Niraparib and Temozolomide in Patients Glioblastoma

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.

Diffuse malignant gliomas are the most common central nervous system (CNS) primary tumours in adults, characterized by poor prognosis and few treatment options. In the last 15 years, standard treatment consisting of surgery, adjuvant radiotherapy and temozolomide (TMZ)-based chemotherapy has remained unchanged. New therapeutic approaches are urgently needed.

TMZ is a DNA-methylating chemotherapeutic agent with good CNS penetration. Its mechanism of action is increased by either gene promoter methylation or consumption of the methylguanine-DNA methyltransferase (MGMT), an enzyme repairing chemotherapy-induced genome damages.

Alternative, intensified schedules of TMZ (dose-dense TMZ, dd-TMZ) can give patients an increased total dose of drugs per each cycle, progressively consuming MGMT and overcoming resistance of cancer cells to standard first-line schedule. They are usually used at disease recurrence, with a tolerable safety profile. For example, a clinical study testing the 7 day on / 7 day off schedule showed that MGMT activity in blood mononuclear cells decreased at day 8 and progressively recovered during the week-off. This may limit haematological toxicity.

The inhibition of Poly (ADP-ribose) polymerase (PARP) proteins, normally involved in genomic stability, may rationally improve TMZ efficacy. Switching off PARP molecules can block both base-excision repair (BER) system and Poly-ADP ribose-ylation of MGMT (a key process for its function), leading to an amplification in DNA damages. In the subset of Isocitrate dehydrogenase (IDH) 1/2 mutant gliomas, the enzyme leads to 2-hydroxy-glutarate (2HG) accumulation in cancer cells. This onco-metabolite increases sensitivity to DNA damages by alkylating agents and induces a Breast Cncer gene(BRCA)-ness phenotype indeed. Considering all this, the use of PARP inhibitors seems promising even for these patients.

When compared to other PARP inhibitors, Niraparib has peculiar pharmacokinetics proprieties, such as higher volume of distribution (Vd) and blood-brain barrier (BBB) penetration. These characteristics lead to a progressive drug accumulation in brain and other body tissues with standard daily administration, reaching concentration well over that necessary for PARP inhibition. Overall, Niraparib can represent an ideal candidate to explore for treatment of malignant gliomas and a non-continuous administration may lead to a reduced bone marrow exposure, decreasing haematological toxicity without compromising anticancer activity.

Previous clinical experiences have already explored PARP inhibitors combined to TMZ in solid malignancies, with scarce tolerability mainly due to bone marrow exhaustion. In one small trial, a continuous administration of Niraparib in combination with standard schedule TMZ across several cohorts confirmed high rate of hematologic toxicities and interestingly showed signals of activity in glioblastoma (GBM).

Considering the peculiar pharmacokinetics proprieties of Niraparib and the recovery in MGMT activity described for dd-TMZ, investigator speculate that different schedules and doses of the two drugs (compared to the ones approved in clinical practice) may be explored to improve tolerability preserving the synergistic activity.

Eligibility Criteria:
Inclusion Criteria:

1. At least 18 years of age.
2. Ability to understand and willingness to sign an ethics committee approved written informed consent document (or that of legally authorized representative, if applicable).
3. Patients with diagnosis of recurrent\\progressive IDH wild-type GBM (WHO 2021, grade 4). All the GBM histological variants are allowed.
4. Patients with diagnosis of recurrent/progressive IDH mutant gliomas (WHO 2021, grade 2-4). Both astrocytoma and oligodendroglioma may be included.
5. Both MGMT methylated and unmethylated patients are allowed.
6. 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
7. 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).
8. 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 \[temozolomide, Procarbazine (PC) scheme\].
9. Enrollment of patients after salvage surgery for recurrent disease is allowed if point number 6 is matched.
10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 or Karnofsky performance status of ≥ 70.
11. Life expectancy \> 12 weeks.
12. Ability to swallow intact solid oral dosage form (without chewing, crushing, or opening).
13. Normal bone marrow and organ function as defined below:

    Neutrophils ≥ 1500/mm3 Platelets ≥ 150x103/mm3 Hemoglobin ≥ 9.0 g/dL Serum creatinine ≤ 1.5 x the upper limit of normal (ULN) or creatinine clearance (CrCl)≥ 40 mL/min (using the Cockcroft-Gault formula) Aspartate aminotransferase (AST) ≤ 2 x ULN Alanine aminotransferase (ALT) ≤ 2 x ULN Bilirubin≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
14. international normalized ratio (INR) ≤ 1.5 x ULN
15. partial thromboplastin time (PTT) ≤ 1.5 x ULN
16. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

    Is not a woman of childbearing potential (WOCBP). or Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \<1% per year), from the Screening Visit through at least 180 days after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment (see also Appendix A).

    A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 72 hours prior to the first dose of study treatment. (The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy).
17. A male participant of reproductive potential is eligible to participate if he agrees to the following starting with the first dose of study treatment through at least 90 days (a spermatogenesis cycle) after the last dose of study treatment:

refrain from donating sperm plus, either: be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent or must agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception, as a condom may break or leak, when having sexual intercourse with a WOCBP who is not currently pregnant

Exclusion Criteria:

1. 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.
2. 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.
3. Previous G4 hematological toxicity (anemia, neutropenia, thrombocytopenia) during concomitant and/or adjuvant TMZ treatment.
4. Previous treatment with a PARP inhibitor.
5. Presence of diffuse and unequivocal leptomeningeal or extra-cranial disease.
6. Steroid therapy with dexamethasone \> 4 mg daily.
7. Chronic (at least 4 weeks) use of drugs with known risk of QT prolongation.
8. 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.
9. Known primary immunodeficiency or active HIV.
10. Known active or chronic viral hepatitis indicated by positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV RNA).
11. 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.

    Uncontrolled hypertension, hypertensive crisis, history of hypertensive encephalopathy or history of posterior reversible encephalopathy syndrome (PRES).

    Clinically significant peripheral vascular disease or vascular disease, including rapidly growing aortic aneurysm or abdominal aortic aneurysm \> 5 cm or aortic dissection.

    Unstable angina.
12. Patients with a history of cerebrovascular accident or transient ischemic attack within 6 months prior to study enrollment are not eligible.
13. Evidence of hemorrhage on the baseline MRI or CT scan other than those that are ≤ grade 1 and either post-operative or stable on at least two consecutive scans.
14. Active diverticular disease of active and/or uncontrolled inflammatory bowel disease (IBD).
15. Gastrointestinal disorders that would impact on drug absorption.
16. Prior history of myelodysplastic syndrome (MDS) and/or myeloid acute leukemia (AML).
17. Other invasive malignancy within 2 years prior to entry into the study, except for those treated with surgical therapy only.
18. History of allergy to study drug components or of severe hypersensitivity reactions to any monoclonal antibodies.
19. Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study.
20. Participant is at an increased bleeding risk due to concurrent conditions (e.g., major injuries or major surgery within the past 28 days prior to start of study treatment).
21. Participant has received a live vaccine within 28 days of planned start of study therapy. Coronavirus Disease 19 (COVID19) vaccines that do not contain live viruses are allowed.
22. Participants have received a transfusion (platelets or red blood cells), colony-stimulating factors (e.g., granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 4 weeks prior to the first dose of study treatment.
23. Participants must not have had radiotherapy encompassing \> 20% of the bone marrow within 2 weeks; or any radiation therapy within 1 week prior to Day 1 of protocol therapy.
24. Women who are breast-feeding or pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG).
25. Women of childbearing potential not using a medically acceptable means of contraception for the duration of the study and unsterilized males not willing to abide by requirements for contraception.