Phase I Trial of DNA-PK Inhibitor (M3814) in Combination With Radiation and Adjuvant Temozolomide in Newly Diagnosed MGMT Unmethylated Glioblastoma

  • End date
    Oct 30, 2023
  • participants needed
  • sponsor
    M.D. Anderson Cancer Center
Updated on 16 October 2022
karnofsky performance status
neutrophil count
tumor cells


This phase I trial investigates the side effects and best dose of nedisertib, and to see how well it works in combination with radiation therapy in treating patients with newly diagnosed MGMT unmethylated glioblastoma or gliosarcoma. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Nedisertib may further stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nedisertib with radiation therapy may work better than radiation therapy alone in treating patients with glioblastoma or gliosarcoma.



I. To determine the maximum tolerated dose (MTD) of nedisertib (M3814) in combination with standard of care radiation dose (60 Gy, 2 Gy/fraction over 6 weeks) in patients with newly diagnosed MGMT unmethylated glioblastoma (GBM). (Stage I) II. To determine the ability of M3814 to cross the blood brain barrier and to evaluate their pharmacodynamic properties in resected tissue. (Stage II)


I. To evaluate the dose limiting toxicities (DLT). (Stage I) (Secondary Objective) II. To determine the overall response rate (ORR), median progression free survival (mPFS) and median overall survival (mOS) of M3814 in combination with radiation. (Stage I) (Secondary Objective) II. To determine the overall response rate (ORR), median progression free survival (mPFS) and median overall survival (mOS) of M3814 in combination with radiation. (Stage II) (Exploratory Objective)


I. To evaluate pharmacodynamic properties of M3814. II. To assess the alterations in tumor immune microenvironment as a result of deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PK) inhibition.

OUTLINE: This is a dose-escalation study of nedisertib. Patients are assigned to 1 of 2 stages.

STAGE I (CONCURRENT): Patients undergo standard of care radiation therapy daily (Monday-Friday) for 30 fractions. Patients also receive nedisertib orally (PO) on each day of radiation therapy and given 1-2 hours before each treatment fraction. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity.

STAGE I (ADJUVANT): Patients receive temozolomide PO once daily (QD) on days 1-5. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

STAGE II (CONCURRENT): Patients receive nedisertib and undergo standard of care radiation therapy as in Stage I. Within 1-14 days after the completion of radiation therapy, patients undergo surgical resection.

STAGE II (ADJUVANT): Patients receive temozolomide as in Stage I.

After completion of study treatment, patients are followed up every 3 months.

Condition Glioblastoma, Gliosarcoma
Treatment radiation therapy, Temozolomide, Resection, Nedisertib
Clinical Study IdentifierNCT04555577
SponsorM.D. Anderson Cancer Center
Last Modified on16 October 2022


Yes No Not Sure

Inclusion Criteria

Signed informed consent form (ICF)
Ability and willingness to comply with the requirement of the study protocol
Histologically confirmed World Health Organization (WHO) grade IV glioma (GBM) or gliosarcoma, IDH wild-type
Documentation of MGMT unmethylated GBM per testing at any Clinical Laboratory Improvement Amendment (CLIA) certified laboratory
Patients must have undergone brain surgery or biopsy and must not have had any further treatments following surgery
Have Karnofsky performance status (KPS) of >= 60 or Eastern Cooperative Oncology Group (ECOG) =< 2
A baseline magnetic resonance imaging (MRI) of brain obtained no more than 14 days prior to study enrollment on a stable or tapering dose of steroids no greater than 4 mg a day of dexamethasone (or equivalent dose of other steroids) for at least 3 days
Patients must start treatment within 8 weeks of last brain surgical procedure (biopsy or resection)
Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days prior to day 1 of the study)
Platelets >= 100,000/mcL (within 14 days prior to day 1 of the study)
Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (within 14 days prior to day 1 of the study)
Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (within 14 days prior to day 1 of the study)
Creatinine clearance should be calculated per institutional standard
Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (within 14 days prior to day 1 of the study)
bilirubin levels > 1.5 x ULN (within 14 days prior to day 1 of the study)
International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN (within 14 days prior to day 1 of the study)
Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (within 14 days prior to day 1 of the study)
Have provided tissue from an archival tissue sample
Female subjects of childbearing potential should have a negative serum pregnancy test within 14 days of day 1 of the study
Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile
Female subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
STAGE I: In the case stage I patients need resection as determined by the treating physicians during or after completion of radiation therapy (RT) and that pathology of resected lesion is not consistent with recurrent GBM, the patient can continue on the study (complete 6 weeks of RT + M3814) if deemed appropriate by the treating physicians. The tissue obtained in such circumstances will be analyzed as in Stage II subjects. However, these cases will not count towards the 5 patients who will be enrolled during Stage II. These patients will contribute to the correlative endpoints detailed above and ORR, OS, and PFS as Stage II patients
Male subjects should agree to use an adequate method of contraception during the
course of the study
STAGE II: Patients meet above criteria, would benefit from further non-urgent surgical resection of at least one enhancing lesion per the treating physician, and would provide consent to undergo surgery after treatment with RT and M3814

