Clinical Trials /

Ph I/II Study of NMS-03305293+TMZ in Adult Patients With Recurrent Glioblastoma

NCT04910022

Description:

Multicenter, randomized, open-label, non-comparative Phase 1/2 study on the safety and efficacy of the combination of NMS-03305293 and temozolomide (TMZ) in adult patients with diffuse gliomas (Phase 1) and isocitrate dehydrogenase (IDH) wild type recurrent glioblastoma (glioblastoma expansion cohort in Phase 1 and Phase 2).

Related Conditions:
  • Diffuse Glioma
  • Glioblastoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ph I/II Study of NMS-03305293+TMZ in Adult Patients With Recurrent Glioblastoma
  • Official Title: A Phase I/II Combination Study of NMS-03305293 and Temozolomide in Adult Patients With Recurrent Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: PARPA-293-002
  • SECONDARY ID: 2020-003417-35
  • NCT ID: NCT04910022

Conditions

  • Glioblastoma
  • Diffuse Glioma

Interventions

DrugSynonymsArms
NMS-03305293 + TMZPhase 1_Dose escalation and MTD expansion cohort
NMS-03305293 + TMZPhase 1_Glioblastoma expansion cohort
LomustinePhase 2_Arm B_Lomustine
NMS-03305293 + TMZPhase 2_Arm A_NMS-03305293+TMZ

Purpose

Multicenter, randomized, open-label, non-comparative Phase 1/2 study on the safety and efficacy of the combination of NMS-03305293 and temozolomide (TMZ) in adult patients with diffuse gliomas (Phase 1) and isocitrate dehydrogenase (IDH) wild type recurrent glioblastoma (glioblastoma expansion cohort in Phase 1 and Phase 2).

Trial Arms

NameTypeDescriptionInterventions
Phase 1_Dose escalation and MTD expansion cohortExperimentalPatients with diffuse gliomas
  • NMS-03305293 + TMZ
Phase 1_Glioblastoma expansion cohortExperimentalPatients with IDH wild type recurrent glioblastoma
  • NMS-03305293 + TMZ
Phase 2_Arm A_NMS-03305293+TMZExperimentalPatients with IDH wild type recurrent glioblastoma
  • NMS-03305293 + TMZ
Phase 2_Arm B_LomustineActive ComparatorPatients with IDH wild type recurrent glioblastoma
  • Lomustine

Eligibility Criteria

        Inclusion Criteria:

        - Phase 1 (except for glioblastoma expansion cohort)

        1. Histologically confirmed diagnosis of an intracranial diffuse glioma (i.e. diffuse
        astrocytoma, oligodendroglioma or glioblastoma).

        2. Patients at first relapse after chemotherapy including temozolomide as long as no more
        than 12 cycles of temozolomide were administered.

        - Phase 2 and Phase 1 glioblastoma expansion cohort

          1. Histologically confirmed diagnosis of IDH wild type glioblastoma as per WHO 2016
             classification or c-IMPACT-NOW 3 definition including diffuse astrocytic glioma,
             IDH-wildtype, with molecular features of glioblastoma, WHO Grade 4. IDH1 status must
             be assessed locally by immunohistochemistry (IHC). If IHC is performed and is
             negative, and patient is < 55 years old, sequencing or a PCR-based validated test must
             be performed to exclude other IDH1 or IDH2 most frequent mutations.

          2. Patients at first relapse after initial standard therapy including temozolomide as
             long as no more than 6 cycles of temozolomide were administered and provided that
             patient completed standard of care concurrent temozolomide and the radiation therapy.

             - Phase 1 and Phase 2

          3. Patients may have been operated for recurrence. If operated:

               -  residual and measurable disease after surgery is not required but pathology must
                  have confirmed tumor recurrence.

               -  a post-surgery MRI should be available within 48 hours following surgery.

               -  surgery completed at least 2 weeks before enrolment/randomization and patient
                  should have fully recovered.

          4. For non-operated patients, recurrent disease must be defined by at least one
             bidimensionally measurable contrast-enhancing lesion with clearly defined margins with
             minimal diameters of 10 mm, visible on 2 or more axial slices 5 mm apart, based on MRI
             scan done within two weeks prior to enrolment/randomization.

          5. Patients on steroids should have stable or decreasing dose of steroids for 7 days
             prior to the baseline MRI scan.

          6. Life expectancy of at least 3 months.

          7. Able to undergo brain MRI scans with IV gadolinium.

          8. No evidence of symptomatic and acute intratumoral hemorrhage on MRI. Patients with MRI
             demonstrating old hemorrhage or subacute blood after a neurosurgical procedure (biopsy
             or resection) are eligible.

