Clinical Trials

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). Sponsor may opt to restrict enrollment based on MGMT status, tumor type, tumor measurability or apply restriction on time to first relapse.

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

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 and patient clinical status should not be worsened respect to pre-surgery condition.

Backfill Cohorts

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.  Sponsor may opt to restrict enrollment based on MGMT status or apply restriction on time to first relapse.

2. Patients must have measurable disease and meet standard of care resection, if indicated, and irradiation, if indicated, with concomitant temozolomide plus up to 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 clinical status should not be worsened respect to pre-surgery condition.

Exclusion Criteria:

• Current enrollment in another interventional clinical trial.
• Current treatment with other anticancer agents or devices, 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 (e.g., 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.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 1/17/24. Questions regarding updates should be directed to the study team contact.