Exclusion Criteria

Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics delivered by local injection or convection enhanced delivery. Prior treatment with Gliadel wafers and laser interstitial thermal therapy (LITT) will be excluded. Active treatment with the tumor treating filed devices such as Optune will be excluded
Currently participating or previously participated in any other newly diagnosed GBM therapeutic trials
History of MGMT methylated status performed at any CLIA certified laboratory
Any serious medical condition that interferes with adherence to study procedures
Malignancies other than the disease under study within 5 years prior to day 1 of the study, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai stage 0, prostate cancer with Gleason score =< 6, and prostate-specific antigen [PSA] =< 10 mg/mL, etc)
Has known disease in the posterior fossa, gliomatous meningitis, extracranial disease or multicentric enhancing disease. Multicentric disease is defined as discrete sites of contrast enhancing disease without contiguous T2/fluid-attenuated inversion recovery (FLAIR) abnormality that require distinct radiotherapy ports. Satellite lesions that are associated with a contiguous area of T2/FLAIR abnormality as the main lesion(s) and that are encompassed within the same radiotherapy port as the main lesion(s) are permitted
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating physician
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the screening visit
Contraindication for undergoing MRIs
Inability to comply with study and follow-up procedures
Signs or symptoms of infection, received oral or intravenous (IV) antibiotics within 2 weeks prior to day 1 of the study
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
History of human immunodeficiency virus (HIV) infection
Administration of a live, attenuated vaccine within 4 weeks before day 1 of the study or anticipation that such a live, attenuated vaccine will be required during the study
Influenza vaccination can be given. Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to day 1 of the study or at any time during the study and for 5 months after completion of adjuvant temozolomide (TMZ)
History of long QT syndrome
Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of M3814 or that may affect the interpretation of the results or render the patient at high risk from treatment complications
Anticipation of need for a major surgical procedure during the course of the study (excluding patients in Stage II with planed non-urgent neuro-surgical resection)
Subjects at increased risk for radiation toxicities, such as known active collagen vascular disease (example; scleroderma, Sjogren's disease, etc) or other inherited radiation hypersensitivity syndromes (example; Gorlin syndrome, Fanconi anemia, ataxia-telangiectasia, etc.)
Active difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions (including pancreas deficiency requiring Creon therapy) that may hamper compliance and/or absorption of M3814
Patients may not receive concomitant chemotherapy, immunotherapy, or radiotherapy (other than as pertained to standard of care for GBM) while patients are on study
Prior treatment with DNA damage response inhibitors (including inhibitors of PARP, ATR, WEE)
Subjects currently receiving or unable to stop using medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A, CYP2C19, CYP2C9 and/or P glycoprotein (P-gp) (CYP and/P-gp must stop at least 1 week before treatment with M3814 for inhibitors and 3 weeks before treatment with M3814 for inducers) or drugs mainly metabolized by CYP3A, CYP2C19, CYP2C9 with a narrow therapeutic index (must stop at least 1 day prior). In addition concomitant use of H2 blockers of proton pump inhibitors (PPIs) is prohibited. Patients must stop H2 blockers and PPIs 4 days prior to the first treatment. Calcium carbonate use is acceptable
STAGE II: Patients who are status post (s/p) gross total resection with no remaining disease available for resection or tumor remaining in a region of the brain not amenable to resection
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