| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| A type of brain tumour called glioblastoma |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of NMS-03305293 in combination with temozolomide (TMZ) in patients with diffuse gliomas at first relapse (Phase I)
To assess the antitumor efficacy of the combination of NMS-03305293 and TMZ in patients with isocitrate dehydrogenase (IDH) wild type glioblastoma (Phase II) at first relapse
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| E.2.2 | Secondary objectives of the trial |
• To characterize the safety profile of NMS-03305293 in combination with TMZ
• To evaluate the pharmacokinetics of NMS-03305293 in combination with TMZ
• To evaluate additional measures of antitumor efficacy of NMS-03305293 in combination with TMZ
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase I
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.
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
Phase II
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.
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.
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.
Phase I and Phase II
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/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 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 stated in the protocol
14. Baseline laboratory values fulfilling defined requirements as stated in 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. |
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| E.4 | Principal 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.
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.
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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- First cycle Dose Limiting Toxicities (DLTs) (Phase I)
- 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 (Phase II)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of DLTs will be performed at each scheduled clinic visit from the point at which the patient signs the Informed Consent until 28 Days after the last on-study treatment administration, or until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever comes first, or until alternative anticancer therapy is initiated (applicable for Phase 1).
Disease assessment (RANO criteria): is required at screening (<2 weeks before enrolment/randomization), every 8 weeks (+/-5 days) for the first 6 months, then every 12 weeks, until disease progression or start of a new anticancer therapy using the standardized brain tumor imaging protocol (applicable for Phase 2). |
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| E.5.2 | Secondary end point(s) |
• Overall safety profile of the combination of NMS-03305293 and TMZ characterized by type, frequency, severity (graded using the NCI CTCAE Version 5.0), duration of adverse events (AEs), ECGs and laboratory abnormalities, and relationship of AEs to the study treatment
• Plasma pharmacokinetic profile of NMS-03305293 and possible identified metabolites (if appropriate) after oral administration
• Renal clearance and fraction of NMS-03305293 and possible identified metabolites (if appropriate) excreted in urine
Secondary efficacy endpoints:
• Phase I
o Objective Tumor Response (Partial and Complete Response) (RANO criteria)
o Duration of response (DoR)
o Progression-free survival (PFS)
o Overall survival (OS)
• Phase II
o Duration of response (DoR) through central retrospective assessment of RANO criteria
o Progression-free survival (PFS) and 6-month PFS rate
o 9 and 12-month overall survival rates
o Overall survival (OS)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
AEs should be assessed and documented at each scheduled clinic visit since patient signs the Informed Consent until 28 Days after the last on-study treatment administration, or until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever comes first, or until alternative anticancer therapy is initiated.
PK Plasma Sampling will be performed D1, D2, D5, D6 and D8 of Cycle 1 in Phase 1 and D1, D2, D5, D6 and D8 of Cycle 1 and D5 of subsequent cycles in Phase 2
Renal clearance at screening, D5 and D6 of cycle 1 (Phase 1)
Disease response every 8 weeks (+/-5 days) for the first 6 months then every 12 weeks, until PD or start of a new therapy. Phase II: assessment at 6 months is required for primary endpoint (6mPFS). |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation and expansion |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| China |
| United States |
| Switzerland |
| Italy |
| Netherlands |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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