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

A Phase I/II Combination Study of NMS-03305293 and Temozolomide in Adult Patients With Recurrent Glioblastoma

Multicenter, open-label, single-arm 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 glioblastoma (Phase 2) at first relapse.

Phase 1 Dose Escalation: All patients will receive NMS-03305293 and temozolomide (TMZ) administered orally (NMS-03305293 once or twice daily on days 1-7; TMZ once daily on days 1-5;) in repeated 4-week cycles aimed at defining the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of NMS-03305293 in combination with TMZ. Each cycle is 28 days. Phase 2: Once the RP2D is defined, the patients will receive TMZ daily on days 1-5 in combination with NMS-03305293 at the RP2D on days 1-7 every 28 days.

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

Objective Response Rate (ORR), calculated as the proportion of evaluable patients who have achieved, as best overall response (BOR), confirmed complete response (CR) or partial response (PR) through central retrospective assessment of RANO criteria

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).

Maximum concentration (Cmax) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug

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

Time to observed Cmax (Tmax) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug

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

Area under the concentration-time curve up to the last detectable plasma concentration (AUClast) of NMS-03305293 and possible identified metabolites (if appropriate) after single and repeated dose of drug.

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

Terminal elimination half-life (t1/2) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug

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

Area under the plasma concentration vs. time curve to infinity (AUCinf) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug.

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

Accumulation ratio (Rac) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug.

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

Oral plasma clearance (CL/F) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug

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

Apparent volume of distribution (Vd/F) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug

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

Phase 1: Renal clearance of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug

Urine samples will be collected in patients treated in the phase 1 and used for pharmacokinetics assessments

Phase 1: Cumulative amount recovered unchanged in the urine (Ae) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug

Urine samples will be collected in patients treated in the phase 1 and used for pharmacokinetics assessments

Phase 1: Cumulative amount recovered unchanged in the urine expressed as a fraction of administered dose (Ae%) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug

Urine samples will be collected in patients treated in the phase 1 and used for pharmacokinetics assessments

At baseline, every 8 weeks until disease progression or start of a new anticancer therapy (approximately 18 months).

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

Progression Free Survival will be calculated from the date of treatment initiation to the date of first documentation of disease progression, or death due to any cause, whichever occurs first

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

Progression Free Survival will be calculated from the date of treatment initiation to the date of first documentation of disease progression, or death due to any cause, whichever occurs first

From date of treatment initiation until the date of first documentation of progression or death for any cause, whichever occurs first, assessed up to 6 months

From the date of treatment initiation until the date of death from any cause, assessed up to 9 and 12 months.

Overall Survival will be calculated from the date of treatment initiation to the date of death due to any cause

Inclusion Criteria: Phase 1 Histologically confirmed diagnosis of an intracranial diffuse glioma (i.e. diffuse astrocytoma, oligodendroglioma or glioblastoma). Patients at first relapse after chemotherapy including temozolomide as long as no more than 12 cycles of temozolomide were administered. 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 and patient clinical status should not be worsened respect to pre-surgery condition Phase 2 Histologically confirmed diagnosis of Glioblastoma, IDH-wildtype as per WHO 2021 classification, including IDH-wildtype diffuse and astrocytic glioma in adults if there is microvascular proliferation or necrosis or TERT promoter mutation or EGFR gene amplification or +7/-10 chromosome copy number changes 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. 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. Patients may have been operated for recurrence. If operated: residual and measurable disease after surgery is required a post-surgery MRI should be available within 48 hours following surgery surgery completed at least 2 weeks before enrolment and patient clinical status should not be worsened respect to pre-surgery condition. Phase 1 and Phase 2 4. For non-operated patients with measurable disease in Phase I and for all patients in Phase 2, 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. 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 I and II) and IDH status evaluation (Phase I). 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. Being NMS-03305293 a potential CYP3A perpetrator, hormonal contraception may lose efficacy while on treatment with NMS-03305293, therefore this should be taken into account. 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: Current enrollment in another interventional clinical trial. Current treatment with other anticancer agents, or treatment at recurrence with carmustine wafer implants and proteasome inhibitors. Previous treatment with PCV (procarbazine, lomustine and vincristine) or any of its components, carmustine wafer implants, or bevacizumab. Previous treatment with PARP inhibitors. Major surgery, other than surgery for recurrent diffuse glioma, within 4 weeks prior to treatment. 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. Prior radiotherapy with a dose over 65 Gy, stereotactic radiosurgery or brachytherapy, unless the recurrence is histologically proven. 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 Treatment with concomitant medications known to be sensitive substrates of CYP2D6 and CYP2C19 that cannot be replaced with another treatment. 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. Pregnant or breast-feeding women. Known hypersensitivity to any component of NMS-03305293 or TMZ drug formulations. Known active infections (bacterial, fungal, viral including HIV positivity) requiring systemic treatment. Patients with QTc interval ≥460 milliseconds for women, ≥450 milliseconds for men 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 prior to enrollment is mandatory. 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. 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. Prior invasive malignancy (except for non melanoma skin cancer, carcinoma in situ or localized cancer) unless the patient has been disease-free and off therapy for that disease for ≥ 3 years. 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.