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Malignant Glioma (WHO Grade III or IV)Phase 1NCT01989052

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

A Phase 1 study testing CTO and Lomustine in people with Malignant Glioma (WHO Grade III or IV), run by Annick Desjardins at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Malignant Glioma (WHO Grade III or IV)
What is being tested?
CTO and Lomustine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
9 participants
Where
1 siteUnited States
Study dates
May 2014to Feb 2016
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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
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  • 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)
  • Prior history of gastrointestinal perforation or abscess
  • Clinically significant (i.e. 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 II 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 (e.g. seizures) unrelated to cancer unless adequately controlled by medication or potentially interfering with protocol treatment
  • Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to start of study treatment
  • History of pulmonary hemorrhage/hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL bright red blood per episode) within 1 month of first study treatment
  • History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation)
  • Current or recent (within 10 days of study enrollment) use of aspirin (>325 mg/day), clopidogrel (>75 mg/day) or equivalent. Prophylactic or therapeutic low molecular weight heparin (LMWH) is allowed
  • Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to first study treatment, or anticipation of need for major surgical procedure during the course of the study
  • Minor surgical procedure, e.g. stereotactic biopsy, within 7 days of first study treatment; placement of a vascular access device, within 2 days of first study treatment
  • History of intracranial abscess within 6 months prior to first study treatment
  • History of active gastrointestinal bleeding within 6 months prior to first study treatment
  • Serious, non-healing wound, active ulcer, or untreated bone fracture

Trial locations and contacts

1 site in 1 country.

United States1 site

  • The Preston Robert Tisch Brain Tumor Center at Duke

    Durham, North Carolina, 27710

Other trials in United States

About this study

Official title: 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

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.

Read the 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.

Being tested
CTO, Lomustine
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
Medical subject headings
Glioma, Lymphoma, Follicular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CTODrug

    Also called Carboxyamidotriazole Orotate

  • LomustineDrug

    Also called CCNU, CeeNU, Gleostine

Study groups in NCT01989052
Study groupRoleWhat they receive
Phase 1: CTO and lomustineExperimentalThe 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
Receives: Drug: CTO; Drug: Lomustine
Phase 2: CTO aloneExperimentalCTO alone at the MTD established in the Phase 1 portion of this study
Receives: Drug: CTO
Phase 2: CTO and lomustineExperimentalCTO at the same daily dose of as in the CTO alone arm in combination with 110 mg/m2 oral lomustine every 6 weeks
Receives: Drug: CTO; Drug: Lomustine
Phase 2: Lomustine aloneExperimentalOral lomustine alone at 110 mg/m2 every 6 weeks
Receives: Drug: Lomustine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 1 year

  2. 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.

    Measured: 6 months

Secondary outcomes (5)

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

    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

    Measured: 2 years

  2. Phase 2: Median Overall Survival (OS)

    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.

    Measured: 2 years

  3. Phase 2: 12 month Overall Survival (OS)

    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.

    Measured: 12 months

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

    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.

    Measured: 2 years

  5. Phase 2: Median PFS

    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.

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Nov 2013 (estimated)
  2. Study startMay 2014
  3. Primary completionMar 2015
  4. Study completionFeb 2016

Why it stopped: This study was terminated early due to funding issues prior to completion of phase I

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
9 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01989052
Sponsor's protocol ID
Pro00047969
Status last verified
Aug 2016
First submitted
21 Oct 2013
Last updated
4 Aug 2016
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing CTO and Lomustine in people with Malignant Glioma (WHO Grade III or IV), run by Annick Desjardins at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 4 Aug 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: This study was terminated early due to funding issues prior to completion of phase I). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase 1: Determine the maximum tolerated dose (MTD) of CTO when combined with lomustine (time frame: 1 year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01989052.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Aug 2016.

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