Inclusion Criteria:
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.
1. 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. 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.
1. 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-IMPACTNOW 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 at first radiographic relapse after initial
standard therapy including temozolomide as long as no more than 6 cycles of
adjuvant temozolomide were administered and provided that patient completed
standard of care concurrent temozolomide and the radiation therapy; multiple
surgeries are allowed as long as patient is at first relapse and TMZ was
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 clinical
status 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 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 highly effective contraception or true 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 plus 5x
NMS-03305293 half-life (3 days) 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 highly effective
contraception or true abstinence during the period of therapy and in the following 90
days plus 5x NMS-03305293 half-life (3 days) 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 devices, 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. 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.
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 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. If concomitant use of anti-emetics is considered essential for the care of
the patients, instruction in protocol will be followed.
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. 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 or
localized cancer) unless the patient has been disease-free and off therapy for that
disease for ≥ 3 years.
18. 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.
