Phase I Trial of DNA-PK Inhibitor (M3814) in Combination With Radiation and Adjuvant Temozolomide in Newly Diagnosed MGMT Unmethylated Glioblastoma
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 29
- Locations
- 1
- Primary Endpoint
- Ability of Peposertib (M3814) to cross the blood brain barrier (Stage II)
Overview
Brief 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. 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.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of Peposertib (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)
SECONDARY AND EXPLORATORY OBJECTIVES:
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)
CORRELATIVE OBJECTIVES:
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 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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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
- •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
- •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.
Exclusion Criteria
- •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.
- •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.
Arms & Interventions
Stage I (Peposertib, Radiation therapy, Temozolomide)
CONCURRENT: 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.
Intervention: Peposertib (Drug)
Stage I (Peposertib, Radiation therapy, Temozolomide)
CONCURRENT: 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.
Intervention: Radiation Therapy (Radiation)
Stage I (Peposertib, Radiation therapy, Temozolomide)
CONCURRENT: 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.
Intervention: Temozolomide (Drug)
Stage II (Peposertib, Radiation, Temozolomide, Surgery)
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.
ADJUVANT: Patients receive temozolomide as in Stage I.
Intervention: Peposertib (Drug)
Stage II (Peposertib, Radiation, Temozolomide, Surgery)
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.
ADJUVANT: Patients receive temozolomide as in Stage I.
Intervention: Radiation Therapy (Radiation)
Stage II (Peposertib, Radiation, Temozolomide, Surgery)
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.
ADJUVANT: Patients receive temozolomide as in Stage I.
Intervention: Resection (Procedure)
Stage II (Peposertib, Radiation, Temozolomide, Surgery)
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.
ADJUVANT: Patients receive temozolomide as in Stage I.
Intervention: Temozolomide (Drug)
Outcomes
Primary Outcomes
Ability of Peposertib (M3814) to cross the blood brain barrier (Stage II)
Time Frame: 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
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.
Maximum tolerated dose (MTD) (Stage I)
Time Frame: Within the first 10 weeks of study treatment
Will employ the Bayesian optimal interval to find the MTD.
Secondary Outcomes
- Median progression-free survival (Stage I)(From study enrollment until time of first occurrence of disease progression, relapse, or death due to disease, assessed up to 3 years)
- Median overall survival (Stage I)(Up to 3 years)
- Overall response rate (Stage II)(Up to 3 years)
- Median progression-free survival (Stage II)(From study enrollment until time of first occurrence of disease progression, relapse, or death due to disease, assessed up to 3 years)
- Dose-limiting toxicities (DLT) (Stage I)(Within the first 10 weeks of study treatment)
- Overall response rate (Stage I)(Up to 3 years)
- Median overall survival (Stage II)(Up to 3 years)