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Nedisertib and Radiation Therapy, Followed by Temozolomide for the Treatment of Patients With Newly Diagnosed MGMT Unmethylated Glioblastoma or Gliosarcoma

NCT04555577

Description:

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 an ezyme needed for cell growth (DNA-PK). 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.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Nedisertib and Radiation Therapy, Followed by Temozolomide for the Treatment of Patients With Newly Diagnosed MGMT Unmethylated Glioblastoma or Gliosarcoma
  • Official Title: Phase I Trial of DNA-PK Inhibitor (M3814) in Combination With Radiation and Adjuvant Temozolomide in Newly Diagnosed MGMT Unmethylated Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: 2019-1035
  • SECONDARY ID: NCI-2020-04491
  • SECONDARY ID: 2019-1035
  • NCT ID: NCT04555577

Conditions

  • Glioblastoma
  • Gliosarcoma

Interventions

DrugSynonymsArms
NedisertibStage I (nedisertib, radiation therapy, temozolomide)
TemozolomideCCRG-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, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, Temomedac, TMZStage I (nedisertib, radiation therapy, temozolomide)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      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)

      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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Stage I (nedisertib, radiation therapy, temozolomide)ExperimentalCONCURRENT: Patients undergo standard of care radiation therapy daily (Monday-Friday) for 30 fractions. Patients also receive nedisertib 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.
  • Nedisertib
  • Temozolomide
Stage II (nedisertib, radiation, temozolomide, surgery)ExperimentalCONCURRENT: 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. ADJUVANT: Patients receive temozolomide as in Stage I.
  • Nedisertib
  • Temozolomide

Eligibility Criteria

        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
             bilirubin levels > 1.5 x ULN (within 14 days prior to day 1 of the study)

          -  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)

          -  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

          -  Male subjects should agree to use an adequate method of contraception during the
             course of the study

          -  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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) (Stage I)
Time Frame:Within the first 10 weeks of study treatment
Safety Issue:
Description:Will employ the Bayesian optimal interval to find the MTD.

Secondary Outcome Measures

Measure:Dose-limiting toxicities (DLT) (Stage I)
Time Frame:Within the first 10 weeks of study treatment
Safety Issue:
Description: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.
Measure:Overall response rate (Stage I)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Median progression-free survival (Stage I)
Time Frame:From study enrollment until time of first occurrence of disease progression, relapse, or death due to disease, assessed up to 3 years
Safety Issue:
Description:
Measure:Median overall survival (Stage I)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Overall response rate (Stage II)
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure:Median progression-free survival (Stage II)
Time Frame:From study enrollment until time of first occurrence of disease progression, relapse, or death due to disease, assessed up to 3 years
Safety Issue:
Description: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.
Measure:Median overall survival (Stage II)
Time Frame:Up to 3 years
Safety Issue:
Description:Overall survival will be evaluated using the Kaplan-Meier product-limit survival curve methodology and will be compared to historical controls.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

September 14, 2020