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GlioblastomaPhase 1NCT04555577

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

A Phase 1 study testing Peposertib, Radiation Therapy and Resection in people with Glioblastoma and Gliosarcoma, run by M.D. Anderson Cancer Center at 1 site in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This phase I trial investigates the side effects and best dose of Peposertib, 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Glioblastoma, Gliosarcoma
What is being tested?
Peposertib, Radiation Therapy and Resection
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
29 participants
Where
1 siteUnited States
Study dates
20 Sep 2020to 31 Dec 2027
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Signed Informed Consent Form (ICF)
  • Be willing and able to provide written informed consent for the trial. Participants with cognitive impairment will be enrolled. Cognitive function will be assessed by the treating physician or designee through a neurological examination. The formal consent for such participants will be obtained from their legally authorized representative. For cognitively impaired adults who are enrolling in the study by consent of a legally authorized representative, assent of the subject is required for the subjects with the ability to communicate assent. This assent will be documented in subject fs consent note.
  • Age 18 years or older
  • Histologically confirmed World Health Organization (WHO) grade 4 glioma (GBM) or gliosarcoma, IDH wild-type, per WHO 2021 classification .IDH status is to be determined by IDH1 R132H immunohistochemistry except for patients ≤ age 54 in whom IDH sequencing will be required to detect non-canonical IDH mutations.
  • Have KPS of 3 60 or ECOG . 2 according to appendix 5.
  • A baseline MRI of brain obtained no more than 14 days prior to study enrollment on a stable or tapering dose of steroids for at least 3 days
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  • Demonstrate adequate organ function as defined below.
  • All screening labs should be performed within 14 days prior to Day 1 of the study.
  • 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.
  • All screening labs should be performed within 14 days prior to Day 1 of the study.
  • 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.
  • Male subjects should agree to use an adequate method of contraception during the course of the study.
  • Newly diagnosed GBM only
  • 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 cancer treatments following surgery Recurrent GBM only
  • Any number of recurrences
  • Presence of enhancing, resectable disease
  • Candidate for re-radiation with ability to meet optic nerve and brainstem departmental dose constraints per treating physicians
  • 6 mos or more since last radiation
  • Has not received re-radiation for GBM in the past except for stereotactic radiosurgery
  • Stage II: Inclusion Criteria:
  • Patients would benefit from further non-emergent surgical resection of at least one enhancing lesion per the treating physicians

Who cannot join

  • Has received prior interstitial brachytherapy or implanted chemotherapy.
  • Active treatment with the tumor treating filed devices such as Optune during radiation will be excluded. Concurrent use of Optune during the adjuvant temozolomide cycles is allowed.
  • Any serious medical condition that interferes with adherence to study procedures.
  • Malignancies other than the disease under study within 2 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, gliomatosis cerebri, leptomeningeal disease, extracranial disease. 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.
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  • 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 serious infection such as surgical wound infection, received IV antibiotics within 2 weeks prior to Day 1 of the study.
  • oPatients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.
  • oPatients receiving oral antibiotics for minor infections such as urinary tract infection are eligible.
  • 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., FluMistâ) 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 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 PEPOSERTIB 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 PEPOSERTIB.
  • Patients may not receive concomitant chemotherapy, immunotherapy, or radiotherapy (other than as pertained to GBM as described in section 1.1) while patients are on study.
  • Newly diagnosed GBM only
  • History of MGMT methylated status performed at any CLIA certified laboratory. Recurrent GBM only
  • Prior history of scalp / surgical wound infection or wound dehiscence
  • Prior exposure to bevacizumab 6 weeks before enrollment.
  • Patients in Stage IIC and D (recurrent GBM) may receive bevacizumab during the adjuvant phase of treatment at the discretion of the treating physician, provided at least 6 weeks have elapsed since surgery and there are no wound healing concerns. A minimum washout period of 6-8 weeks is required from the last dose of prior bevacizumab before study enrollment.
  • Medication-Related Exclusion Criteria:
  • PEPOSERTIB
  • No clinical drug-drug interaction (DDI) studies have been conducted with peposertib. Based on nonclinical data and basic static modeling using the proposed maximum therapeutic doses of 200 mg BID or 300 mg QD (tablet formulation), the following guidance applies: Subjects receiving or unable to discontinue foods, medications, or herbal supplements that are strong inducers or inhibitors of CYP3A4/5, CYP2C19, or CYP2C9 should be excluded from treatment with peposertib due to potential impact on drug exposure.
  • Substrates of CYP1A2, CYP2B6, CYP2C8, and CYP3A4/5 should be used with caution and monitored. Substrates with a narrow therapeutic index are prohibited during treatment with peposertib. Please refer to https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers for a list of drugs metabolized by the above mentioned enzymes. H2-blockers may be allowed but should be taken at least 2 hours after peposertib dosing and stopped at least 6 hours before the next dose of peposertib. Calcium carbonate use is acceptable.
  • Stage II: Exclusion Criteria:
  • Patients without residual resectable disease.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

