Niraparib and Temozolomide in Patients Glioblastoma

NCT06258018 | Not Yet Recruiting Phase 1

• 1 other identifier: ONC-2022-001
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 1

Brief Summary

The study evaluates safety, tolerability, pharmacokinetics at recommended phase II dose (RP2D) and preliminary antitumor activity of Niraparib + dd-TMZ "one week on, one week off" in patients affected by recurrent GBM IDH wild-type and recurrent IDH mutant (WHO grade 2-4) gliomas. The treatment will be administered until progressive disease, unacceptable toxicity, consent withdrawal, lost to follow-up or death. The entire study is expected to last approximately 40 months.

Conditions

Glioma, Malignant

Keywords

Glioma; Niraparib; Temodal

Outcome Measures

Primary Outcomes (2)

• Escalation Phase : maximum tolerated dose (MTD)

  To determine the MTD of the combination of dd-TMZ and Niraparib, established in the first cycle of therapy, in order to determine the recommended phase II dose (RP2D).

  1 year

• Expansion Phase : PFS

  To assess the proportion of patients progression-free at 6 months for recurrent IDH wild-type glioblastoma (Cohort 1) and at 8 months for recurrent IDH-mutant lower-grade gliomas (Cohort 2)

  8 months

Secondary Outcomes (11)

• pharmacokinetics CMAX

  1 year

• cerebrospinal fluid drug concentration

  1 year

• Adverse event monitoring

  2 years

• tumour tissue drug concentration

  2 years

• assess objective response rate (ORR)

  2 years

Study Arms (6)

Niraparib + Temodal Level 0

EXPERIMENTAL

Niraparib 100 mg/die + TMZ 75 mg/m2 both given for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days (starting dose).

Drug: Temodal; Drug: Niraparib

Niraparib + Temodal Level 1

EXPERIMENTAL

Niraparib 100 mg/die + TMZ 100 mg/m2 both given for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days.

Drug: Temodal; Drug: Niraparib

Niraparib + Temodal Level 2

EXPERIMENTAL

Niraparib 200 mg/die + TMZ 75 mg/m2 both given for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days

Drug: Temodal; Drug: Niraparib

Niraparib + Temodal Level 3

EXPERIMENTAL

Level 3: Niraparib 200 mg/die + TMZ 100 mg/m2 both given for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days.

Drug: Temodal; Drug: Niraparib

Niraparib + Temodal Level -1

EXPERIMENTAL

Niraparib 100 mg given on alternate days for 7 days, followed by 7 days of OFF + TMZ given 75 mg/m2 for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days.

Drug: Temodal; Drug: Niraparib

Niraparib + Temodal Expansion Phase

EXPERIMENTAL

Niraparib RP2D dose given on alternate days for 7 days, followed by 7 days of OFF + TMZ given RP2D for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days.

Drug: Temodal; Drug: Niraparib

Interventions

Temodal DRUG

given orally for 7 consecutive days, followed by 7 days OFF, in a cycle of 28 days

Also known as: Temozolomide

Niraparib + Temodal Expansion Phase; Niraparib + Temodal Level -1; Niraparib + Temodal Level 0; Niraparib + Temodal Level 1; Niraparib + Temodal Level 2; Niraparib + Temodal Level 3

Niraparib DRUG

given orally in continous

Niraparib + Temodal Expansion Phase; Niraparib + Temodal Level -1; Niraparib + Temodal Level 0; Niraparib + Temodal Level 1; Niraparib + Temodal Level 2; Niraparib + Temodal Level 3

Eligibility Criteria

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

You may qualify if:

• At least 18 years of age.
• Ability to understand and willingness to sign an ethics committee approved written informed consent document (or that of legally authorized representative, if applicable).
• Patients with diagnosis of recurrent\\progressive IDH wild-type GBM (WHO 2021, grade 4). All the GBM histological variants are allowed.
• Patients with diagnosis of recurrent/progressive IDH mutant gliomas (WHO 2021, grade 2-4). Both astrocytoma and oligodendroglioma may be included.
• Both MGMT methylated and unmethylated patients are allowed.
• Unequivocal evidence of tumor progression with at least one target lesion based on MRI scan according to Response Assessment in Neuro-Oncology criteria (RANO) or low-grade gliomas (LGGs) Response Assessment in Neuro-Oncology (RANO) criteria for non-enhancing tumors
• Patients with IDH wild-type GBM (WHO grade 4) must have received at least the standard front-line therapy defined as below:
• \- Surgery (biopsy alone is allowed), concomitant radio-chemotherapy (hypo-fractionated regimens are allowed) and maintenance temozolomide chemotherapy (up to 6 cycles completed).
• Patients with IDH mutant gliomas (WHO 2021 grade 2-4, both astrocytoma and oligodendroglioma may be included) must have received at least:
• \- Surgery (biopsy alone allowed), radiotherapy (hypo-fractionated regimens allowed) and/or one chemotherapy line \[temozolomide, Procarbazine (PC) scheme\].
• Enrollment of patients after salvage surgery for recurrent disease is allowed if point number 6 is matched.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 or Karnofsky performance status of ≥ 70.
• Life expectancy \> 12 weeks.
• Ability to swallow intact solid oral dosage form (without chewing, crushing, or opening).
• Normal bone marrow and organ function as defined below:

You may not qualify if:

• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive the planned therapy (including brain surgery), or interfere with the interpretation of study results.
• Anticancer treatment within the last 14 days before the start of trial treatment, for example chemotherapy, radiotherapy, immunotherapy. A shorter interval can be approved by the principal investigator, if deemed appropriate.
• Previous G4 hematological toxicity (anemia, neutropenia, thrombocytopenia) during concomitant and/or adjuvant TMZ treatment.
• Previous treatment with a PARP inhibitor.
• Presence of diffuse and unequivocal leptomeningeal or extra-cranial disease.
• Steroid therapy with dexamethasone \> 4 mg daily.
• Chronic (at least 4 weeks) use of drugs with known risk of QT prolongation.
• Use of anticoagulant agents at therapeutic dose (e.g. Low-molecular-weight heparin ( LWMH), new anti-coagulation oral drug (NAO) , Warfarin). Prophylactic dose is allowed. Antiplatelet agents are allowed.
• Known primary immunodeficiency or active HIV.
• Known active or chronic viral hepatitis indicated by positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV RNA).
• Clinically significant cardiovascular disease within 6 months prior to enrollment (or randomization), including:
• Prior events including myocardial infarction, pericardial effusion, and myocarditis.
• Prior cardiac arrhythmia including atrial fibrillation and atrial flutter or requiring concurrent use of drugs or biologics with pro-arrhythmic potential.
• New York Heart Association (NYHA) Class II or greater heart failure. If cardiac function assessment is clinically indicated or performed, an Ejection fraction (LVEF) less than normal per institutional guidelines, or \< 55%, if threshold for normal is not otherwise specified by institutional guidelines.
• corrected QT interval (QTc) prolongation \> 470 millisecond or other significant ECG abnormality noted within 14 days of treatment.

Sponsors & Collaborators

• Armando Santoro, MD: lead
• Istituto Clinico Humanitas: collaborator
• GlaxoSmithKline: collaborator

Study Sites (1)

Istituto clinico humanitas

Rozzano, Mi, 20089, Italy

Location

Related Publications (23)

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MeSH Terms

Conditions

Glioma

Interventions

Temozolomide; niraparib

Condition Hierarchy (Ancestors)

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 Officials

• Matteo Simonelli, MD

  Istituto Clinico Humanitas

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Matteo Simonelli, MD

CONTACT

+39028224; matteo.simonelli@hunimed.eu

Angelo Dipasquale, MD

CONTACT

+390282243591; angelo.dipasquale@humanitas.it

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: The "3+3 method" will be followed in the safety run-in.

Study Record Dates

• First Submitted: January 11, 2024
• First Posted: February 14, 2024
• Study Start: September 1, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): September 1, 2027
• Last Updated: August 30, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)