PARP Inhibitor + Temozolomide for Brain Cancer

(PNOC017 Trial)

Recruiting at 22 trial locations

Overseen By Sabine Mueller, MD, PhD, MAS

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, San Francisco

Must not be taking: PARP inhibitors, Anticoagulants

Disqualifiers: Active infection, Other malignancy, Bleeding disorder, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 24 months

78 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of two drugs, BGB-290 (Pamiparib, a PARP inhibitor) and temozolomide, to determine their effectiveness in treating glioma, a type of brain cancer. BGB-290 may stop tumor growth by blocking certain enzymes, while temozolomide is a chemotherapy drug that can kill cancer cells or prevent their spread. The trial seeks to find the optimal dose and understand any side effects for adolescents and young adults with IDH1/2-mutant glioma, whether newly diagnosed or recurring. Individuals who have undergone treatment for this type of brain cancer and have an IDH1/2 mutation may be suitable candidates for the trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are on certain investigational agents, have previously used PARP inhibitors, or are on specific anticoagulants like warfarin. It's best to discuss your current medications with the study team to ensure eligibility.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of Pamiparib (BGB-290) and Temozolomide has been tested in patients with brain tumors, particularly gliomas. In earlier studies, some patients experienced tumor growth stopping, and a few even saw tumors shrink. However, a higher dose of Temozolomide with Pamiparib proved difficult for patients to tolerate, leading to a reduction to 20 mg in ongoing studies. This indicates that while the treatment can be effective, careful dose management is crucial to handle side effects.

Temozolomide is already used in chemotherapy, providing extensive knowledge about its safety. When combined with Pamiparib, the drug levels in the blood remain similar to when these drugs are used separately, which is a positive sign for safety. However, as this is an early-phase trial, the primary goal is to determine the safest dose and understand potential side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine a PARP inhibitor, pamiparib (BGB-290), with temozolomide, offering a fresh angle for tackling IDH1/2 mutant gliomas. Unlike standard chemotherapy which targets rapidly dividing cells, PARP inhibitors like pamiparib work by preventing cancer cells from repairing their DNA, leading to cell death. This approach is particularly promising for patients with brain cancer, as it targets the tumor's specific genetic vulnerabilities, potentially increasing the effectiveness of treatment. Additionally, the treatment is administered orally, which might improve convenience compared to some existing intravenous options.

What evidence suggests that this trial's treatments could be effective for brain cancer?

This trial will evaluate the combination of pamiparib (BGB-290) and temozolomide for managing brain tumors, specifically gliomas with IDH1/2 mutations. Studies have shown that in patients with recurring glioblastoma, 40.9% experienced tumor stabilization, and 13.6% saw tumor reduction, suggesting the treatment might effectively slow tumor growth. Temozolomide is a chemotherapy drug that kills tumor cells or stops them from multiplying. When combined with pamiparib, which blocks enzymes necessary for tumor cell growth, the treatment effect may be stronger. The data shows promise, but more research is needed to fully understand how well these drugs work together. Participants in this trial will receive this combination therapy to further explore its effectiveness. ^{1 6 7 8 9}

Who Is on the Research Team?

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

Adolescents and young adults with newly diagnosed or recurrent IDH1/2-mutant grade I-IV glioma. Participants must have stable neurological deficits, not be on certain medications, have specific blood counts and organ functions within normal ranges, be able to swallow capsules, agree to use contraception if of childbearing potential, and provide tissue samples for study. Exclusions include prior treatment with IDH inhibitors, active infections or other cancers, bleeding disorders within the last 6 months, unresolved effects from previous therapies that pose a safety risk.

Inclusion Criteria

My lower grade glioma has worsened after surgery but I've had other treatments.

I have had surgery to remove as much of my tumor as safely possible.

It has been long enough since my last monoclonal antibody treatment to join this study.

Exclusion Criteria

I can attend all required follow-up visits and tests.

I do not have diffuse intrinsic pontine glioma.

I am taking low-dose aspirin or NSAIDs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BGB-290 and temozolomide. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Up to 24 months

Surgery and Recovery (Cohort B0)

Patients receive BGB-290 for 7 days pre-surgery. After recovery from surgery (14-28 days), patients proceed to the efficacy component of the trial.

3-5 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

5 years

What Are the Treatments Tested in This Trial?

Interventions

• BGB-290
• Temozolomide

Trial Overview The trial is testing the combination of BGB-290 (a PARP inhibitor) and Temozolomide (a chemotherapy drug) in treating brain tumors with specific genetic mutations. The goal is to determine the safest doses while assessing how well these drugs work together to inhibit tumor growth by blocking enzymes needed for cell growth and killing or stopping cancer cells from dividing.

How Is the Trial Designed?

Group I: Arm B (BGB-290, Temozolomide) Experimental Treatment 2 Interventions

Participants with grades I-IV recurrent IDH1/2 mutant glioma receive 60mg PARP inhibitor pamiparib (BGB-290) PO BID on days 1-28 and 20mg temozolomide PO daily on days 1-21. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Cohort B0: Participants who are surgical candidates with grades I-IV recurrent IDH1/2 mutant glioma receive 60mg PARP inhibitor BGB-290 PO BID for 7 days, pre-surgery. After recovery from surgery, participants receive PARP inhibitor BGB-290 PO BID on days 1-28 and 20mg temozolomide PO daily on days 1-21. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (Pamiparib (BGB-290), Temozolomide (TMZ)) Experimental Treatment 2 Interventions

Participants with grades III-IV newly diagnosed IDH1/2 mutant glioma receive 60mg pamiparib (BGB-290) PO BID on days 1-28 and 20mg temozolomide (TMZ) PO daily on days 1-21. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Pacific Pediatric Neuro-Oncology Consortium

Collaborator

Trials

16

Recruited

840+

BeiGene USA, Inc.

Industry Sponsor

Trials

5

Recruited

490+

Published Research Related to This Trial

Olaparib effectively penetrated recurrent glioblastoma tumors in patients, with measurable concentrations found in all tumor core and margin specimens, indicating its potential for therapeutic use.

The combination of olaparib with low-dose temozolomide (TMZ) was associated with increased hematological toxicity, leading to the need for intermittent dosing, but showed promising efficacy with 36% of patients remaining progression-free at 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Hanna, C., Kurian, KM., Williams, K., et al.[2022]

PARP inhibitors (PARPi) can effectively restore sensitivity to the chemotherapy drug temozolomide (TMZ) in glioblastoma cells that lack the MSH6 protein, which is important for DNA repair, indicating a potential treatment strategy for resistant gliomas.

The combination of PARPi and TMZ significantly suppressed tumor growth in MSH6-deficient glioma models, and this effect was independent of the base excision repair pathway, suggesting a unique mechanism of action for PARPi in overcoming chemoresistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restoration of Temozolomide Sensitivity by PARP Inhibitors in Mismatch Repair Deficient Glioblastoma is Independent of Base Excision Repair. Higuchi, F., Nagashima, H., Ning, J., et al.[2021]

The PARP inhibitor veliparib enhances the effectiveness of temozolomide (TMZ) in treating glioblastoma, particularly in TMZ-sensitive models, but its ability to sensitize TMZ-resistant tumors is limited by achievable drug concentrations in vivo.

In vivo studies showed that while veliparib combined with TMZ significantly delayed tumor growth in sensitive GBM models, it did not have the same effect in resistant models, indicating that higher doses than tolerable are needed for effective sensitization in resistant cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discordant in vitro and in vivo chemopotentiating effects of the PARP inhibitor veliparib in temozolomide-sensitive versus -resistant glioblastoma multiforme xenografts. Gupta, SK., Mladek, AC., Carlson, BL., et al.[2021]

The combination of the PARP inhibitor olaparib with temozolomide significantly enhanced the cytotoxic effects against glioblastoma cells in vitro, regardless of the MGMT promoter methylation status.

In vivo studies showed that while the combination treatment improved survival and reduced tumor volume compared to untreated mice, it did not significantly outperform temozolomide alone, suggesting that olaparib may not provide additional benefits in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Combination PARP Inhibitor Olaparib With Temozolomide in an Experimental Glioblastoma Model. Hwang, K., Lee, JH., Kim, SH., et al.[2021]

The study evaluated the combination of ABT-888 (a PARP inhibitor) and temozolomide (TMZ) in glioblastoma patients, showing a 6-month progression-free survival (PFS6) of 17% in bevacizumab (BEV) naïve patients compared to only 4.4% in BEV refractory patients, indicating potential efficacy in treatment-naïve cases.

The incidence of severe myelosuppression (grade 3/4) was 20%, highlighting a safety concern with the combination therapy, while overall survival rates were similar across treatment arms, suggesting that the combination did not significantly improve survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study. Robins, HI., Zhang, P., Gilbert, MR., et al.[2019]

Pamiparib is a highly selective PARP inhibitor that shows strong anti-proliferation effects in tumor cell lines with BRCA1/2 mutations, being 16-fold more potent than olaparib in a breast cancer model.

The combination of pamiparib with temozolomide (TMZ) effectively overcomes resistance in brain tumors, demonstrating significant tumor inhibition and prolonged survival in preclinical models, indicating its potential for treating brain tumors in ongoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor. Xiong, Y., Guo, Y., Liu, Y., et al.[2021]

In a phase I trial involving 29 children with recurrent brain tumors, the combination of veliparib and temozolomide was found to be well tolerated, with established recommended phase II doses of 25 mg/m² for veliparib and 135 mg/m² for temozolomide.

While no objective responses were observed, 4 patients maintained stable disease for over 6 months, indicating potential efficacy in this challenging population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: a pediatric brain tumor consortium report. Su, JM., Thompson, P., Adesina, A., et al.[2021]

AZD9574 is a selective PARP1 inhibitor that effectively penetrates the blood-brain barrier, demonstrating strong anticancer activity in preclinical models, particularly in tumors with homologous recombination repair deficiencies.

In combination with temozolomide (TMZ), AZD9574 significantly improved survival in mouse models of glioma compared to TMZ alone, indicating its potential as a leading treatment option for brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1. Staniszewska, AD., Pilger, D., Gill, SJ., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03914742

BGB-290 and Temozolomide in Treating Patients With ... This phase I/II trial studies the side effects and how well BGB-290 and temozolomide work in treating patients with gliomas (brain tumors) with IDH1/2 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12562933/

Phase Ib/II Study of Pamiparib Plus Radiation Therapy and/or ... In patients with recurrent glioblastoma, 40.9% had their tumor stop growing with 13.6% showing tumor shrinkage, and median overall survival of ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03749187

NCT03749187 | BGB-290 and Temozolomide in Treating ... This phase I trial studies the side effects and best dose of BGB-290 and temozolomide in treating adolescents and young adults with IDH1/2-mutant grade I-IV ...

4. hopkinsmedicine.org hopkinsmedicine.org/brain-tumor/clinical-trials

Brain Tumor Clinical Trials Clinical trials often help improve outcomes, especially for patients with aggressive tumors. View a list of studies for patients with brain tumors.

5. beonemedinfo.com beonemedinfo.com/CongressDocuments/Piotrowski%20BGB-290%20104%20SNO%20Poster%202019.pdf

pamiparib in combination with radiation therapy and/or ... — Pamiparib + TMZ showed limited activity in R/R GBM. Analysis of efficacy data in the newly diagnosed population is ongoing. Safety. — The most common TEAEs ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03150862

NCT03150862 | A Study Assessing Pamiparib With ... The primary objective of this study is to evaluate the safety, efficacy and clinical activity of Pamiparib in combination with radiation therapy (RT) and/or ...

7. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2018-02193

Testing the Safety of the Study Drug Pamiparib (BGB-290) ... This phase I/II trial studies the side effects and how well pamiparib and temozolomide work in treating patients with gliomas (brain tumors) with IDH1/2 ...

8. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)48888-1/fulltext

Preliminary results of pamiparib (BGB-290), a PARP1/2 ... Plasma exposure for pamiparib and TMZ were consistent with single-agent trials. One pt with peritoneal cancer in Arm A had a 99.5% decrease in CA125 by wk 12.

9. beonemedinfo.com beonemedinfo.com/CongressDocuments/Shih%20BGB-290%20104%20SNO%20Presentation%202018.pdf

Phase 1b/2 Study to Assess the Clinical Effects of – Pamiparib in combination with 21 days of 40 mg TMZ was not tolerable; 20 mg TMZ is ongoing. – Preliminary data suggest that pamiparib in combination with TMZ ...