with protocol treatment

Sponsors & Collaborators

• Annick Desjardins: lead
• Tactical Therapeutics, Inc.: collaborator

Study Sites (1)

The Preston Robert Tisch Brain Tumor Center at Duke

Durham, North Carolina, 27710, United States

Location

Related Links

• The Preston Robert Tisch Brain Tumor Center at Duke

MeSH Terms

Conditions

Glioma; Lymphoma, Follicular

Interventions

Bevacizumab

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Annick Desjardins, MD, FRCPC

  Duke University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: September 26, 2013
• First Posted: October 1, 2013
• Study Start: October 1, 2013
• Primary Completion: July 1, 2015
• Study Completion: July 1, 2015
• Last Updated: February 19, 2016

Record last verified: 2016-02

Locations

US (1)