A prospective randomized open-label phase II clinical study evaluating the efficacy and safety of zoledronic acid addition to standard therapy in patients with glioblastoma

Prior treatment

• Participants who are pregnant or breastfeeding, or intending to become pregnant during the study or within 90 days after the final dose of zoledronic acid or temozolamide, or within the time period specified per local prescribing guidelines after the final dose of chemotherapy
• Participants who have had a serious infection requiring oral or IV antibiotics within 14 days prior to screening or other clinically significant infection within 14 days prior to screening
• Participants who have received treatment with bisphosphonates within 2 years prior to initiation of study treatment or is currently enrolled in any other type of medical research judged by the investigator not to be scientifically or medically compatible with this study
• Participants who have relapsed glioblastoma or previous other type of glioma who has transformed to glioblastoma
• Participants who have a known clinically significant history of liver disease consistent with Child-Pugh Class C, including hepatitis (e.g., hepatitis B virus [HBV] or hepatitis C virus [HCV]), current alcohol abuse, cirrhosis, or positive test for viral hepatitis, as defined: Active infection is defined as requiring treatment with antiviral therapy or presence of positive test results for hepatitis B (hepatitis B surface antigen and/or total hepatitis B core antibody [HBcAb]) or HCV antibody; Participants who test positive for HBcAb are eligible only if test results are also positive for hepatitis B surface antibody and polymerase chain reaction is negative for HBV DNA; Participants who are positive for HCV serology are eligible only if testing for HCV RNA is negative

Other illness

• Participants who have any other active malignancy
• Participants who have serious mouth and dental infections and may need a dental procedures (except dental filling) in near future
• Participants who have a known allergy or hypersensitivity to any of the study drugs or any of their excipients

Lab values

• Participants who have had any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes an individual's safe participation in and completion of the study
• Participants who have acute or chronic kidney failure and GFR less than 60 ml/min
• Participants who have level of calcium in blood less than 2 mmol/l

Other

• Participants who are unable or unwilling to comply with the requirements of the protocol in the opinion of the investigator

• Participants who are capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form and in this protocol
• Participants who have adequate organ function as defined by the following criteria: ANC higher than 1x 109/L, Platelet count higher than 100 x 109/L, AST and serum ALT lower than 3 times ULN, ALP lower than 3 times ULN, Hemoglobin higher than 80 g/L, Estimated creatinine clearance more than 60 mL/min and calculated per institutional guidelines, Serum bilirubin lower than 1.5 times ULN with the following exception: Participants with known Gilbert syndrome: lower than 3 times ULN
• For women of childbearing potential: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception as defined below: o Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 90 days after the final dose of zoledronic acid or temozolamide. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form
• For men assigned: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, as defined below: o With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 90 days after the final dose of zoledronic acid or temozolamide to avoid exposing the embryo. Men must refrain from donating sperm during this same period. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.
• Participants (females and males) who are age ≥ 18 years at the time of signing Informed Consent Form
• IDH negative (wild type) glioblastoma
• Participants who have multicentric (the presence of two or more tumor foci within different lobes of brain) and/or multifocal (the presence of two or more tumor foci within a single lobes of brain) glioblastoma are eligible
• Participants must have undergone surgery or stereotactic biopsy of the glioblastoma
• Participants must have completed concurrent radio-chemotherapy prior to randomization. A washout period of at least 28 days is required between the last chemotherapy dose and randomization
• Participants for whom resolution of all acute toxic effects of prior anti-cancer therapy to NCI CTCAE v5.0 Grade 1 or better (except alopecia, Grade 2 or better peripheral neuropathy, arthralgia or other toxicities not considered a safety risk for the participant per the investigator’s judgment)
• Participants who have Eastern Cooperative Oncology Group Performance (ECOG) Performance Status 0, 1 or 2. Also ECOG 3 if it is caused by irreversible neurological deficit due to glioblastoma
• Participants who are able and willing to swallow and retain oral medication