PARP Inhibitor + Temozolomide for Brain Cancer

(PNOC017 Trial)

Recruiting at21 trial locations

Overseen by Sabine Mueller, MD, PhD, MAS

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: University of California, San Francisco

Must not be taking: PARP inhibitors, Anticoagulants

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

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial studies the safety and best dose of BGB-290 and temozolomide in treating young people with a specific type of brain tumor. BGB-290 blocks enzymes needed for tumor growth, while temozolomide kills or stops cancer cells from growing. The goal is to find out if this combination works better for these patients.

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.

What data supports the effectiveness of the drug combination of PARP Inhibitor and Temozolomide for brain cancer?

Research shows that Pamiparib, a PARP inhibitor, works well with Temozolomide to fight brain tumors, especially in cases where the cancer is resistant to Temozolomide alone. This combination has shown strong anti-tumor effects and can cross the blood-brain barrier effectively, which is important for treating brain cancer. ^{1 2 3 4 5}

Is the combination of PARP inhibitors and temozolomide safe for humans?

The combination of PARP inhibitors and temozolomide can increase the risk of blood-related side effects, as seen in clinical trials with similar drugs. However, specific safety data for pamiparib combined with temozolomide in humans is still being evaluated in ongoing clinical trials. ^{1 2 4 6 7}

What makes the drug combination of PARP Inhibitor and Temozolomide unique for brain cancer?

This drug combination is unique because Pamiparib, a PARP inhibitor, has better penetration into the brain compared to other similar drugs, and when combined with Temozolomide, it can overcome resistance in brain tumors, showing significant tumor reduction and prolonged survival. ^{1 2 4 6 8}

Research Team

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• BGB-290 (PARP Inhibitor)
• Temozolomide (Alkylating agents)

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.

Participant Groups

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

Patients with grades I-IV recurrent IDH1/2 mutant glioma receive 60mg 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. Cohort B0: Patients 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, patients 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 (BGB-290, temozolomide) Experimental Treatment 2 Interventions

Patients with grades III-IV newly diagnosed IDH1/2 mutant glioma receive 60mg 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.

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Suresh Gunasekaran

University of California, San Francisco

Chief Executive Officer since 2022

MBA from Southern Methodist University

Dr. Lukejohn Day

University of California, San Francisco

Chief Medical Officer

MD from Stanford University School of Medicine

Pacific Pediatric Neuro-Oncology Consortium

Collaborator

Trials

16

Recruited

840+

BeiGene USA, Inc.

Industry Sponsor

Trials

5

Recruited

490+

Findings from Research

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]

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]

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]

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]

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 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]

References

1. United States 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. [2019]

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

Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor. [2021]

3. United States 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. [2021]

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

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1. [2023]

5. England 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. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. [2022]

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

Restoration of Temozolomide Sensitivity by PARP Inhibitors in Mismatch Repair Deficient Glioblastoma is Independent of Base Excision Repair. [2021]

8. Greece pubmed.ncbi.nlm.nih.gov

The Combination PARP Inhibitor Olaparib With Temozolomide in an Experimental Glioblastoma Model. [2021]