Pamiparib + Standard Care for Glioblastoma

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Nader Sanai

Must not be taking: Coumarin anticoagulants, PARP inhibitors

Disqualifiers: Pregnancy, Active infection, Cardiovascular issues, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a new drug, pamiparib, combined with radiation therapy, can help treat glioblastoma, an aggressive brain cancer. The trial includes different parts: one for newly diagnosed patients and others for those whose cancer has returned. In some cases, researchers will test a similar drug, olaparib. This trial might suit those who have had surgery for suspected glioblastoma and plan to undergo radiation or those whose glioblastoma has returned after standard treatment. As an Early Phase 1 trial, this research focuses on understanding how pamiparib works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you must stop taking your current medications. However, there is a required washout period of at least 21 days after your last chemotherapy dose before starting the trial, provided you did not receive radiotherapy. Additionally, if you are using coumarin-derived anticoagulants, you must discontinue them before surgery. It's best to discuss your specific medications with the trial team.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot use coumarin-derived anticoagulants unless they can be stopped before surgery. If you have been on chemotherapy, a 21-day washout period (time without taking the medication) is required before starting the trial.

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

Research shows that pamiparib is usually well-tolerated, but important considerations remain. In earlier studies, some patients experienced side effects such as tiredness, chills, and dizziness, which were serious enough to limit the dose and, in some cases, led to discontinuation of treatment. However, with careful monitoring, most patients can manage pamiparib.

For olaparib, research indicates it is generally safe as well. It has been used with other treatments like temozolomide and radiation for glioblastoma, a type of brain cancer. Most patients reported manageable side effects, making it a promising option.

Both treatments have shown potential but come with risks. Participants in any clinical trial should discuss these risks with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatment options for glioblastoma, which often involve surgery, radiation, and chemotherapy with drugs like temozolomide, pamiparib offers a novel approach. Pamiparib is a PARP inhibitor, which works by targeting and blocking a protein that cancer cells use to repair their DNA, thereby potentially enhancing the effectiveness of radiation therapy and chemotherapy. Researchers are excited about pamiparib because it could improve outcomes for patients by making cancer cells more vulnerable to treatment. Additionally, the trial is exploring another PARP inhibitor, olaparib, in a separate arm, offering further insight into how these drugs might provide new avenues for treating recurrent glioblastoma.

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

Studies have shown that pamiparib, one of the treatments in this trial, may benefit people with glioblastoma, a type of brain cancer. In one study, 40.9% of patients with recurring glioblastoma experienced tumor stabilization, and 13.6% saw tumor reduction. Most patients tolerated the treatment well, without severe side effects. In this trial, some participants will receive pamiparib, while others will receive olaparib, another similar drug. Research indicates that olaparib effectively reaches brain tumors and works well with other treatments. Both drugs show promise in slowing brain tumor growth and enhancing the effects of radiation therapy. ^{1 2 4 6 7}

Who Is on the Research Team?

Nader Sanai, MD

Principal Investigator

Director, Ivy Brain Tumor Center

Are You a Good Fit for This Trial?

Adults with new or recurrent glioblastoma who've had surgery and are set for standard treatment, including radiation. They must be able to swallow pills, have good organ function, not be pregnant or breastfeeding, use effective contraception, and not have severe infections or certain chronic diseases. Those with prior PARP inhibitor treatments or allergic reactions to trial drugs cannot join.

Inclusion Criteria

Agreement to adhere to Lifestyle Considerations throughout study duration

I am not pregnant or cannot become pregnant due to menopause or surgery.

I had surgery for glioblastoma and have undergone standard treatment including radiation and temozolomide.

Exclusion Criteria

I have been treated with PARP inhibitors before.

Treatment with another investigational drug or other intervention within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer

I haven't needed antibiotics or antivirals for an infection or high fever in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 0

Participants receive pamiparib or olaparib for 4 days prior to surgical resection

1 week

1 visit (in-person)

Exploratory Phase 2

Participants receive pamiparib or olaparib in combination with 6-7 weeks of radiation therapy and pamiparib in combination with TMZ in the maintenance phase

6-7 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Pamiparib
• Radiation therapy

Trial Overview The study is testing Pamiparib in combination with radiotherapy for newly diagnosed glioblastoma without MGMT promoter methylation and for recurrent cases. Olaparib plus radiotherapy is also being tested for recurrent cases after assessing PK response in Phase 0 of the trial.

