Phase II study of VAL-083 in patients with MGMT unmethylated, bevacizumab-naive recurrent glioblastoma
Barbara J. O'Brien
The goal of this clinical research study is to learn if VAL-083 can help to control relapsed unmethylated MGMT glioblastoma. The safety of the study drug will also be studied.
Disease Group: Malignant neoplasms of eye brain and other parts of central nervous system
Treatment Agent: VAL-083
Treatment Location: Only at MDACC
Sponsor: DelMar Pharmaceuticals, Inc.
1. Primary objective: To determine if treatment of O-6-methylguanine-DNA methyltransferase (MGMT) unmethylated recurrent glioblastoma (GBM) with VAL-083 improves overall survival (OS), compared to historical control 2. Secondary objectives: To determine progression-free survival (PFS) at 6 months in patients with MGMT unmethylated recurrent GBM treated with VAL-083 To determine median PFS in patients with MGMT unmethylated recurrent GBM treated with VAL-083 To determine median OS in patients with MGMT unmethylated recurrent GBM treated with VAL-083 To determine overall response rate (ORR) OS in patients with MGMT unmethylated recurrent GBM treated with VAL-083 To determine duration of response (DOR) in patients with MGMT unmethylated recurrent GBM treated with VAL-083 To evaluate the safety and toxicity profile of VAL-083 treatment in patients with recurrent GBM To evaluate the occurrence of symptoms and to evaluate quality of life (QOL) measures during the progression-free period using the MD Anderson Symptom Inventory- Brain Tumor Module (MDASI-BT) self-reporting tool To characterize the plasma PK of VAL-083 after the first dose administration on Cycle 1 (Cycle 1 Day 1).
IRB Review and Approval Date: 01/20/2017
Recruitment Status: Open
Projected Accrual: N/A
1) Patient must willingly provide written consent after being informed
of the procedure to be followed, the experimental nature of the therapy,
alternatives, potential benefits, side effects, risks, and discomforts.
2) Patients must be >/= 18 years old.
3) Patients must have histologically confirmed initial diagnosis of primary intracranial WHO Grade IV malignant glioma (glioblastoma), now recurrent. Patients with recurrent disease whose initial diagnostic pathology confirmed glioblastoma will not need re-biopsy. Alternately, patients with prior intracranial low-grade glioma or anaplastic glioma will be eligible, if histologic assessment demonstrates transformation to GBM (first diagnosis of secondary GBM).
4) Patients must have radiographic evidence of recurrent/progressive GBM after prior therapy (biopsy or resection and chemoradiation); 1st recurrence of GBM only, per Response Assessment in NeuroOncology (RANO) criteria. Histologically documented transformation from a lower grade gliomas will be considered first recurrence.
5) Patients must have confirmed GBM MGMT status (tumor must be MGMT promoter unmethylated) by central laboratory CLIA certified testing at MD Anderson, prior to registration. If initial MGMT testing obtained at an outside institution, MGMT status must be centrally retested at MD Anderson.
6) Patients must have Karnofsky Performance Status (KPS) > 60% (i.e., 70, 80, 90 or 100)
7) Patients must have been previously treated for GBM with radiation with concurrent and adjuvant temozolomide chemotherapy.
8) Adequate recovery from all recent surgery is required. At least 21-days must have elapsed from the time of any major surgery, including craniotomy/tumor resection. Patients must have recovered from all surgery-related toxicities to Grade 1 or less.
9) Patients must be >/= 12 weeks from radiotherapy, to minimize the potential for Magnetic resonance imaging (MRI) changes related to treatment (pseudoprogression) that might be misdiagnosed as true progression of disease, unless the patient fulfills criteria for early progressive disease by RANO.
10) Prior therapy with gamma knife or other focal high-dose radiation is allowed, but at least 2 weeks must have elapsed from the time of treatment, and the patient must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field.
11) Patients must be at least 4 weeks from last dose of chemotherapy.
12) Patients must be at least 4 weeks or 5 half-lives (whichever is shorter) from the last dose of prior investigational anti-cancer drugs.
13) Patients must have recovered from all treatment-related toxicities to Grade 1 or less.
14) If receiving corticosteroids, patients must be on a stable or decreasing dose of corticosteroids for >/= 5 days prior to baseline MRI.
15) Patients must have a predicted life expectancy of at least 12 weeks.
