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

• ClinicalTrials.gov Identifier: NCT04910022
• Recruitment Status: Recruiting
• First Posted: June 2, 2021
• Last Update Posted: November 8, 2022
• Sponsor: Nerviano Medical Sciences
• Information provided by (Responsible Party): Nerviano Medical Sciences

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Glioblastoma; Diffuse Glioma	Drug: NMS-03305293 + TMZ; Drug: Lomustine	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 125 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Phase 1 including a dose escalation part and a subsequent dose expansion followed by a phase 2
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Combination Study of NMS-03305293 and Temozolomide in Adult Patients With Recurrent Glioblastoma
• Actual Study Start Date: December 1, 2021
• Estimated Primary Completion Date: June 30, 2025
• Estimated Study Completion Date: November 30, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1_Dose escalation and MTD expansion cohort; Patients with diffuse gliomas	Drug: NMS-03305293 + TMZ; NMS-03305293 will be administered orally for 7 consecutive days from Day 1 to Day 7 of each treatment cycle. TMZ will be administered orally once daily for 5 consecutive days from Day 1 to Day 5 of each treatment cycle. A treatment cycle duration is 28 days (a 4-week period).
Experimental: Phase 1_Glioblastoma expansion cohort; Patients with IDH wild type recurrent glioblastoma	Drug: NMS-03305293 + TMZ; Patients will receive NMS-03305293 at the RP2D with the escalating dose of TMZ used as standard of care for newly diagnosed glioblastoma patients.
Experimental: Phase 2_Arm A_NMS-03305293+TMZ; Patients with IDH wild type recurrent glioblastoma	Drug: NMS-03305293 + TMZ; NMS-03305293 will be administered orally for 7 consecutive days from Day 1 to Day 7 of each treatment cycle. TMZ will be administered orally once daily for 5 consecutive days from Day 1 to Day 5 of each treatment cycle. A treatment cycle duration is 28 days (a 4-week period).
Active Comparator: Phase 2_Arm B_Lomustine; Patients with IDH wild type recurrent glioblastoma	Drug: Lomustine; Patients will receive lomustine orally on day 1 of each 6-week cycle.

Outcome Measures

Primary Outcome Measures :

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: Progression Free Survival rate at 6 months (PFS6) [ Time Frame: From randomization up to data cut-off or 6-months since randomization ]

Secondary Outcome Measures :

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 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 ]
   Plasma samples will be collected and used for pharmacokinetics assessments
3. 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 ]
   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 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 ]
   Plasma samples will be collected and used for pharmacokinetics assessments
5. 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 ]
   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 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 ]
   Plasma samples will be collected and used for pharmacokinetics assessments
7. 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 ]
   Plasma samples will be collected and used for pharmacokinetics assessments
8. 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 ]
   Plasma samples will be collected and used for pharmacokinetics assessments
9. 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 ]
   Plasma samples will be collected and used for pharmacokinetics assessments
10. 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 ]
    Urine samples will be collected in patients treated in the phase 1 and used for pharmacokinetics assessments
11. 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 ]
    Urine samples will be collected in patients treated in the phase 1 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 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 used for pharmacokinetics assessments
13. 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). ]
    Complete and partial responses will be assessed according to RANO criteria
14. 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). ]
    Percentage of patients achieving a complete response or partial response assessed according to RANO criteria
15. 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
16. 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) ]
    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
17. 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) ]
    Overall Survival will be calculated from the date of treatment initiation or randomization to the date of death due to any cause
18. 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. ]
    Percentage of patients alive at 9 and 12 months from randomization.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Dejan Brkic, PhD; +39.3351351495; dejan.brkic@nervianoms.com

Contact: Pamela Ghioni, PhD; +39.3426925706; pamela.ghioni@nervianoms.com

Locations

United States, Florida

Mayo Clinic Florida; Recruiting

Jacksonville, Florida, United States, 32224

United States, Minnesota

Mayo Clinic Cancer Center; Recruiting

Rochester, Minnesota, United States, 55905

Italy

IRCCS Istituto Neurologico Carlo Besta; Recruiting

Milan, Italy, 20133

Netherlands

Erasmus Medical Center; Recruiting

Rotterdam, Netherlands, 3015

Switzerland

University Hospital Zurich; Recruiting

Zurich, Switzerland, 8091

Sponsors and Collaborators

Nerviano Medical Sciences

More Information

• Responsible Party: Nerviano Medical Sciences
• ClinicalTrials.gov Identifier: NCT04910022
• Other Study ID Numbers: PARPA-293-002; 2020-003417-35 ( EudraCT Number )
• First Posted: June 2, 2021
• Last Update Posted: November 8, 2022
• Last Verified: March 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nerviano Medical Sciences:

IDH wild type; PARP inhibitor

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Lomustine; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents