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

Inclusion Criteria:

• Phase 1

1. Histologically confirmed diagnosis of an intracranial diffuse glioma (i.e.diffuse astrocytoma, oligodendroglioma or glioblastoma). Sponsor may opt torestrict enrollment based on MGMT status, tumor type, tumor measurability orapply restriction on time to first relapse.

2. Patients at first radiographic relapse after chemotherapy includingtemozolomide as long as no more than 12 cycles of temozolomide wereadministered.

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

• residual and measurable disease after surgery is not required butpathology 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 clinicalstatus should not be worsened respect to pre-surgery condition

• Backfill cohorts

1. Histologically confirmed diagnosis of Glioblastoma, IDH-wildtype as per WHO 2021 classification, including IDH-wildtype diffuse and astrocytic glioma inadults if there is microvascular proliferation or necrosis or TERT promotermutation or EGFR gene amplification or +7/-10 chromosome copy number changes orc-IMPACT-NOW 3 definition including diffuse astrocytic glioma, IDH-wildtype,with molecular features of glioblastoma, WHO Grade 4. IDH1 status must beassessed locally by immunohistochemistry (IHC). If IHC is performed and isnegative, and patient is < 55 years old, sequencing or a PCR-based validatedtest must be performed to exclude other IDH1 or IDH2 most frequent mutations.Sponsor may opt to restrict enrollment based on MGMT status or applyrestriction on time to first relapse.

2. Patients must have measurable disease and meet standard of care resection, ifindicated, and irradiation, if indicated, with concomitant temozolomide plus upto 6 cycles of adjuvant temozolomide consistent with local standards of care.

3. 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 clinicalstatus should not be worsened respect to pre-surgery condition.

• Phase 2

1. Histologically confirmed diagnosis of Glioblastoma, IDH-wildtype as per WHO 2021 classification, including IDH-wildtype diffuse and astrocytic glioma inadults if there is microvascular proliferation or necrosis or TERT promotermutation or EGFR gene amplification or +7/-10 chromosome copy number changes orc-IMPACTNOW 3 definition including diffuse astrocytic glioma, IDH-wildtype,with molecular features of glioblastoma, WHO Grade 4. IDH1 status must beassessed locally by immunohistochemistry (IHC). If IHC is performed and isnegative, and patient is < 55 years old, sequencing or a PCR-based validatedtest must be performed to exclude other IDH1 or IDH2 most frequent mutations.Sponsor may opt to restrict enrollment based on MGMT status or applyrestriction on time to first relapse.

2. Patients must have measurable disease at first radiographic relapse afterinitial standard therapy including temozolomide as long as no more than 6cycles of adjuvant temozolomide were administered and provided that patientcompleted standard of care concurrent temozolomide and the radiation therapy;multiple surgeries are allowed as long as patient is at first relapse and TMZwas administered as standard of care.

3. 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 clinicalstatus should not be worsened respect to pre-surgery condition.

• Phase 1 (including backfill) and Phase 2

4. For non-operated patients with measurable disease in Phase I, for backfill andfor all patients in Phase 2, recurrent disease must be defined by at least onebidimensionally measurable contrast-enhancing lesion with clearly definedmargins with minimal diameters of 10 mm, visible on 2 or more axial slices 5 mmapart, based on MRI scan done within two weeks prior to enrolment.

5. Patients on steroids should have stable or decreasing dose of steroids for 7days 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. Patientswith MRI demonstrating old hemorrhage or subacute blood after a neurosurgicalprocedure (biopsy or resection) are eligible.

9. Sufficient tissue representative of the disease available for central MGMTpromoter methylation status (Phase I and II) and IDH status evaluation (PhaseI).

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 prioranticancer therapy to NCI CTCAE (Version 5.0) Grade ≤ 1 or to the baselinelaboratory values as defined in Inclusion Criterion Number 14.

14. Baseline laboratory values fulfilling the requirements declared into theProtocol

15. Patients must use highly effective contraception or true abstinence. Femalepatients of childbearing potential must agree to use effective contraception orabstinence during the period of therapy and in the following 6 months plus 5xNMS-03305293 half-life (3 days) after discontinuation of study treatment. BeingNMS-03305293 a potential CYP3A perpetrator, hormonal contraception may loseefficacy while on treatment with NMS-03305293, therefore this should be takeninto account. Male patients must be surgically sterile or must agree to usehighly effective contraception or true abstinence during the period of therapyand in the following 90 days plus 5x NMS-03305293 half-life (3 days) afterdiscontinuation 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 devices, or treatment atrecurrence with carmustine wafer implants and proteasome inhibitors.

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

4. Previous treatment with PARP inhibitors.

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

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

7. Prior radiotherapy with a dose over 65 Gy, stereotactic radiosurgery orbrachytherapy, 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 astable dose of anticoagulants for at least two weeks before enrollment

9. Treatment with concomitant medications known to be sensitive substrates of CYP2D6and CYP2C19 that cannot be replaced with another treatment.

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

11. Pregnant or breast-feeding women.

12. Known hypersensitivity to any component of NMS-03305293 or TMZ drug formulations.

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

14. Patients with QTc interval ≥460 milliseconds for women, ≥450 milliseconds for men orwith risk factors for torsade de pointes (e.g., uncontrolled heart failure,uncontrolled hypokalemia, history of prolonged QTc interval or family history oflong QT syndrome). For patients receiving treatment with concomitant medicationsknown to prolong the QTc interval, replacement with another treatment prior toenrollment is mandatory. If concomitant use of anti-emetics is considered essentialfor the care of the patients, instruction in protocol will be followed.

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

16. 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.

17. Prior invasive malignancy (except for non melanoma skin cancer, carcinoma in situ orlocalized cancer) unless the patient has been disease-free and off therapy for thatdisease for ≥ 3 years.

18. Other severe acute or chronic medical or psychiatric condition or laboratoryabnormality that may increase the risk associated with study participation or studydrug administration or may interfere with the interpretation of study results and,in the judgment of the Investigator, would make the patient inappropriate for entryinto this study or could compromise protocol objectives in the opinion of theInvestigator and/or the Sponsor.