JOURNAL ONKOLOGIE – STUDIE

Ph I/II Study of NMS-03305293+TMZ in Adult Patients With Recurrent Glioblastoma

Studien-Informationen Einschlusskriterien Studien-Rationale Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT04910022

Studienbeginn:
Dezember 2021

Letztes Update:
15.03.2024

Wirkstoff:
NMS-03305293, Temozolomide

Indikation (Clinical Trials):
Glioblastoma

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
Nerviano Medical Sciences

Collaborator:
-

Kontakt

Domenico Roberti
Kontakt:
Phone: +39 0331-581111
E-Mail: clinicaltrials@nervianoms.com» Kontaktdaten anzeigen

Studienlocations
(3 von 5)

Mayo Clinic Florida
32224 Jacksonville
United StatesRekrutierend» Google-Maps

Mayo Clinic Cancer Center
55905 Rochester
United StatesRekrutierend» Google-Maps

IRCCS Istituto Neurologico Carlo Besta
20133 Milan
ItalyRekrutierend» Google-Maps

Erasmus Medical Center
3015 Rotterdam
NetherlandsRekrutierend» Google-Maps

University Hospital Zurich
8091 Zurich
SwitzerlandRekrutierend» Google-Maps

Alle anzeigen

Studien-Informationen

Brief Summary:

Multicenter, open-label, single-arm Phase 1/2 study on the safety and efficacy of the

combination of NMS-03305293 and temozolomide (TMZ) in adult patients with diffuse gliomas

(Phase 1) and isocitrate dehydrogenase (IDH) wild type glioblastoma (Phase 2) at first

relapse.

Ein-/Ausschlusskriterien

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.

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.

Studien-Rationale

Primary outcome:

1. Phase 1: Number of Participants with first-cycle dose limiting toxicity (Time Frame - Time interval between the first dose administration in Cycle 1 and the first dose administration in Cycle 2 which is expected to be 28 days or up to 42 days in case of dose delay due to drug related toxicity)

2. Phase 2: Objective Response Rate (Time Frame - From the date of first response up to data cut-off (approximately 18 months)):
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

Secondary outcome:

1. Number of participants with Adverse Events (AEs) (Time Frame - From the Informed Consent signature to 28 days after the last dose of study treatment administration):
Safety will be assessed by adverse events (AEs), which include clinically significant abnormalities identified during a medical test (e.g. laboratory tests, electrocardiogram, vital signs, physical examinations). AEs will be coded by Medical Dictionary for Regulatory Activities (MedDRA) and their severity will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).The analysis will focus on the events reported after the start of treatment (treatment emergent adverse events).

2. Maximum concentration (Cmax) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug (Time Frame - Phase 1 and backfill cohorts: Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8; Cycle 2 on Days 5 and 15 (day 15 only if 28 days schedule). Phase 2: Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5)):
Plasma samples will be collected and used for pharmacokinetics assessments

3. Time to observed Cmax (Tmax) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug (Time Frame - Phase 1 and backfill cohorts: Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8; Cycle 2 on Days 5 and 15 (day 15 only if 28 days schedule). Phase 2: Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5)):
Plasma samples will be collected and used for pharmacokinetics assessments

4. 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. (Time Frame - Phase 1 and backfill cohorts: Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8; Cycle 2 on Days 5 and 15 (day 15 only if 28 days schedule). Phase 2: Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5)):
Plasma samples will be collected and used for pharmacokinetics assessments

5. Terminal elimination half-life (t1/2) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug (Time Frame - Phase 1 and backfill cohorts: Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8; Cycle 2 on Days 5 and 15 (day 15 only if 28 days schedule). Phase 2: Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5)):
Plasma samples will be collected and used for pharmacokinetics assessments

6. 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. (Time Frame - Phase 1 and backfill cohorts: Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8; Cycle 2 on Days 5 and 15 (day 15 only if 28 days schedule). Phase 2: Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5)):
Plasma samples will be collected and used for pharmacokinetics assessments