How Is the Trial Designed?

Group I: Arm C Recurrent Glioblastoma Participant treated with Olaparib Experimental Treatment 3 Interventions

Arm C will be an exploratory arm in recurrent glioblastoma patients (rGBM) treated with Olaparib for 4 days prior to surgical resection. Patients who proceed to Phase 2 will receive olaparib administered orally BID continuously in combination with 6-7 weeks of radiation therapy and pamiparib in combination with TMZ in the maintenance phase.

Group II: Arm B Recurrent Glioblastoma Participant treated with Pamiparib Experimental Treatment 3 Interventions

Recurrent glioblastoma (rGBM) patients who are scheduled for surgery and expected to receive postoperative fractionated radiotherapy (RT) will be treated with pamiparib for 4 days prior to surgical resection. Patients who proceed to Phase 2 will receive pamiparib administered orally BID continuously in combination with 6-7 weeks of radiation therapy and pamiparib in combination with TMZ in the maintenance phase.

Group III: Arm A Newly-diagnosed Glioblastoma Participant treated with Pamiparib Experimental Treatment 3 Interventions

Participants undergoing resection for a presumed newly diagnosed glioblastoma (nGBM) will be treated with pamiparib for 4 days prior to surgical resection. Patients who proceed to Phase 2 will receive pamiparib administered orally BID continuously in combination with 6-7 weeks of radiation therapy and pamiparib in combination with TMZ in the maintenance phase.

Pamiparib is already approved in China for the following indications:

Approved in China as Pamiparib for:

• Ovarian cancer

Who Is Running the Clinical Trial?

Nader Sanai

Lead Sponsor

Trials

11

Recruited

440+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Ivy Brain Tumor Center

Collaborator

Trials

12

Recruited

910+

Barrow Neurological Institute

Collaborator

Trials

27

Recruited

7,100+

Published Research Related to This Trial

In a phase II trial involving 65 patients with recurrent glioblastoma, the pan-PI3K inhibitor buparlisib showed minimal efficacy as a single agent, with only 8% of patients achieving 6-month progression-free survival.

Despite demonstrating significant brain penetration and some reduction in PI3K pathway activity in tumor tissue, the incomplete blockade of the pathway likely contributed to the lack of clinical effectiveness, suggesting that more effective PI3K inhibitors may be needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. Wen, PY., Touat, M., Alexander, BM., et al.[2020]

In a Phase I trial involving 24 patients with newly diagnosed glioblastoma, Veliparib combined with temozolomide (TMZ) was generally well tolerated at a dose of 10 mg BID, with only one dose-limiting toxicity observed in the initial cohort.

However, when Veliparib was combined with TMZ and radiation therapy, 33% of patients experienced dose-limiting hematologic toxicities, leading to a dose reduction and ultimately the termination of the trial, indicating a significant risk of myelosuppression with this combination treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multi-Site Phase I Trial of Veliparib with Standard Radiation and Temozolomide in Patients with Newly Diagnosed Glioblastoma Multiforme (GBM). Kleinberg, L., Ye, X., Supko, J., et al.[2023]

Iniparib, when combined with standard radiotherapy and temozolomide, showed a median overall survival of 22 months in patients with newly diagnosed glioblastoma, indicating its potential effectiveness as a treatment option.

The treatment was generally well tolerated, with 27% of patients experiencing grade 3 adverse events, suggesting that while there are some side effects, iniparib can be safely administered alongside other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Iniparib with Concurrent Chemoradiation in Patients with Newly Diagnosed Glioblastoma. Blakeley, JO., Grossman, SA., Chi, AS., et al.[2020]

In a phase I study involving patients with newly diagnosed glioblastoma, the maximum tolerated dose (MTD) of buparlisib when combined with temozolomide was determined to be 80 mg/day, but the MTD for the combination with both temozolomide and radiotherapy could not be established due to significant dose-limiting toxicities.