          9. Sufficient tissue representative of the disease available for central MGMT promoter
             methylation status (Phase 1 and 2) and IDH status evaluation (Phase 1).

         10. Male or female patients with age ≥ 18 years.

         11. ECOG performance status ≤ 2.

         12. Signed and dated IEC or IRB-approved Informed Consent.

         13. Resolution of all acute toxic effects (excluding alopecia) of any prior anticancer
             therapy to NCI CTCAE (Version 5.0) Grade ≤ 1 or to the baseline laboratory values as
             defined in Inclusion Criterion Number 14.

         14. Baseline laboratory values fulfilling the requirements declared into the Protocol

         15. Patients must use effective contraception or abstinence. Female patients of
             childbearing potential must agree to use effective contraception or abstinence during
             the period of therapy and in the following 6 months after discontinuation of study
             treatment. Male patients must be surgically sterile or must agree to use effective
             contraception or abstinence during the period of therapy and in the following 6 months
             after discontinuation of study treatment.

         16. Ability to swallow capsules intact (without chewing, crushing, or opening).

         17. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
             tests and other study indications or procedures.

        Exclusion Criteria:

          1. Current enrollment in another interventional clinical trial.

          2. Current treatment with other anticancer agents, or treatment at recurrence with
             carmustine wafer implants and proteasome inhibitors.

          3. Previous treatment with PCV (procarbazine, lomustine and vincristine) or any of its
             components, carmustine wafer implants, or bevacizumab.

          4. Previous treatment with PARP inhibitors.

          5. Major surgery, other than surgery for recurrent diffuse glioma, within 4 weeks prior
             to treatment.

          6. Standard radiotherapy within the three months (12 weeks) prior to the diagnosis of
             progression unless the progression is clearly outside the radiation field (eg, beyond
             the high-dose region or 80% isodose line) or unless the recurrence is histologically
             proven.

          7. Prior radiotherapy with a dose over 65 Gy, stereotactic radiosurgery or brachytherapy,
             unless the recurrence is histologically proven.

          8. Use of full-dose anticoagulants unless the INR or aPTT is within therapeutic limits
             (according to the medical standard in the institution) and the patient has been on a
             stable dose of anticoagulants for at least two weeks before enrollment (Phase 1) or
             randomization (Phase 2).

          9. Treatment with concomitant medications known to be sensitive substrates of CYP2D6 and
             CYP2C19 that cannot be replaced with another treatment.

         10. Treatment with enzyme-inducing anti-epileptic drugs (EIAED). Patients may be on
             non-EIAED or not be taking any anti-epileptic drugs. Patients previously on EIAED must
             be fully switched to non-EIAED at least 2 weeks prior to enrolment/randomization.

         11. Pregnant or breast-feeding women.

         12. Known hypersensitivity to any component of NMS-03305293 or TMZ (Phase 1, Phase 2) or
             lomustine (Phase 2) drug formulations.

         13. Known active infections (bacterial, fungal, viral including HIV positivity) requiring
             systemic treatment.

         14. Patients with QTc interval ≥480 milliseconds or with risk factors for torsade de
             pointes (e.g., uncontrolled heart failure, uncontrolled hypokalemia, history of
             prolonged QTc interval or family history of long QT syndrome). For patients receiving
             treatment with concomitant medications known to prolong the QTc interval, replacement
             with another treatment should be considered. If replacement is not possible, a careful
             risk/benefit evaluation should be performed prior to enrollment.

         15. Active gastrointestinal disease (e.g., documented gastrointestinal ulcer, Crohn's
             disease, ulcerative colitis, or short gut syndrome) or other syndromes that would
             impact on drug absorption.

         16. Planned vaccinations with live vaccines (Phase 2).

         17. Any of the following in the past 6 months: myocardial infarction, unstable angina,
             coronary/peripheral artery bypass graft, symptomatic congestive heart failure,
             cerebrovascular accident or transient ischemic attack, active bleeding disorder.

         18. Prior invasive malignancy (except for non melanoma skin cancer, carcinoma in situ of
             the cervix or localized cancer) unless the patient has been disease-free and off
             therapy for that disease for ≥ 3 years.

