Study of experimental drug NMS-03305293 in combination with Temozolomide in adult patients with recurrent brain tumor.
- Conditions
- Recurrent glioblastomaMedDRA version: 20.0Level: PTClassification code 10018336Term: GlioblastomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2020-003417-35-IT
- Lead Sponsor
- ERVIANO MEDICAL SCIENCES SR
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 125
Phase I (except for glioblastoma expansion cohort)
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.
Phase II and Phase I glioblastoma expansion cohort
3. 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.
4. 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.
Phase I and Phase II
5. 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/randomization and patient should have fully recovered.
6. For non-operated patients, 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.
7. Patients on steroids should have stable or decreasing dose of steroids for 7 days prior to the baseline MRI scan.
8. Life expectancy of at least 3 months.
9. Able to undergo brain MRI scans with IV gadolinium.
10. 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.
11. Sufficient tissue representative of the disease available for central MGMT promoter methylation status (Phase I and II) and IDH status evaluation (Phase I).
12. Male or female patients with age = 18 years.
13. ECOG performance status 14. Signed and dated IEC or IRB-approved Informed Consent.
15. 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.
16. Adequate baseline hematological, renal and hepatic functions. Negative pregnancy test for female with reproductive potential.
17. 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. 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.
18. Ability to swallow capsules intact (without chewing, crushing, or opening).
19. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study indications or procedu
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 (Phase I) or randomization (Phase II).
9. Treatment with concomitant medications known to be sensitive substrates of CYP2D6 and CYP2C19 that cannot be replaced with another treatment (see Table 5).
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/randomization.
11. Pregnant or breast-feeding women.
12. Known hypersensitivity to any component of NMS-03305293 or TMZ (Phase I, Phase II) or lomustine (Phase II) drug formulations.
13. Known active infections (bacterial, fungal, viral including HIV positivity) requiring systemic treatment.
14. Patients with QTc interval =480 milliseconds 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 should be considered. If replacement is not possible, a careful risk/benefit evaluation should be performed prior to
enrollment.
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. Planned vaccinations with live vaccines (Phase II).
17. 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.
18. Prior invasive malignancy (except for non melanoma skin cancer, carcinoma in situ of the cervix or localized cancer) unless the patient has been disease-free and off therapy for that disease for = 3 years.
19. History of coeliac disease and wheat allergy (Phase II).
20. 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 o
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: • 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)<br>• To determine the antitumor efficacy of the combination of NMS-03305293 and TMZ in patients with isocitrate dehydrogenase (IDH) wild type glioblastoma (Phase II);Secondary Objective: • To characterize the safety profile of NMS-03305293 in combination with TMZ<br>• To evaluate the pharmacokinetics of NMS-03305293 in combination with TMZ<br>• To evaluate additional measures of antitumor efficacy of NMS-03305293 in combination with TMZ;Primary end point(s): • First cycle Dose Limiting Toxicities (DLTs) (Phase I)<br>• 6-month Progression Free Survival (PFS6) rate (Phase II);Timepoint(s) of evaluation of this end point: During the first cycle (Phase I).<br>Six months after treatment start (Phase II).
- Secondary Outcome Measures
Name Time Method 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), timing of adverse events (AEs) and laboratory abnormalities, and relationship of AEs to the study treatment.; Plasma pharmacokinetic profile of NMS-03305293 after oral administration (such as Cmax, AUC and other parameters as appropriate).; Renal clearance and fraction of NMS-03305293 excreted unchanged in urine.;Timepoint(s) of evaluation of this end point: All the study duration.; Phase I : at cycle 1.<br>Phase II; at Cycles 1, 2 and or 3 or 4.; In all patients enrolled in the Phase I at the pretreatment and cycle 1 days 5 and 6 .