7. Accumulation ratio (Rac) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug. (Time Frame - Phase 1 and backfill cohorts: Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8; Cycle 2 on Days 5 and 15 (day 15 only if 28 days schedule). Phase 2: Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5)):
Plasma samples will be collected and used for pharmacokinetics assessments

8. Oral plasma clearance (CL/F) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug (Time Frame - Phase 1 and backfill cohorts: Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8; Cycle 2 on Days 5 and 15 (day 15 only if 28 days schedule). Phase 2: Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5)):
Plasma samples will be collected and used for pharmacokinetics assessments

9. Apparent volume of distribution (Vd/F) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug (Time Frame - Phase 1 and backfill cohorts: Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8; Cycle 2 on Days 5 and 15 (day 15 only if 28 days schedule). Phase 2: Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5)):
Plasma samples will be collected and used for pharmacokinetics assessments

10. Phase 1: Renal clearance of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug (Time Frame - At baseline, at Cycle 1 (each cycle is 28 days) Day 5 at different timepoints):
Urine samples will be collected in patients treated in the phase 1 and in backfill cohorts and used for pharmacokinetics assessments

11. Phase 1: Cumulative amount recovered unchanged in the urine (Ae) of NMS-03305293 and possible identified metabolites (if appropriate) after multiple doses of drug (Time Frame - At baseline, at Cycle 1 (each cycle is 28 days) Day 5 at different timepoints):
Urine samples will be collected in patients treated in the phase 1 and in backfill cohorts and used for pharmacokinetics assessments

12. 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 (Time Frame - At baseline, at Cycle 1 (each cycle is 28 days) Day 5 at different timepoints.):
Urine samples will be collected in patients treated in the phase 1 and in backfill cohorts and used for pharmacokinetics assessments

13. Phase 1: Objective Tumor Response (Time Frame - At baseline, every 8 weeks until disease progression or start of a new anticancer therapy (approximately 18 months).):
Complete and partial responses will be assessed according to RANO criteria

14. Phase 1: Duration of Response (Time Frame - From the date of first response up to data cut-off (approximately 18 months).):
Duration of response will be calculated from the date of either first CR or PR until the date of documented progression for patients who achieved CR or PR. Patients who died without report of progression will be considered non-events and censored at their last disease-free assessment date

15. Phase 1: Progression Free Survival (Time Frame - From the date of treatment initiation up to data cut-off (approximately 18 months)):
Progression Free Survival will be calculated from the date of treatment initiation to the date of first documentation of disease progression, or death due to any cause, whichever occurs first

16. Phase 2: Duration of response (DoR) through central retrospective assessment of RANO criteria (Time Frame - From the date of first response up to data cut-off (approximately 18 months).):
Duration of response will be calculated from the date of either first CR or PR until the date of documented progression for patients who achieved CR or PR. Patients who died without report of progression will be considered non-events and censored at their last disease-free assessment date

17. Phase 2: Progression-free survival (PFS) (Time Frame - From the date of treatment initiation up to data cut-off (approximately 18 months)):
Progression Free Survival will be calculated from the date of treatment initiation to the date of first documentation of disease progression, or death due to any cause, whichever occurs first

18. Phase 2: 6-month PFS Rate (Time Frame - From date of treatment initiation until the date of first documentation of progression or death for any cause, whichever occurs first, assessed up to 6 months):
Percentage of patients progressive-free at 6 months from treatment initiation

19. Phase 2: 9 and 12-Months Overall Survival Rates (Time Frame - From the date of treatment initiation until the date of death from any cause, assessed up to 9 and 12 months.):
Percentage of patients alive at 9 and 12 months from treatment initiation.

20. Overall Survival (Time Frame - From the date of treatment initiation up to data cut-off (approximately 24 months)):
Overall Survival will be calculated from the date of treatment initiation to the date of death due to any cause

Geprüfte Regime

NMS-03305293:
Route of administration: Oral
Temozolomide:
Route of administration: Oral Commercially available temozolomide

Quelle: ClinicalTrials.gov

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