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

NCT04910022 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: PARPA-293-0022020-003417-352023-508318-41-00
• Study Type: interventional
• Target: 150
• Locations: 5 countries
• Sites: 18

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.

Conditions

Glioblastoma; Diffuse Glioma

Keywords

IDH wild type; PARP inhibitor

Outcome Measures

Primary Outcomes (2)

• Phase 1: Number of Participants with first-cycle dose limiting toxicity

  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

• Phase 2: Objective Response Rate

  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

  From the date of first response up to data cut-off (approximately 18 months)

Secondary Outcomes (20)

• Number of participants with Adverse Events (AEs)

  From the Informed Consent signature to 28 days after the last dose of study treatment administration

• Maximum concentration (Cmax) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug

  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)

• Time to observed Cmax (Tmax) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug

  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)

• 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.

  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)

• Terminal elimination half-life (t1/2) of NMS-03305293 and possible identified metabolites (if appropriate) after single and multiple doses of drug

  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)

Study Arms (1)

NMS-03305293 +TMZ

EXPERIMENTAL

Phase 1 Dose Escalation: All patients will receive NMS-03305293 and temozolomide (TMZ) administered orally (NMS-03305293 once or twice daily on days 1-7 or 28 consecutive days from Day 1 to Day 28; TMZ once daily on days 1-5;) in repeated 4-week cycles aimed at defining the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Doses (RP2Ds) of NMS-03305293 in combination with TMZ. Each cycle is 28 days. Phase 2: Once the RP2D is defined, the patients will receive TMZ daily on days 1-5 in combination with NMS-03305293 at the RP2D on days 1-7 or on days 1-28 every 28 days. Backfill cohorts: additional patients may be treated with TMZ daily on days 1-5 and NMS-03305293 at different dose levels/schedules that have been previously assessed and determined to be safe, in order to properly characterize the exposure relationship over a range of doses/schedules. The backfill cohorts may run in parallel.

Drug: NMS-03305293; Drug: Temozolomide

Interventions

NMS-03305293 DRUG

Route of administration: Oral

NMS-03305293 +TMZ

Temozolomide DRUG

Route of administration: Oral Commercially available temozolomide

NMS-03305293 +TMZ

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Phase 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.
• Patients at first radiographic relapse after chemotherapy including temozolomide as long as no more than 12 cycles of temozolomide were administered.
• 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
• 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.
• 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.
• 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

You may not qualify if:

• 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, instruction in protocol will be followed.
• 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.

Sponsors & Collaborators

• Nerviano Medical Sciences: lead

Study Sites (18)

Mayo Clinic Hospital - Phoenix

Phoenix, Arizona, 85054, United States

Location

University of California Irvine Medical Center (UCIMC) - Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

Location

Mayo Clinic Florida

Jacksonville, Florida, 32224, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Mayo Clinic Cancer Center

Rochester, Minnesota, 55905, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Utah, University Hospital

Salt Lake City, Utah, 84112, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

Swedish Medical Center - First Hill Campus

Seattle, Washington, 98122, United States

Location

IRCCS Istituto delle Scienze Neurologiche di Bologna

Bologna, 40139, Italy

Location

IRCCS Istituto Neurologico Carlo Besta

Milan, 20133, Italy

Location

Istituto Oncologico Veneto - IRCCS

Padua, 35128, Italy

Location

Istituto Clinico Humanitas

Rozzano, 20089, Italy

Location

Erasmus Medical Center

Rotterdam, 3015, Netherlands

Location

PanOncology Trials (Pan American Center for Oncology Trials, LLC)

Rio Piedras, 00935, Puerto Rico

Location

University Hospital Zurich

Zurich, 8091, Switzerland

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2021
• First Posted: June 2, 2021
• Study Start: December 1, 2021
• Primary Completion (Estimated): May 30, 2027
• Study Completion (Estimated): September 7, 2027
• Last Updated: August 19, 2025

Record last verified: 2025-08

Locations

IT (4); US (11); NL (1); PR (1); CH (1)