This phase I trial investigates the side effects and best dose of Peposertib, 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. Peposertib 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 Peposertib with radiation therapy may work better than radiation therapy alone in treating patients with glioblastoma or gliosarcoma.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the maximum tolerated dose (MTD) of Peposertib 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 Peposertib to cross the blood brain barrier and to evaluate their pharmacodynamic properties in resected tissue. (Stage II)

SECONDARY AND EXPLORATORY OBJECTIVES:

  1. 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 Peposertib 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 Peposertib in combination with radiation. (Stage II) (Exploratory Objective)

CORRELATIVE OBJECTIVES:

  1. To evaluate pharmacodynamic properties of Peposertib. 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 Peposertib. 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 Peposertib 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 Peposertib 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.

Being tested
Peposertib, Radiation Therapy, Resection, Temozolomide
Medical subject headings
Glioblastoma, Gliosarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PeposertibDrug

    Given PO

  • Radiation TherapyRadiation

    Also called Cancer Radiotherapy, ENERGY_TYPE, Irradiate, Irradiated

    Undergo radiation therapy

  • ResectionProcedure or surgery

    Also called Surgical Resection

    Undergo surgical resection

  • TemozolomideDrug

    Also called CCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831

    Given PO

Study groups in NCT04555577
Study groupRoleWhat they receive
Stage I (Peposertib, Radiation therapy, Temozolomide)ExperimentalCONCURRENT: Patients undergo standard of care radiation therapy daily (Monday-Friday) for 30 fractions. Patients also receive Peposertib 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. ADJUVANT: Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Peposertib; Radiation: Radiation Therapy; Drug: Temozolomide
Stage II (Peposertib, Radiation, Temozolomide, Surgery)ExperimentalCONCURRENT: Patients receive Peposertib 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. ADJUVANT: Patients receive temozolomide as in Stage I.
Receives: Drug: Peposertib; Radiation: Radiation Therapy; Procedure: Resection; Drug: Temozolomide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum tolerated dose (MTD) (Stage I)

    Will employ the Bayesian optimal interval to find the MTD.

    Measured: Within the first 10 weeks of study treatment

  2. Ability of Peposertib (M3814) to cross the blood brain barrier (Stage II)

    Ability of the investigational drug to cross the blood brain barrier will be tested by measuring concentration of the drug within the blood and the resected brain tumor tissue. This will be correlated with biomarkers of deoxyribonucleic acid (DNA) damage in brain tumor tissue, blood, and hair follicle.

    Measured: At 1, 2, and 4 hours after drug administration on fraction day 1 and at pre-dose and 1, 2, and 4 hours after drug administration on fraction day 10

Secondary outcomes (7)

  1. Dose-limiting toxicities (DLT) (Stage I)

    A DLT is defined as a clinically significant adverse event considered at least possibly related to M3814 in combination with radiation during the first 10 weeks of study treatment (4 weeks after completion of radiation and DNA damage response [DDR] inhibitors) for both stage I and stage II patients.

    Measured: Within the first 10 weeks of study treatment

  2. Overall response rate (Stage I)

    Measured: Up to 3 years

  3. Median progression-free survival (Stage I)

    Measured: From study enrollment until time of first occurrence of disease progression, relapse, or death due to disease, assessed up to 3 years

  4. Median overall survival (Stage I)

    Measured: Up to 3 years

  5. Overall response rate (Stage II)

    Measured: Up to 3 years

  6. Median progression-free survival (Stage II)

    Progression-free survival will be evaluated using the Kaplan-Meier product-limit survival curve methodology and will be compared to historical controls. Median progression free survival will be estimated using Kaplan-Meier estimates and associated two-sided 95% confidence intervals.

    Measured: From study enrollment until time of first occurrence of disease progression, relapse, or death due to disease, assessed up to 3 years

  7. Median overall survival (Stage II)

    Overall survival will be evaluated using the Kaplan-Meier product-limit survival curve methodology and will be compared to historical controls.

    Measured: Up to 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Sep 2020
  2. Study start20 Sep 2020
  3. Primary completion31 Dec 2027 (estimated)
  4. Study completion31 Dec 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
29 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04555577
Sponsor's protocol ID
2019-1035
Other IDs
NCI-2020-04491, 2019-1035
Status last verified
Oct 2026
First submitted
10 Aug 2020
Last updated
16 Oct 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Peposertib, Radiation Therapy and Resection in people with Glioblastoma and Gliosarcoma, run by M.D. Anderson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 16 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose (MTD) (Stage I) (time frame: Within the first 10 weeks of study treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04555577.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Oct 2026.

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