         19. History of coeliac disease and wheat allergy (Phase 2).

         20. Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or study
             drug administration or may interfere with the interpretation of study results and, in
             the judgment of the Investigator, would make the patient inappropriate for entry into
             this study or could compromise protocol objectives in the opinion of the Investigator
             and/or the Sponsor.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Number of Participants with first-cycle dose limiting toxicity
Time Frame:Time interval between the first dose administration in Cycle 1 and the first dose administration in Cycle 2 which is expected to be 28 days or up to 42 days in case of dose delay due to drug related toxicity
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Number of participants with Adverse Events (AEs)
Time Frame:From the Informed Consent signature to 28 days after the last dose of study treatment administration
Safety Issue:
Description:Safety will be assessed by adverse events (AEs), which include clinically significant abnormalities identified during a medical test (e.g. laboratory tests, electrocardiogram, vital signs, physical examinations). AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA) and their severity will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).The analysis will focus on the events reported after the start of treatment (treatment emergent adverse events).
Measure:Maximum concentration (Cmax) of NMS-03305293 after single and multiple doses of drug
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments
Measure:Time to observed Cmax (Tmax) of NMS-03305293 after single and multiple doses of drug
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments
Measure:Area under the concentration-time curve up to the last detectable plasma concentration (AUClast) of NMS-03305293 after single and repeated dose of drug.
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments
Measure:Terminal elimination half-life (t1/2) of NMS-03305293 after single and multiple doses of drug
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments
Measure:Area under the plasma concentration vs. time curve to infinity (AUCinf) of NMS-03305293 after multiple doses of drug.
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments
Measure:Accumulation ratio (Rac) of NMS-03305293 after multiple doses of drug.
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments
Measure:Oral plasma clearance (CL/F) of NMS-03305293 after multiple doses of drug
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments
Measure:Apparent volume of distribution (Vd/F) of NMS-03305293 after multiple doses of drug
Time Frame:At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints
Safety Issue:
Description:Plasma samples will be collected and used for pharmacokinetics assessments
Measure:Phase 1: Renal clearance of NMS-03305293 after multiple doses of drug
Time Frame:At baseline, at Cycle 1 (each cycle is 28 days) Day 5 at different timepoints
Safety Issue:
Description:Urine samples will be collected in patients treated in the phase 1 and used for pharmacokinetics assessments
Measure:Phase 1: Cumulative amount recovered unchanged in the urine (Ae) of NMS-03305293 after multiple doses of drug
Time Frame:At baseline, at Cycle 1 (each cycle is 28 days) Day 5 at different timepoints
Safety Issue:
Description:Urine samples will be collected in patients treated in the phase 1 and used for pharmacokinetics assessments
Measure:Phase 1: Cumulative amount recovered unchanged in the urine expressed as a fraction of administered dose (Ae%) of NMS-03305293 after multiple doses of drug
Time Frame:At baseline, at Cycle 1 (each cycle is 28 days) Day 5 at different timepoints.
Safety Issue:
Description:Urine samples will be collected in patients treated in the phase 1 and used for pharmacokinetics assessments
Measure:Phase 1: Objective Tumor Response
Time Frame:At baseline, every 8 weeks for the first 6 months from treatment start, then every 12 weeks, until disease progression or start of a new anticancer therapy (approximately 12 months).
Safety Issue:
Description:Complete and partial responses will be assessed according to RANO criteria
Measure:Phase 2: Objective Tumor Response Rate
Time Frame:At baseline, every 8 weeks for the first 6 months from randomization, then every 12 weeks, until disease progression or start of a new anticancer therapy (approximately 18 months).
Safety Issue:
Description:Percentage of patients achieving a complete response or partial response assessed according to RANO criteria
Measure:Duration of Response
Time Frame:From the date of first response up to data cut-off (approximately 18 months).
Safety Issue:
Description:Duration of response will be calculated from the date of either first CR or PR until the date of documented progression for patients who achieved CR or PR. Patients who died without report of progression will be considered non-events and censored at their last disease-free assessment date
Measure:Progression Free Survival
Time Frame:From first dose of study drug (Phase 1) or from randomization (Phase 2) up to data cut-off (approximately 18 months)
Safety Issue:
Description:Progression Free Survival will be calculated from the date of treatment initiation or randomization to the date of first documentation of disease progression, or death due to any cause, whichever occurs first
Measure:Overall Survival
Time Frame:From first dose of study drug (Phase 1) or from randomization (Phase 2) up to data cut-off (approximately 24 months)
Safety Issue:
Description:Overall Survival will be calculated from the date of treatment initiation or randomization to the date of death due to any cause
Measure:Phase 2: 9 and 12-Months Overall Survival Rates
Time Frame:From date of randomization until the date of death from any cause, assessed up to 9 and 12 months.
Safety Issue:
Description:Percentage of patients alive at 9 and 12 months from randomization.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Nerviano Medical Sciences

Trial Keywords

  • IDH wild type
  • PARP inhibitor

Last Updated

June 2, 2021