Multicenter, randomized, open-label, non-comparative 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 recurrent glioblastoma (glioblastoma expansion cohort in Phase 1 and Phase 2).
Not yet recruiting
Phase 1/Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| NMS-03305293 + TMZ | Phase 1_Dose escalation and MTD expansion cohort | |
| NMS-03305293 + TMZ | Phase 1_Glioblastoma expansion cohort | |
| Lomustine | Phase 2_Arm B_Lomustine | |
| NMS-03305293 + TMZ | Phase 2_Arm A_NMS-03305293+TMZ |
| Name | Type | Description | Interventions |
|---|---|---|---|
| Phase 1_Dose escalation and MTD expansion cohort | Experimental | Patients with diffuse gliomas |
|
| Phase 1_Glioblastoma expansion cohort | Experimental | Patients with IDH wild type recurrent glioblastoma |
|
| Phase 2_Arm A_NMS-03305293+TMZ | Experimental | Patients with IDH wild type recurrent glioblastoma |
|
| Phase 2_Arm B_Lomustine | Active Comparator | Patients with IDH wild type recurrent glioblastoma |
|
Inclusion Criteria:
- Phase 1 (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 2 and Phase 1 glioblastoma expansion cohort
1. 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.
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.
- Phase 1 and Phase 2
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/randomization and patient
should have fully recovered.
4. 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.
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 1 and 2) and IDH status evaluation (Phase 1).
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 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. 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.
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 (Phase 1) or
randomization (Phase 2).
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/randomization.
11. Pregnant or breast-feeding women.
12. Known hypersensitivity to any component of NMS-03305293 or TMZ (Phase 1, Phase 2) or
lomustine (Phase 2) 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 2).
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 2).
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 objectives in the opinion of the Investigator
and/or the Sponsor.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | 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 |
| Safety Issue: | |
| Description: |
| Measure: | 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 Issue: | |
| Description: | 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). |
| Measure: | Maximum concentration (Cmax) of NMS-03305293 after single and multiple doses of drug |
| Time Frame: | At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints |
| Safety Issue: | |
| Description: | Plasma samples will be collected and used for pharmacokinetics assessments |
| Measure: | Time to observed Cmax (Tmax) of NMS-03305293 after single and multiple doses of drug |
| Time Frame: | At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints |
| Safety Issue: | |
| Description: | Plasma samples will be collected and used for pharmacokinetics assessments |
| Measure: | Area under the concentration-time curve up to the last detectable plasma concentration (AUClast) of NMS-03305293 after single and repeated dose of drug. |
| Time Frame: | At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints |
| Safety Issue: | |
| Description: | Plasma samples will be collected and used for pharmacokinetics assessments |
| Measure: | Terminal elimination half-life (t1/2) of NMS-03305293 after single and multiple doses of drug |
| Time Frame: | At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints |
| Safety Issue: | |
| Description: | Plasma samples will be collected and used for pharmacokinetics assessments |
| Measure: | Area under the plasma concentration vs. time curve to infinity (AUCinf) of NMS-03305293 after multiple doses of drug. |
| Time Frame: | At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints |
| Safety Issue: | |
| Description: | Plasma samples will be collected and used for pharmacokinetics assessments |
| Measure: | Accumulation ratio (Rac) of NMS-03305293 after multiple doses of drug. |
| Time Frame: | At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints |
| Safety Issue: | |
| Description: | Plasma samples will be collected and used for pharmacokinetics assessments |
| Measure: | Oral plasma clearance (CL/F) of NMS-03305293 after multiple doses of drug |
| Time Frame: | At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints |
| Safety Issue: | |
| Description: | Plasma samples will be collected and used for pharmacokinetics assessments |
| Measure: | Apparent volume of distribution (Vd/F) of NMS-03305293 after multiple doses of drug |
| Time Frame: | At Cycle 1 (each cycle is 28 days) on Days 1, 2, 5, 6 and 8 at different timepoints. Sparse sampling adopted for phase 2: at Cycle 1 (Days 1 and 5), Cycle 2 (Day 5) and Cycle 3 or Cycle 4 (Day 5) at different timepoints |
| Safety Issue: | |
| Description: | Plasma samples will be collected and used for pharmacokinetics assessments |
| Measure: | Phase 1: Renal clearance of NMS-03305293 after multiple doses of drug |
| Time Frame: | At baseline, at Cycle 1 (each cycle is 28 days) Day 5 at different timepoints |
| Safety Issue: | |
| Description: | Urine samples will be collected in patients treated in the phase 1 and used for pharmacokinetics assessments |
| Measure: | Phase 1: Cumulative amount recovered unchanged in the urine (Ae) of NMS-03305293 after multiple doses of drug |
| Time Frame: | At baseline, at Cycle 1 (each cycle is 28 days) Day 5 at different timepoints |
| Safety Issue: | |
| Description: | Urine samples will be collected in patients treated in the phase 1 and used for pharmacokinetics assessments |
| Measure: | Phase 1: Cumulative amount recovered unchanged in the urine expressed as a fraction of administered dose (Ae%) of NMS-03305293 after multiple doses of drug |
| Time Frame: | At baseline, at Cycle 1 (each cycle is 28 days) Day 5 at different timepoints. |
| Safety Issue: | |
| Description: | Urine samples will be collected in patients treated in the phase 1 and used for pharmacokinetics assessments |
| Measure: | Phase 1: Objective Tumor Response |
| Time Frame: | At baseline, every 8 weeks for the first 6 months from treatment start, then every 12 weeks, until disease progression or start of a new anticancer therapy (approximately 12 months). |
| Safety Issue: | |
| Description: | Complete and partial responses will be assessed according to RANO criteria |
| Measure: | Phase 2: Objective Tumor Response Rate |
| Time Frame: | At baseline, every 8 weeks for the first 6 months from randomization, then every 12 weeks, until disease progression or start of a new anticancer therapy (approximately 18 months). |
| Safety Issue: | |
| Description: | Percentage of patients achieving a complete response or partial response assessed according to RANO criteria |
| Measure: | Duration of Response |
| Time Frame: | From the date of first response up to data cut-off (approximately 18 months). |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Progression Free Survival |
| Time Frame: | From first dose of study drug (Phase 1) or from randomization (Phase 2) up to data cut-off (approximately 18 months) |
| Safety Issue: | |
| Description: | Progression Free Survival will be calculated from the date of treatment initiation or randomization to the date of first documentation of disease progression, or death due to any cause, whichever occurs first |
| Measure: | Overall Survival |
| Time Frame: | From first dose of study drug (Phase 1) or from randomization (Phase 2) up to data cut-off (approximately 24 months) |
| Safety Issue: | |
| Description: | Overall Survival will be calculated from the date of treatment initiation or randomization to the date of death due to any cause |
| Measure: | Phase 2: 9 and 12-Months Overall Survival Rates |
| Time Frame: | From date of randomization until the date of death from any cause, assessed up to 9 and 12 months. |
| Safety Issue: | |
| Description: | Percentage of patients alive at 9 and 12 months from randomization. |
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Not yet recruiting |
| Lead Sponsor: | Nerviano Medical Sciences |
August 12, 2021
