A study of the experimental drug NMS-03305293 in combination with Temozolomide in adult patients with a type of brain tumor called glioblastoma

Italy, Netherlands, Puerto Rico, Switzerland, United States (ICTRP)

ICTRP Trial ID
NCT04910022 (ICTRP)

Official title (approved by ethics committee)
A Phase I/II Combination Study of NMS-03305293 and Temozolomide in Adult Patients with Recurrent Glioblastoma (BASEC)

Academic title
A Phase I/II Combination Study of NMS-03305293 and Temozolomide in Adult Patients With Recurrent Glioblastoma (ICTRP)

Public title
Ph I/II Study of NMS-03305293+TMZ in Adult Patients With Recurrent Glioblastoma (ICTRP)

Disease under investigation
GlioblastomaDiffuse Glioma (ICTRP)

Intervention under investigation
Drug: NMS-03305293Drug: Temozolomide (ICTRP)

Type of trial
Interventional (ICTRP)

Trial design
Allocation: N/A. Intervention model: Sequential Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Inclusion/Exclusion criteria
Inclusion Criteria:

- Phase 1

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 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.

- Phase 2

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. (ICTRP)

not available

Primary and secondary end points
Phase 1: Number of Participants with first-cycle dose limiting toxicity;Phase 2: Objective Response Rate (ICTRP)

Number of participants with Adverse Events (AEs);Maximum concentration (Cmax) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug;Time to observed Cmax (Tmax) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug;Area under the concentration-time curve up to the last detectable plasma concentration (AUClast) of NMS-03305293 and possible identified metabolites (if appropriate) after single and repeated dose of drug.;Terminal elimination half-life (t1/2) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug;Area under the plasma concentration vs. time curve to infinity (AUCinf) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug.;Accumulation ratio (Rac) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug.;Oral plasma clearance (CL/F) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug;Apparent volume of distribution (Vd/F) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug;Phase 1: Renal clearance of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug;Phase 1: Cumulative amount recovered unchanged in the urine (Ae) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug;Phase 1: Cumulative amount recovered unchanged in the urine expressed as a fraction of administered dose (Ae%) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug;Phase 1: Objective Tumor Response;Phase 1: Duration of Response;Phase 1: Progression Free Survival;Phase 2: Duration of response (DoR) through central retrospective assessment of RANO criteria;Phase 2: Progression-free survival (PFS);Phase 2: 6-month PFS Rate;Phase 2: 9 and 12-Months Overall Survival Rates;Overall Survival (ICTRP)

Registration date
not available

Incorporation of the first participant
not available

Secondary sponsors
not available

Additional contacts
Domenico Roberti, clinicaltrials@nervianoms.com, +39 0331-581111 (ICTRP)

Secondary trial IDs
2020-003417-35, 2023-508318-41-00, PARPA-293-002 (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://clinicaltrials.gov/study/NCT04910022 (ICTRP)