The study reported high rates of adverse events, particularly nausea and fatigue, leading to treatment discontinuations, which contributed to Novartis's decision to halt further development of buparlisib for this indication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. Wen, PY., Rodon, JA., Mason, W., et al.[2021]

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]

Pamiparib demonstrated promising efficacy in treating locally advanced or metastatic HER2-negative breast cancer with deleterious or suspected deleterious BRCA1/2 mutations, achieving an objective response rate of 38.2% in triple-negative breast cancer and 61.9% in hormone receptor-positive cohorts.

The treatment was generally well-tolerated, although hematologic adverse events were common, leading to dose reductions in 64.8% of patients, indicating a need for monitoring but an overall acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pamiparib in patients with locally advanced or metastatic HER2-negative breast cancer with germline BRCA mutations: a phase II study. Xu, B., Sun, T., Shi, Y., et al.[2023]

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 phase II trial involving 49 patients with recurrent glioblastoma and EGFR amplification, dacomitinib showed limited efficacy, with a 6-month progression-free survival rate of only 10.6%.

The treatment was associated with significant adverse effects, as 40.8% of patients experienced grade 3-4 drug-related side effects, primarily diarrhea and rash, highlighting the need for careful patient selection based on molecular characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of dacomitinib, a pan-human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification. Sepúlveda-Sánchez, JM., Vaz, MÁ., Balañá, C., et al.[2022]

Dasatinib, a multitargeted tyrosine kinase inhibitor, was evaluated in a phase II trial for adults with recurrent glioblastoma, but the study found it ineffective, with no radiographic responses and a median overall survival of only 7.9 months.

Although intrapatient dose escalation was feasible and tolerated by some participants, the clinical benefit was insufficient, leading to the trial's closure without proceeding to further stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627). Lassman, AB., Pugh, SL., Gilbert, MR., et al.[2019]

A highly sensitive and validated method was developed to measure pamiparib concentrations in human plasma and brain tumor tissue, allowing for accurate pharmacokinetic assessments in patients with glioma.

Pamiparib, a PARP1 and PARP2 inhibitor, demonstrated stability in plasma for at least 6 months at -80°C, indicating its potential for effective long-term treatment in glioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and validation of a liquid chromatography coupled with tandem mass spectrometry method for determining total and unbound pamiparib in human plasma and brain tumors. Jiang, J., Bao, X., Yue, Y., et al.[2023]

Targeting PARP with inhibitors like Olaparib and PJ34 significantly enhances the effectiveness of TRAIL in inducing cell death in glioblastoma (GBM) cells, both in laboratory settings and in animal models.

The combination treatment not only increased apoptosis through the activation of caspases but also did not show toxicity in human astrocytes, suggesting a safer approach to treating GBM while effectively reducing tumor growth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. Karpel-Massler, G., Pareja, F., Aimé, P., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7746945/

Pharmacokinetics, safety, and tolerability of olaparib and ... Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11570871/

Olaparib Enhances the Efficacy of Third‐Generation Oncolytic ... In summary, our study showed that combination therapy with olaparib and TS‐2021 was effective against human GBM in vivo and in vitro. ...

3. nature.com nature.com/articles/s41416-024-02878-2

Neurosurgical application of olaparib from a thermo- ... Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0360301624000154

Concurrent Olaparib and Radiation Therapy in Older ... Median overall survival and progression-free survival were 10.8 months (80% CI, 7.3-11.4) and 5.5 months (80% CI, 3.9-5.9), respectively. Mini Mental State ...

5. asco.org asco.org/abstracts-presentations/ABSTRACT189334

A phase I dose escalation study of olaparib in combination ... Background: Olaparib, a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), may improve GBM outcomes by enhancing cytotoxic effects of ionising ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.2055

Safety and tolerability of olaparib, temozolomide ... The combination of olaparib, temozolomide, and pembrolizumab demonstrates a tolerable safety profile in patients with progressive glioblastoma.

7. aacrjournals.org aacrjournals.org/clincancerres/article/31/7/1212/754263/Olaparib-Temozolomide-and-Concomitant-Radiotherapy

Olaparib, Temozolomide, and Concomitant Radiotherapy for ... PARP inhibitors like olaparib may improve GBM outcomes. We implemented a phase I to IIa trial to assess the safety and efficacy of olaparib combined with ...