A Phase I/II Combination Study of NMS-03305293 and Temozolomide in Adult Patients with Recurrent Glioblastoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Nerviano Medical Sciences S.r.l.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

30 Sep 2021 → ongoing

Decision date (initial)

2023-12-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Nerviano Medical Sciences

External identifiers

EU CT number

2023-508318-41-00

EudraCT number

2020-003417-35

ClinicalTrials.gov

NCT04910022

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response

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.

Secondary objectives 3

1. To characterize the safety profile of NMS-03305293 in combination with TMZ
2. To evaluate the pharmacokinetics of NMS-03305293 in combination with TMZ
3. To evaluate additional measures of antitumor efficacy of NMS-03305293 in combination with TMZ

Conditions and MedDRA coding

Recurrent Glioblastoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. Phase I - 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. Phase I (including Backfill) and Phase II - 7. Able to undergo brain MRI scans with IV gadolinium.
3. Phase I (including Backfill) and Phase II - 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.
4. Phase I (including Backfill) and Phase II - 9. Sufficient tissue representative of the disease available for central MGMT promoter methylation status (Phase I and II) and IDH status evaluation (Phase I).
5. Phase I (including Backfill) and Phase II - 10. Male or female patients with age ≥ 18 years.
6. Phase I (including Backfill) and Phase II - 11. ECOG performance status ≤2.
7. Phase I (including Backfill) and Phase II - 12. Signed and dated IEC or IRB-approved Informed Consent.
8. Phase I (including Backfill) and Phase II - 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
9. Phase I (including Backfill) and Phase II - 14. Baseline laboratory values fulfilling defined requirements as stated in the protocol
10. Phase I (including Backfill) and Phase II - 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.
11. Phase I (including Backfill) and Phase II - 16. Ability to swallow capsules intact (without chewing, crushing, or opening).
12. Phase I - 2. Patients at first radiographic relapse after chemotherapy including temozolomide as long as no more than 12 cycles of temozolomide were administered.
13. Phase I (including Backfill) and Phase II - 17. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study indications or procedures.
14. Phase I - 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
15. Backfill cohorts - 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-1. NOW 3 definition including diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO Grade 4. Sponsor may opt to restrict enrollment based on MGMT status or apply restriction on time to first relapse.
16. Backfill cohorts - 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 and concurrent temozolomide and the radiation therapy consistent with local standards of care.
17. Backfill cohorts - 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.
18. Phase I (including Backfill) and Phase II - 4. For non-operated patients with measurable disease in Phase I, for backfill and for all patients in Phase II, 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.
19. Phase I (including Backfill) and Phase II - 5. Patients on steroids should have stable or decreasing dose of steroids for 7 days prior to the baseline MRI scan.
20. Phase I (including Backfill) and Phase II - 6. Life expectancy of at least 3 months.
21. 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-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.
22. Phase II - 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.
23. Phase II - 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 18

1. 1. Current enrollment in another interventional clinical trial.
2. 2. Current treatment with other anticancer agents or devices, or treatment at recurrence with carmustine wafer implants and proteasome inhibitors.
3. 3. Previous treatment with PCV (procarbazine, lomustine and vincristine) or any of its components, carmustine wafer implants, or bevacizumab.
4. 4. Previous treatment with PARP inhibitors.
5. 5. Major surgery, other than surgery for recurrent diffuse glioma, within 4 weeks prior to treatment.
6. 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. 7. Prior radiotherapy with a dose over 65 Gy, stereotactic radiosurgery or brachytherapy, unless the recurrence is histologically proven.
8. 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. 9. Treatment with concomitant medications known to be sensitive substrates of CYP2D6 and CYP2C19 that cannot be replaced with another treatment
10. 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. 11. Pregnant or breast-feeding women.
12. 12. Known hypersensitivity to any component of NMS-03305293 or TMZ drug formulations.
13. 13. Known active infections (bacterial, fungal, viral including HIV positivity) requiring systemic treatment.
14. 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, follow instruction in specific section of the protocol
15. 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. 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. 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. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. First cycle Dose Limiting Toxicities (DLTs) (Phase I)
2. 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)

Secondary endpoints 5

1. 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
2. Plasma pharmacokinetic profile of NMS-03305293 and possible identified metabolites (if appropriate) after oral administration
3. Renal clearance and fraction of NMS-03305293 and possible identified metabolites (if appropriate) excreted in urine
4. Secondary efficacy endpoints Phase I: -Objective Tumor Response (Partial and Complete Response) (RANO criteria) - Duration of response (DoR) - Progression-free survival (PFS) - Overall survival (OS)
5. Secondary efficacy endpoints Phase II: - Duration of response (DoR) through central retrospective assessment of RANO criteria - Progression-free survival (PFS) and 6-month PFS rate - 9 and 12-month overall survival rates - Overall survival (OS)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Nerviano Medical Sciences S.r.l.

Sponsor organisation

Nerviano Medical Sciences S.r.l.

Address

Via Louis Pasteur 10

City

Nerviano

Postcode

20014

Country

Italy

Scientific contact point

Organisation

Nerviano Medical Sciences S.r.l.

Contact name

Clinical Operations Team

Public contact point

Organisation

Nerviano Medical Sciences S.r.l.

Contact name

Clinical Operations Team

Third parties 4

Locations

2 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 2 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications