Niraparib vs Temozolomide for Brain Cancer

Recruiting at 30 trial locations

Overseen By Study Navigator

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Ivy Brain Tumor Center

Must not be taking: PARP inhibitors

Disqualifiers: Metastatic disease, Pneumonitis, Cirrhosis, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 16

Duration: 6-7 weeks

450 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The goal of this Phase 3 clinical trial is to compare the efficacy of niraparib versus temozolomide (TMZ) in adult participants with newly-diagnosed, MGMT unmethylated glioblastoma multiforme (GBM). The main questions it aims to answer are: Does niraparib improve progression-free survival (PFS) compared to TMZ? Does niraparib improve overall survival (OS) compared to TMZ? Participants will be randomly assigned to one of two treatment arms: niraparib or TMZ. * study drug (Niraparib) or * comparator drug (Temozolomide - which is the standard approved treatment for MGMT unmethylated glioblastoma). The study medication will be taken daily while receiving standard of care radiation therapy (RT) for 6-7 weeks. Participants may continue to take the niraparib or TMZ adjuvantly as long as the cancer does not get worse or completion of 6 cycles of treatment (TMZ). A total of 450 participants will be enrolled in the study. Participants' tasks will include: * Complete study visits as scheduled * Complete a diary to record study medication

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that you should have stable or decreased doses of dexamethasone, not exceeding 5 mg daily, within 7 days before randomization.

Is there safety data available for Temozolomide in humans?

Temozolomide has been studied in humans, particularly for brain cancer, and is generally considered safe when used in combination with other treatments like radiotherapy. It has been shown to reduce the odds of death in patients with glioblastoma, a type of brain cancer, indicating its safety and effectiveness in this context. ^{1 2 3 4 5}

How does the drug Niraparib differ from Temozolomide for brain cancer?

Niraparib is a PARP inhibitor, which works by preventing cancer cells from repairing their DNA, while Temozolomide is a chemotherapy drug that can cross the blood-brain barrier to treat brain tumors. Niraparib's unique mechanism of action may offer a novel approach compared to the traditional chemotherapy method of Temozolomide. ^{3 6 7 8 9}

What data supports the effectiveness of the drug Niraparib for brain cancer?

Niraparib has been shown to be effective in treating brain metastases in patients with ovarian and endometrial cancer, as it can enter the brain and suppress tumor growth. In one case, a patient with brain metastases from endometrial cancer remained free of disease progression for 6 months after treatment with Niraparib. ^{10 11 12 13 14}

Who Is on the Research Team?

Nader Sanai, MD

Principal Investigator

Ivy Brain Tumor Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with a new diagnosis of glioblastoma multiforme (GBM) that hasn't been treated yet, except for surgery. Participants need to be in good physical condition and not planning pregnancy or breastfeeding. They must agree to use effective contraception.

Inclusion Criteria

My diagnosis is a new brain tumor identified as GBM.

I am considered suitable for a specific radiation therapy plan.

I have enough tissue samples for further testing, or I might get approval for less.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily study medication (Niraparib or Temozolomide) while undergoing standard of care radiation therapy for 6-7 weeks

6-7 weeks

Weekly visits during radiation therapy

Adjuvant Treatment

Participants may continue to take Niraparib or Temozolomide as long as the cancer does not progress or until completion of 6 cycles of treatment

Up to 6 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Every 16 weeks on days of MRI

What Are the Treatments Tested in This Trial?

Interventions

• Niraparib
• Temozolomide

Trial Overview The study compares the effectiveness of niraparib against temozolomide (TMZ), which is standard treatment for GBM without MGMT methylation. It will assess if niraparib can extend the time before cancer worsens or improve overall survival compared to TMZ.

How Is the Trial Designed?

Group I: Arm A: Niraparib Experimental Treatment 1 Intervention

Group II: Arm B: Temozolomide Active Control 1 Intervention

Niraparib is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Zejula for:

• Maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy
• Maintenance treatment of adults with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy

Approved in United States as Zejula for:

• Maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy
• Treatment of adults with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)-positive status

Approved in Canada as Zejula for:

• Maintenance treatment of adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy

Who Is Running the Clinical Trial?

Ivy Brain Tumor Center

Lead Sponsor

Trials

12

Recruited

910+

GlaxoSmithKline

Industry Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Published Research Related to This Trial

Niraparib, a PARP inhibitor, was successfully used to treat a 62-year-old woman with endometrial cancer and brain metastases, leading to 6 months of disease-free progression, highlighting its potential efficacy in this rare condition.

The drug's ability to cross the blood-brain barrier allows for higher concentrations in brain tissues, which may enhance its tumor-suppressing effects, suggesting a promising mechanism of action for treating brain metastases from endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of a patient with brain metastases from endometrial cancer using Niraparib: a case report. Wang, Q., Zhang, F., Gao, H., et al.[2021]

Niraparib, a recently approved treatment for recurrent platinum-sensitive ovarian cancer, has demonstrated a high oral bioavailability of 72.7% in humans, indicating effective absorption when taken orally.

The study involved six patients who received a therapeutic dose of 300 mg of niraparib, followed by a small intravenous dose to measure its levels in the bloodstream, confirming its potential as a convenient oral treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. van Andel, L., Rosing, H., Zhang, Z., et al.[2019]

Niraparib, a PARP inhibitor, is recommended as a maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer, leveraging the concept of synthetic lethality in BRCA mutation carriers.

A case study of a 68-year-old woman with brain metastases from high-grade serous ovarian cancer showed that she remained free of disease progression for over 17 months while on niraparib after second-line chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib as maintenance therapy in a patient with ovarian cancer and brain metastases. Gray, S., Khor, XY., Yiannakis, D.[2021]

Niraparib significantly extends progression-free survival in patients with newly diagnosed advanced ovarian cancer, showing efficacy in both homologous-recombination deficiency positive (HRd) and negative (HRp) populations, based on a phase III trial.

The treatment has a manageable safety profile, with myelosuppression as the main concern, which can be effectively managed through monitoring and individualized dosing based on weight and platelet count.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer. Lee, A.[2022]

In a Phase 2 study involving 20 Japanese women with heavily pretreated ovarian cancer, niraparib demonstrated an objective response rate of 35%, indicating that it can effectively reduce tumor size in some patients.

The treatment was generally well-tolerated, with a high disease control rate of 90%, although common side effects included anemia and nausea, and 70% of patients experienced dose reductions or interruptions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 single-arm study on the efficacy and safety of niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer. Okamoto, A., Kondo, E., Nakamura, T., et al.[2021]

In a phase II trial involving 115 patients with non-small-cell lung cancer (NSCLC) and treated brain metastases, the addition of bevacizumab to chemotherapy or erlotinib showed a low incidence of serious CNS hemorrhage, with no cases of grade 2 or higher reported among 106 safety-evaluable patients.

The study suggests that bevacizumab is safe for use in this patient population, as it was well-tolerated with a median treatment duration of 6.3 months and only a small percentage of patients (24.5%) discontinuing due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. Socinski, MA., Langer, CJ., Huang, JE., et al.[2022]

In a phase II clinical trial involving 158 patients with newly diagnosed glioblastoma, cediranib combined with radiation and temozolomide significantly improved 6-month progression-free survival (PFS) to 46.6% compared to 24.5% for the placebo group (P = 0.005).

Although cediranib showed efficacy in prolonging PFS, it was associated with a higher incidence of grade ≥3 adverse events compared to placebo (P = 0.02), and there was no significant difference in overall survival between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma. Batchelor, TT., Won, M., Chakravarti, A., et al.[2023]

In a study involving seven nude rats with gliomas, the combination of the anti-angiogenesis agent cediranib with the chemotherapy drug temozolomide (TMZ) resulted in a slight increase in the intratumoral concentration of TMZ, suggesting improved drug delivery to the tumor.

The MRI results indicated that cediranib treatment led to a normalization of the blood-brain barrier, which may enhance the effectiveness of chemotherapy in treating malignant gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model. Grossman, R., Tyler, B., Rudek, MA., et al.[2021]

The study analyzed data from the SEER database for glioblastoma patients diagnosed between 2000 and 2009, revealing that the introduction of temozolomide (TMZ) significantly reduced the odds of death by 12% at 6 months and 36% at 1 year after diagnosis compared to the pre-TMZ era.

The addition of bevacizumab (BZM) to TMZ further improved survival rates, with a 31% reduction in odds of death at 6 months and 50% at 1 year, indicating that combining these treatments offers enhanced benefits for glioblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Odds of death after glioblastoma diagnosis in the United States by chemotherapeutic era. Wachtel, MS., Yang, S.[2021]

Combining temozolomide with radiotherapy significantly improves the overall response rate (ORR) in patients with brain metastases, particularly in those with non-small cell lung cancer, with a risk ratio of 1.35.

However, this combination treatment does not lead to significant improvements in progression-free survival (PFS) or overall survival (OS) and is associated with a higher incidence of side effects compared to radiotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Temozolomide and Radiotherapy on Brain Metastatic Tumor: A Systematic Review and Meta-Analysis. Ma, W., Li, N., An, Y., et al.[2018]

Temozolomide is a chemotherapeutic agent that effectively crosses the blood-brain barrier and has shown a good safety profile in treating brain metastases from solid tumors, with clinical activity observed in heavily pretreated patients.

In a randomized phase II trial, temozolomide combined with radiation therapy resulted in a significantly higher objective response rate (96% vs. 67%) compared to radiation alone, particularly benefiting patients with newly diagnosed brain and lung metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide for treating brain metastases. Abrey, LE., Christodoulou, C.[2019]

In a phase 2 trial involving 25 patients with 1 to 4 brain metastases, temozolomide was used alongside radiosurgery, resulting in a 1-year risk of distant brain failure (DBF) of 37%, indicating a relatively low risk in the nonmelanoma subgroup.

The study suggests that patient selection factors may have influenced the low DBF risk observed, rather than the efficacy of temozolomide itself, highlighting the need for careful consideration of these factors in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 study of radiosurgery and temozolomide for patients with 1 to 4 brain metastases. Fiveash, JB., Arafat, WO., Naoum, GE., et al.[2020]

Temozolomide effectively prevented the formation of brain metastases from breast cancer cells that do not express the MGMT enzyme, demonstrating a dose-dependent efficacy in experimental models with complete prevention at higher doses.

The study found that temozolomide was ineffective in preventing brain metastases in cells that express MGMT, highlighting the importance of MGMT status in determining treatment outcomes and suggesting a need for further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profound prevention of experimental brain metastases of breast cancer by temozolomide in an MGMT-dependent manner. Palmieri, D., Duchnowska, R., Woditschka, S., et al.[2021]

Cediranib, a potent receptor tyrosine kinase inhibitor, did not enhance the effectiveness of radiation therapy in glioblastoma models but significantly improved the effectiveness of temozolomide (TMZ) treatment.

The study involved U87 glioblastoma xenografts expressing either the wild-type EGFR or the mutant EGFRvIII, and the combination of cediranib with TMZ suggests a promising new treatment strategy for better tumor control in glioblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cediranib enhances control of wild type EGFR and EGFRvIII-expressing gliomas through potentiating temozolomide, but not through radiosensitization: implications for the clinic. Wachsberger, PR., Lawrence, RY., Liu, Y., et al.[2021]

Citations

1. China pubmed.ncbi.nlm.nih.gov

Successful treatment of a patient with brain metastases from endometrial cancer using Niraparib: a case report. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Niraparib as maintenance therapy in a patient with ovarian cancer and brain metastases. [2021]

4. France pubmed.ncbi.nlm.nih.gov

Niraparib: A Review in First-Line Maintenance Therapy in Advanced Ovarian Cancer. [2022]

5. Korea (South) pubmed.ncbi.nlm.nih.gov

Phase 2 single-arm study on the efficacy and safety of niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. [2022]

7. England pubmed.ncbi.nlm.nih.gov

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Odds of death after glioblastoma diagnosis in the United States by chemotherapeutic era. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Effects of Temozolomide and Radiotherapy on Brain Metastatic Tumor: A Systematic Review and Meta-Analysis. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Temozolomide for treating brain metastases. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

A phase 2 study of radiosurgery and temozolomide for patients with 1 to 4 brain metastases. [2020]

13. United States pubmed.ncbi.nlm.nih.gov

Profound prevention of experimental brain metastases of breast cancer by temozolomide in an MGMT-dependent manner. [2021]

14. United States pubmed.ncbi.nlm.nih.gov

Cediranib enhances control of wild type EGFR and EGFRvIII-expressing gliomas through potentiating temozolomide, but not through radiosensitization: implications for the clinic. [2021]