A Phase 3, Randomized, Open-Label Study To Evaluate the Efficacy and Safety of Eflornithine with Lomustine Compared to Lomustine Alone in Patients with Anaplastic Astrocytoma That Progress/Recur After Irradiation and Adjuvant Temozolomide Chemotherapy
The goal of this clinical research study is to learn if adding eflornithine to lomustine can help to control anaplastic astrocytoma (AA) better than treatment with lomustine alone. The safety of the drug combinations will also be studied.
Disease Group: Malignant neoplasms of eye brain and other parts of central nervous system
Treatment Agent: CCNU,Eflornithine
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Orbus Therapeutics, Inc.
The primary objective of this study is to demonstrate superiority in overall survival(OS) and comparable safety when eflornithine is added to lomustine compared to lomustine alone in patients with anaplastic astrocytoma (AA) that progress/recur after irradiation and adjuvant temozolomide chemotherapy. The secondary objectives of this study are progression free survival (PFS), objective response rate (ORR). The exploratory objectives of this study are to determine: CBR based on MRI criteria OS rate at 18 months (OS-18) Relevance of OS, PFS, ORR, and CBR to commonly used molecular/genetic biomarkers obtained from most recent pre-study tumor samples (i.e., p53 mutation, deletion of chromosomes 1p and 19q, Isocitrate dehydrogenase 1 [IDH1] mutations, ATRX mutation, Mib-1 labeling index, O6-Methylguanine DNA methyltransferase [MGMT] promoter methylation) Steady-state plasma Pharmacokinetic (PK) for eflornithine in patients within 2 weeks of initial dosing
IRB Review and Approval Date: 12/12/2016
Recruitment Status: Open
Projected Accrual: 280
1) The ability to understand and sign a written informed consent form,
which must be obtained prior to initiation of study procedures.
2) Age >/= 18 years.
3) Surgical or biopsy-proven diagnosis of WHO grade 3 AA.
4) Unequivocal evidence of first AA tumor progression or recurrence </= 3 months prior to randomization based on MRI criteria for tumor progression using enlarging Gd-contrast enhancement and/or T2 hyperintensity . Patients with non-measurable Gd-contrast enhancing tumors will only be eligible if there is no necrosis seen on MRI and/or histopathological confirmation of AA per standard of care procedures is obtained.
5) First tumor progression or recurrence following surgical resection or biopsy, if resection is not feasible, external beam radiation therapy (EBRT) and temozolomide chemotherapy.
6) Completion of EBRT >/= 6 months prior to randomization.
7) Stained, unstained slides or tumor tissue block(s) are available from their most recent tumor surgery are available for central histological confirmation.
8) A patient whose AA tumor has progressed or recurred and has had another surgical resection prior to randomization will be eligible if a) pathology review confirms AA, and b) post-surgical MRI demonstrates measurable tumor on T2/FLAIR.
9) If taking corticosteroids, must be on a stable or decreasing dose for at least 5 days prior to the screening MRI.
10) Karnofsky Performance Status (KPS) score of > 70.
11) Off anticancer therapy for at least 4 weeks and recovered from any significant treatment-related toxicities to Grade </= 1 prior to randomization.
12) Adequate recovery from any major surgery is required; at least 4 weeks must have elapsed from the time of any major surgery and must have recovered from all surgery-related toxicities to Grade </= 1 prior to randomization.
13) Adequate hematologic function (ANC >/= 1,500/µL, platelet count >/= 100,000/µL, and hemoglobin >/= 10.5 gm/dL) within 14 days prior to randomization.
14) Total bilirubin </= 1.5x upper limit of normal (ULN) within 14 days prior to randomization.
15) Hepatic transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) </= 2x upper limit of the normal range (ULN) within 14 days prior to randomization.
16) Adequate renal function (serum creatinine </= 1.5x ULN) within 14 days prior to randomization.
17) Life expectancy >/= 6 months.
18) Female patients of childbearing potential must agree to utilize acceptable contraceptive methods from screening throughout the duration of the study period, and for 30 days following the last dose of study drug. Abstinence is an acceptable method of contraception. Otherwise, consistent and current use of 1 of the following methods of birth control is accepted: oral contraceptive, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), tubal sterilization, Essure micro-insert system, or vasectomy in the male partner. Female patients must also refrain from egg donation and in vitro fertilization during treatment and until at least 30 days from the last dose of study drug.
19) Male patients must agree to abstain from sexual intercourse or use an acceptable contraceptive method (e.g. condoms) from screening throughout the duration of the study period, and for 90 days following the last dose of study drug. Male patients must also refrain from sperm donation during treatment and until at least 90 days from the last dose of study drug.
1) MRI defining progression is consistent with a diagnosis of
glioblastoma or radiation necrosis.
2) Prior systemic therapy for recurrence of AA.
3) Presence of extracranial or leptomeningeal disease.
4) Prior lomustine use.
5) History of other invasive malignancy, unless adequately treated with curative intent and with no known active disease present within 2 years prior to the first dose of study drug. Patients with non-melanoma skin cancer, carcinoma in situ (including superficial bladder cancer), cervical intraepithelial neoplasia and organ-confined prostate cancer deemed by the investigator to be at low risk of recurrence are not excluded.
6) Active infection or serious intercurrent medical illness. Serious intercurrent medical illness includes any severe and/or uncontrolled concurrent disease affecting the cardiovascular system, liver, kidneys, hematopoietic system or else considered as clinically important by the investigator and that could be incompatible with patient's participation in this trial or would likely interfere with study procedures/results or compromise compliance with the protocol.
7) Known to be HIV positive or to have an AIDS-related illness, Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) positive.
8) Poorly controlled epilepsy.
9) Unable to undergo an MRI with contrast.
10) Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) Class III or IV congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis.
11) Malabsorption syndrome, history of resection of the stomach or small bowel, active ulcerative colitis or Crohn’s disease, or partial or complete bowel obstruction or other conditions that would be expected to alter the absorption or PK of study drugs.
12) Receipt of any other anticancer therapy while receiving protocol-defined therapy.
13) Concurrent use of any other investigational agent during the study or within 30 days prior to randomization.
14) Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the patient unsuitable for the study.
15) Pregnant or breastfeeding.
16) Patients who are considered to be refractory to EBRT and temozolomide but who havenot progressed.
Information and next steps
Malignant neoplasms of eye brain and other parts of central nervous system
For general questions about clinical trials: