Ph 1/2 CTO With Lomustine for Bevacizumab-Naive Recurrent... | NCT01989052

Name	Class
Tactical Therapeutics, Inc.	INDUSTRY

Description Module

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
CTO	Drug		Phase 1: CTO and lomustine Phase 2: CTO alone Phase 2: CTO and lomustine	Carboxyamidotriazole Orotate

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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

Measure	Description	Time Frame
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

Eligibility Module

Eligibility Criteria

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.
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.

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
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

Exclusion Criteria are:

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

ID	Term
D005910	Glioma
D008224	Lymphoma, Follicular

ID	Term
D018302	Neoplasms, Neuroepithelial
D017599	Neuroectodermal Tumors
D009373	Neoplasms, Germ Cell and Embryonal
D009370	Neoplasms by Histologic Type

ID	Term
D009607	Nitrosourea Compounds
D014508	Urea
D000577	Amides
D009930	Organic Chemicals