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

NCT01989052 | Terminated Phase 1

• 1 other identifier: Pro00047969
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Malignant Glioma (WHO Grade III or IV)

Keywords

Carboxyamidotriazole Orotate; CTO; Lomustine; N-(2-chloroethyl)-N'-cyclo-hexyl-N-nitrosourea (CCNU); CeeNU; Malignant Glioma; Pro00047969; 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 lomustine

  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.

  1 year

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

  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.

  6 months

Secondary Outcomes (5)

• 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: 12 month Overall Survival (OS)

  12 months

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

  2 years

• Phase 2: Median PFS

  2 years

Study Arms (4)

Phase 1: CTO and lomustine

EXPERIMENTAL

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

Drug: CTO; Drug: Lomustine

Phase 2: CTO alone

EXPERIMENTAL

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

Drug: CTO

Phase 2: CTO and lomustine

EXPERIMENTAL

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

Drug: CTO; Drug: Lomustine

Phase 2: Lomustine alone

EXPERIMENTAL

Oral lomustine alone at 110 mg/m2 every 6 weeks

Drug: Lomustine

Interventions

CTO DRUG

Also known as: Carboxyamidotriazole Orotate

Phase 1: CTO and lomustine; Phase 2: CTO alone; Phase 2: CTO and lomustine

Lomustine DRUG

Also known as: CCNU, CeeNU, Gleostine

Phase 1: CTO and lomustine; Phase 2: CTO and lomustine; Phase 2: Lomustine alone

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 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.
• Signed informed consent approved by the Institutional Review Board
• No evidence of \> grade 1 active central nervous system (CNS) hemorrhage on the baseline MRI or 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 \[intrauterine device (IUD); only hormonal\], 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 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
• 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), or planned use of an experimental drug, unless the patient has recovered from the expected toxic effects of such therapy
• Vascular endothelial growth factor (VEGF) Inhibitor-Specific
• 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)

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

Lomustine

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)

Nitrosourea Compounds; Urea; Amides; Organic Chemicals; Nitroso Compounds

Study Officials

• Annick Desjardins, MD, FRCPC

  Duke University

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: October 21, 2013
• First Posted: November 20, 2013
• Study Start: May 1, 2014
• Primary Completion: March 1, 2015
• Study Completion: February 1, 2016
• Last Updated: August 4, 2016

Record last verified: 2016-08

Locations

US (1)