16) Patients must have adequate bone marrow and organ function including: a. serum Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) </= 2 × Upper limit of normal (ULN), and bilirubin within the normal range at the time of investigational drug commencement. Patients with known Gilbert’s disease who have serumbilirubin </= 3 × ULN (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 Grade 2) may be enrolled. b. serum creatinine </= 1.5 × ULN or creatinine clearance >60 mL/min (measured or calculated by the Cockcroft-Gault formula) Ccr (mL/mim) = (((140-Age) x Weight)/(72xScr))/(0.85female) where weight is expressed in Kg, age in years, and serum creatinine (Scr) in mg/dL. c. No evidence of myelosuppression i. absolute neutrophil count (ANC) >/= 1500 cells/mm3; platelets >/= 100,000 cells/mm3.
17) (16. continued) d. International normalized ratio (INR) </= 1.5 and activated partial thromboplastin time (aPTT) </= 1.5 × the ULN e. QTc < 450 msec on screening Electrocardiogram (ECG). f. No clinically significant cardiac conduction disorder on screening.
18) Patients must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests and accessible for follow-up.
19) If the patient has been using the Optune™ device, it will be discontinued before initiating treatment with either study medication, and per inclusion criterion listed above, the patient must have recovered from all treatment-related toxicities to Grade 1 or less.
20) Pregnancy restrictions a) Women of childbearing potential must have a negative B-Human chorionic gonadotropin (HCG) documented within 7 days prior to registration and must agree to practice adequate contraception as defined below. 1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), includes any female who has had: e) A hysterectomy f) A bilateral oophorectomy g) A bilateral tubal ligation h) Is post-menopausal: i. Subjects not using hormone replacement therapy (HRT) must have experienced total cessation of menses for >/= 1 year and be greater than 45 years in age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value > 40 mIU/mL and an estradiol value < 40pg/mL (< 140 pmol/L). ii. Subjects using HRT must have experienced total cessation of menses for >= 1 year and be greater than 45 years of age OR have had documented evidence of menopause based on FSH and estradiol concentrations prior to initiation of HRT.
21) (20. continued) 2. Childbearing potential, includes any female who has had a negative serum pregnancy test within 7 days of study registration, and agrees to use adequate contraception. Acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of the physician, are as follows: a. Complete abstinence from sexual intercourse for 14 days before starting treatment, through the treatment, and for at least 1 month after the last dose b. Oral contraceptive, either combined or progestogen alone. A second barrier method is required during the first month of treatment with oral contraceptives. c. Injectable progestogen. d. Implants of levonorgestrel. e. Estrogenic vaginal ring. f. Percutaneous contraceptive patches. g. Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year.
22) (21. continued) h. Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. i. Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository). b) Male patients must be sterile or willing to use an approved method of contraception from the time of Informed Consent to 30 days after study drug treatment. Males should use a condom with a vaginal spermicidal agent (foam/gel/cream suppository). The female partner should use one of the methods listed above. Males must be willing to refrain from sperm donation within 30 days after study treatment.
23) Prior therapy with Laser Induced Thermal Therapy (LITT) is allowed, but at least 21 days must have elapsed from last LITT, with recovery from all LITT-related toxicities to Grade 1 or less and subsequent histologic documentation of recurrence.
1) Within 12 weeks of chemoradiation unless the patient fulfills
criteria for early progressive disease by RANO
2) Receipt of investigational agents within 5 half-lives of last dose of investigational agent
3) Concurrent use of other investigational agents or Optune™ device
4) Prior therapy with lomustine
5) Prior therapy with bevacizumab
6) Current history of neoplasm other than the entry diagnosis. Patients with previous cancers treated and cured with local therapy alone may be considered with approval of the PI
7) Evidence of leptomeningeal spread of disease
8) Need for urgent palliative intervention (e.g., impending herniation)
9) Severe, intercurrent illness including, but not limited to unstable systemic disease, including ongoing or active infection, uncontrolled hypertension, serious cardiac arrhythmia requiring medication, or psychiatric illness/social situations that would limit compliance with study requirements
10) Patients with a known sensitivity to any of the products to be administered during treatment
11) Patients unable to undergo MRI of the brain
12) Women who are pregnant or lactating. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to start of treatment. Women of childbearing potential or men with partners of childbearing potential must use effective birth control measures during treatment.
Information and next steps
Malignant neoplasms of eye brain and other parts of central nervous system
Barbara J. O'Brien
For general questions about clinical trials: