Clinical Trials /

Tinostamustine With or Without Radiation Therapy in Treating Patients With Newly Diagnosed MGMT-Unmethylated Glioblastoma

NCT03452930

Description:

This phase I trial studies the side effects and best dose of tinostamustine (EDO-S101) given with or without radiation therapy in treating patients with newly diagnosed MGMT-unmethylated glioblastoma. Tinostamustine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth in patients with glioblastoma.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: EDO-S101 for MGMT Unmethylated Glioblastoma (nGBM)
  • Official Title: A Phase I Study to Investigate the Safety Profile and the Efficacy of EDO-S101, a First-in-Class Alkylating HDACi Fusion Molecule in Patients With Newly Diagnosed MGMT-promoter Unmethylated Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: 2017-0555
  • NCT ID: NCT03452930

Conditions

  • Malignant Neoplasms of Eye Brain and Other Parts of Central Nervous System
  • Unmethylated Glioblastoma

Interventions

DrugSynonymsArms
EDO-S101Stage 1A - Group 1: EDO-S101

Purpose

The goal of this clinical research study is to find the highest tolerable dose of EDO-S101 that can be given with or after radiation therapy to patients with glioblastoma. The safety of this study drug will also be studied. This is an investigational study. EDO-S101 is not FDA approved or commercially available for the treatment of glioblastoma. It is currently being used for research purposes only. The study doctor can describe how the study drug is designed to work. Up to 128 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

      Study Groups and Drug Administration:

      If participant is found to be eligible to take part in this study, participant will be
      assigned to 1 of 2 groups based on when participant joins the study:

        -  If participant is in Group 1, participant will receive EDO-S101 on Day 1 of each 21-day
           Cycle.

        -  If participant is in Group 2, participant will receive EDO-S101 on Days 1 and 15 of each
           28-day Cycle. Participants in this group will also receive radiation therapy per
           standard of care.

      Additionally, participant will be assigned to a dose level of EDO-S101 based on when
      participant joined this study. Up to 6 dose levels of EDO-S101 will be tested. Up to 6
      participants will be enrolled at each dose level. The first set of participants will receive
      the lowest dose level. Each new set will receive a higher dose than the set before it, if no
      intolerable side effects were seen. This will continue until the highest tolerable dose of
      EDO-S101 is found.

      Each time participant receives EDO-S101, it will be given by vein over about 30 minutes.

      Length of Study:

      Participant may receive EDO-S101 for up to 12 cycles. Participant will no longer be able to
      receive the study drug if the disease gets worse, if intolerable side effects occur, or if
      participant is unable to follow study directions.

      Study Visits for Group 1:

      On Day 1 of each cycle:

        -  Participant will have a physical exam, including a neurological exam. Blood (about 2
           teaspoons) will be drawn for routine tests. If participant can become pregnant, °this
           sample will also be used for a pregnancy test.

        -  Participant will have an EKG before and 2 times over the 60 minutes after the infusion.

      In addition to these tests, on Day 1 of odd-numbered cycles beginning with Cycle 3 (Cycles 3,
      5, 7 and so on):

        -  Urine will be collected for routine tests.

        -  Participant will have an MRI.

      On Days 8 Cycle 1:

        -  Participant will have a physical exam, including a neurological exam.

        -  Blood (about 1 teaspoon) will be drawn for routine tests.

      On Days 15 of Cycle 1, blood (about 1 teaspoon) will be drawn for routine tests.

      Study Visits for Group 2

      On Days 1 and 15 of each cycle:

        -  Participant will have a physical exam, including a neurological exam.

        -  Blood (about 2 teaspoons) will be drawn for routine tests. This sample will also be used
           for a pregnancy test, if participant can become pregnant (Day 1 only).

        -  Participant will have an EKG before and 2 times over the 60 minutes after the infusion.

      In addition to these tests, on Day 1 of Cycle 3 and every odd-numbered cycles beginning with
      Cycle 3 (Cycles 3, 5, 7 and so on):

        -  Urine will be collected for routine tests.

        -  Participant will have an MRI.

      On Days 8 and 22 of Cycle 1, blood (about 1 teaspoon) will be drawn for routine tests.

      At any time during the study, extra tests may be performed if the doctor thinks they are
      needed. The study doctor will tell participant more about any extra tests that may be needed.

      Follow-Up:

      Within 30 days after participant's last dose of study drug, and then every 3 months after
      that, the study staff will call participant to learn how participant is doing. The call
      should take about 5-10 minutes.

      If the disease gets worse and participant has surgery as part of participant's standard care,
      tumor tissue that is removed during this procedure will be collected for biomarker testing,
      including genetic biomarkers.

      If participant stops taking the study drug and the disease has not gotten worse, participant
      will have the following as often as the doctor thinks is needed:

        -  Participant will have a physical exam.

        -  Blood (about 2 teaspoons) will be drawn for routine tests.

        -  Participant will have an MRI.

      The study doctor will discuss with participant how often these tests may be performed. If the
      disease gets worse or the study ends, participant will no longer have these tests for the
      study.
    

Trial Arms

NameTypeDescriptionInterventions
Stage 1A - Group 1: EDO-S101ExperimentalDose Escalation: Participants receive EDO-S101 on Day 1 of each 21 day Cycle.
  • EDO-S101
Stage 1B - Group 2: EDO-S101ExperimentalDose Escalation: Participants receive EDO-S101 on Day 1 and 15 of a 28 day Cycle.
  • EDO-S101
Stage 2: EDO-S101 + Radiation TherapyExperimentalParticipants receive radiation consisting of fractionated focal irradiation administered using 1.8-2 Gy/fraction daily x 5 days/week for ~6 weeks for a total dose of up to 60 Gy. EDO-S101 administered weekly with radiation and the dosing schedule during stage 2 determined based on the results of the 2 dosing schemas evaluated during Stage 1.
  • EDO-S101
Maximum Tolerated Dose (MTD): EDO-S101 + Radiation TherapyExperimentalOnce the MTDs of EDO-S101 in Stage 1 and Stage 2 have been separately determined, the safety and preliminary efficacy of EDO-S101 given in combination with radiation followed by administration of EDO-S101 in the adjuvant phase investigated in an MTD expansion cohort.
  • EDO-S101

Eligibility Criteria

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent for the trial.

          2. Be >/= 18 years of age on day of signing informed consent.

          3. Have histologically confirmed World Health Organization Grade IV glioma (GB or
             gliosarcoma).

          4. Confirmed MGMT-promoter unmethylated status and IDH wildtype. The presence of an IDH
             mutation will be an exclusionary criteria for trial enrollment.

          5. Have a performance status of >/= 60 on the Karnofsky Performance Scale (KPS).

          6. Stable or decreasing dose of steroids for at least 5 days at the time of baseline
             brain MRI.

          7. Demonstrate adequate organ function. All screening labs should be performed within 14
             days (+3 working days) of treatment initiation. Absolute neutrophil count (ANC) >/=
             1,500 /mcL; Platelets >/= 100,000 /mcL; Hemoglobin >/= 9 g/dL or >/= 5.6 mmol/L; Serum
             creatinine OR Measured or calculated creatinine clearance (GFR can also be used in
             place of creatinine or CrCl) </= 1.5 X upper limit of normal (ULN) OR >/= 60 mL/min
             for subject with creatinine levels > 1.5 X institutional ULN; Serum total bilirubin
             </= 1.5 X ULN OR Direct bilirubin </= ULN for subjects with total bilirubin levels >
             1.5 ULN; AST (SGOT) and ALT (SGPT) </= 2.5 X ULN; International Normalized Ratio (INR)
             or Prothrombin Time (PT), Activated Partial Thromboplastin Time (aPTT) </= 1.5 X ULN.

          8. Female subjects of childbearing potential should have a negative serum pregnancy test
             within 72 hours of starting first dose of study drug.

          9. Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the
             duration of the study. Subjects of childbearing potential are those who have not been
             surgically sterilized or have not been free from menses for > 1 year.

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

         11. Patients must have completed standard radiation therapy with concurrent TMZ and must
             not have evidence of progressive disease on post treatment imaging. Progression can
             only be defined using diagnostic imaging if there is new enhancement outside of the
             radiation field (beyond the high-dose region or 80% isodose line) or if there is
             unequivocal evidence of viable tumor on histopathologic sampling (e.g., solid tumor
             areas [i.e, > 70% tumor cell nuclei in areas], high or progressive increase in MIB-1
             proliferation index compared with prior biopsy, or evidence for histologic progression
             or increased anaplasia in tumor). Note: Given the difficulty of differentiating true
             progression from pseudoprogression, clinical decline alone, in the absence of
             radiographic or histologic confirmation of progression, will not be sufficient for
             definition of progressive disease in the first 12 weeks after completion of concurrent
             chemoradiotherapy. (For Stage 1: Post-chemoradiation group only)

         12. Patients must have undergone surgery of their GBM, and must not have had any further
             treatment following surgery. A minimal interval of 7 days between the day of surgery
             and the day of inclusion should be respected; a maximal interval of 31 days between
             the day of surgery and the day of inclusion should be respected; the patient should
             have fully clinically recovered from the surgery. (For Stage 2: Radiation with
             concurrent and adjuvant EDOS101 only)

         13. Patients must undergo surgery and must not have further treatment. (For MTD Expansion
             cohort only)

        Exclusion Criteria:

          1. Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics
             delivered by local injection or convection enhanced delivery. Prior treatment with
             Gliadel® wafers will be excluded. Concomitant use of the Optune device will also be
             excluded.

          2. Is currently participating or has participated in any other investigational or
             therapeutic trial before or after chemoradiation.

          3. Any serious medical condition that interferes with adherence to study procedures.

          4. Has had prior chemotherapy, targeted small molecule therapy, within 2 weeks prior to
             study Day 1 or who has not recovered (i.e., </= Grade 1 or at baseline) from adverse
             events due to a previously administered agent. Note: Subjects with </= Grade 2
             neuropathy are an exception to this criterion and may qualify for the study. Note: If
             subject received major surgery, they must have recovered adequately from the toxicity
             and/or complications from the intervention prior to starting therapy.

          5. Patients with a history of a second malignancy diagnosed within three (3) years of
             study enrollment or have a known additional malignancy that is progressing or requires
             active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
             carcinoma of the skin, or in situ cervical cancer that has undergone potentially
             curative therapy.

          6. New York Heart Association (NYHA) stage III/IV congestive heart failure, arrhythmias
             not adequately controlled.

          7. Patients with prolonged corrected QT (QTc) interval defined as male >450 msec and
             female > 470 msec.

          8. Patients who are on treatment with drugs known to prolong the QT/QTc interval.

          9. Has known gliomatous meningitis, extracranial disease, or multifocal disease.

         10. Has an active infection requiring systemic therapy.

         11. Has an ongoing or previous history of spontaneous intratumoral hemorrhage.

         12. 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 investigator.

         13. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         14. Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the screening visit.

         15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
             Testing not required.

         16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected). (Testing not required for Stage 2 and MTD Expansion
             cohort)

         17. Has received a live vaccine within 30 days prior to the first dose of trial treatment.

         18. Contraindication for undergoing MRIs

         19. Use of any drug with HDAC inhibiting activity.

         20. Use of valproate in any of its indications (epilepsy, mood disorder). Valproate, due
             to its HDAC inhibiting activity is contraindicated. For those patients on valproate,
             valproate will need to be discontinued and switched to a different anti-epileptic
             agent or psychotropic agent. A washout period of 4 days from valproate acid will be
             allowed prior to enrolling into the trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of EDO-S101 for MGMT Unmethylated Glioblastoma (nGBM)
Time Frame:4 weeks after start of study drug.
Safety Issue:
Description:MTD confirmed when six (6) patients are treated at a dose level with less than two (2) dose limiting toxicities (DLTs).

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:6 weeks
Safety Issue:
Description:ORR defined as the number of patients with partial response (PR) and complete response (CR) maintained for a minimum of 6 weeks divided by the total number of patients enrolled.
Measure:Overall Survival (OS)
Time Frame:Start of study treatment up to 2 years
Safety Issue:
Description:OS defined as the time from study enrollment until the time of death.
Measure:Progression-Free Survival (PFS)
Time Frame:6 months
Safety Issue:
Description:PFS defined as the time from study enrollment until the time of first disease progression, relapse, or death due to disease.

Details

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

Trial Keywords

  • Malignant neoplasms of eye brain and other parts of central nervous system
  • Unmethylated Glioblastoma
  • nGBM
  • Glioma
  • Gliosarcoma
  • EDO-S101
  • Radiation Therapy
  • XRT

Last Updated

April 12, 2018