Phase I/II Evaluation of NMS-03305293 and Temozolomide in Adult Patients with Recurrent Glioblastoma
- Trial ID
- 2023-508318-41-00
- Protocol
- PARPA-293-002
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is 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 during Phase I. Additionally, the study aims to assess the antitumor efficacy of the combination of NMS-03305293 and TMZ in patients with isocitrate dehydrogenase (IDH) wild type glioblastoma at first relapse during Phase II. These objectives are clinically relevant as they aim to establish a safe and effective dosing regimen for this combination therapy, potentially offering a new treatment option for patients with recurrent glioblastoma, a condition with limited therapeutic alternatives.
Secondary objectives include:
- Characterizing the safety profile of NMS-03305293 in combination with TMZ.
- Evaluating the pharmacokinetics of NMS-03305293 in combination with TMZ.
- Assessing additional measures of antitumor efficacy of NMS-03305293 in combination with TMZ.
Participants
The clinical trial involves a total of **39 participants** diagnosed with **Recurrent Glioblastoma**. The study population includes both male and female subjects, aged **18 years and older**, who are at first relapse of diffuse gliomas. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of glioblastoma and the ability to comply with study procedures. The trial population is characterized by a requirement for a stable or decreasing dose of steroids prior to baseline MRI scans, and participants must have a life expectancy of at least three months. The study includes individuals who are able to undergo brain MRI scans with IV gadolinium and have no evidence of symptomatic and acute intratumoral hemorrhage on MRI. The trial also considers lifestyle factors such as the ability to swallow capsules intact and the use of effective contraception or abstinence during the study period. The selection process ensures that participants have resolved acute toxic effects of any prior anticancer therapy to a defined grade or baseline laboratory values. The trial includes a vulnerable population, and all participants have provided informed consent. The sponsor has not provided additional information regarding specific lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is designed as a **Phase I/II** study to evaluate the combination of **NMS-03305293** and **temozolomide** in adult patients with recurrent glioblastoma. The trial employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The primary objective in Phase I is to determine the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of NMS-03305293 in combination with temozolomide. In Phase II, the focus shifts to assessing the antitumor efficacy of the combination in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma at first relapse. The trial is expected to conclude by December 15, 2025, with recruitment having commenced on October 29, 2021.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis of glioblastoma and the ability to swallow capsules intact. Follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, assess dose-limiting toxicities, and evaluate objective response rates. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted. The expected length of participant involvement will vary depending on individual response and tolerance to the treatment, but it is anticipated to last several months. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or non-compliance with study procedures.
Treatment
The clinical trial involves the administration of **NMS-03305293**, an experimental medication developed by Nerviano Medical Sciences. This investigational drug is provided in the form of a **hard capsule** and is administered **orally**. The specific dosage and frequency of administration for NMS-03305293 are determined based on the trial phase and the individual participant's response. The primary objective is to establish the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) when used in combination with temozolomide in patients with recurrent glioblastoma.
In addition to the experimental medication, the trial includes the administration of **Temozolomide**, a standard-of-care chemotherapy agent. Temozolomide is provided in hard capsule form and is also administered orally. The trial utilizes three different dosages of Temozolomide: 140 mg, 20 mg, and 5 mg, all manufactured by Sun Pharmaceutical Industries Europe B.V. The dosing schedule for Temozolomide is aligned with the trial protocol to evaluate its efficacy in combination with NMS-03305293. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
The efficacy of the combination of NMS-03305293 and temozolomide in adult patients with recurrent **glioblastoma** will be assessed through a series of primary and secondary endpoints. The primary endpoints include the evaluation of first cycle Dose Limiting Toxicities (DLTs) in Phase I and the Objective Response Rate (ORR) in Phase II. The ORR will be calculated as the proportion of evaluable patients who achieve a confirmed complete response (CR) or partial response (PR) as the best overall response (BOR), assessed retrospectively using the RANO criteria.
Secondary efficacy endpoints for Phase I include Objective Tumor Response (Partial and Complete Response) according to RANO criteria, Duration of Response (DoR), Progression-Free Survival (PFS), and Overall Survival (OS). For Phase II, secondary endpoints will focus on the Duration of Response (DoR) through central retrospective assessment of RANO criteria, Progression-Free Survival (PFS) and the 6-month PFS rate, as well as 9 and 12-month overall survival rates and Overall Survival (OS).
The assessment of these endpoints will involve the use of validated scales and criteria, such as the RANO criteria for tumor response evaluation. The schedule for measuring and collecting these efficacy parameters will be aligned with the trial's protocol, ensuring systematic and consistent data collection throughout the study duration. The analysis of these parameters will provide insights into the antitumor efficacy of the drug combination in the specified patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- Phase I (including Backfill) and Phase II - 7. Able to undergo brain MRI scans with IV gadolinium.
- 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.
- 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).
- Phase I (including Backfill) and Phase II - 10. Male or female patients with age ≥ 18 years.
- Phase I (including Backfill) and Phase II - 11. ECOG performance status ≤2.
- Phase I (including Backfill) and Phase II - 12. Signed and dated IEC or IRB-approved Informed Consent.
- 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
- Phase I (including Backfill) and Phase II - 14. Baseline laboratory values fulfilling defined requirements as stated in the protocol
- 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.
- Phase I (including Backfill) and Phase II - 16. Ability to swallow capsules intact (without chewing, crushing, or opening).
- Phase I - 2. Patients at first radiographic relapse after chemotherapy including temozolomide as long as no more than 12 cycles of temozolomide were administered.
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- Phase I (including Backfill) and Phase II - 6. Life expectancy of at least 3 months.
- 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.
- 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.
- 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
- Current enrollment in another interventional clinical trial.
- Current treatment with other anticancer agents or devices, or treatment at recurrence with carmustine wafer implants and proteasome inhibitors.
- Previous treatment with PCV (procarbazine, lomustine and vincristine) or any of its components, carmustine wafer implants, or bevacizumab.
- Previous treatment with PARP inhibitors.
- Major surgery, other than surgery for recurrent diffuse glioma, within 4 weeks prior to treatment.
- 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.
- Prior radiotherapy with a dose over 65 Gy, stereotactic radiosurgery or brachytherapy, unless the recurrence is histologically proven.
- 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.
- Treatment with concomitant medications known to be sensitive substrates of CYP2D6 and CYP2C19 that cannot be replaced with another treatment
- 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.
- Pregnant or breast-feeding women.
- Known hypersensitivity to any component of NMS-03305293 or TMZ drug formulations.
- Known active infections (bacterial, fungal, viral including HIV positivity) requiring systemic treatment.
- 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
- 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.
- 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.
- 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.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Yet Recruiting | 29 Oct 2021 | 10 |
 The Netherlands | Not Recruiting | 29 Oct 2021 | — |
| Netherlands | — | — | 26 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Temozolomide SUN 140 mg hard capsules | Test | HARD CAPSULES | ORAL USE | — | — | PRD3492533 |
Temozolomide SUN 20 mg hard capsules | Test | HARD CAPSULES | ORAL USE | — | — | PRD3490534 |
Temozolomide SUN 5 mg hard capsules | Test | HARD CAPSULES | ORAL USE | — | — | PRD3492002 |