Pamiparib + Standard Care for Glioblastoma

Recruiting in Palo Alto (17 mi)

Overseen by Nader Sanai, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Waitlist Available

Sponsor: Nader Sanai

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial is testing pamiparib and olaparib combined with radiation therapy in patients with newly diagnosed and recurrent glioblastoma. These drugs help make cancer cells more sensitive to radiation by stopping them from repairing their DNA. The goal is to see if this combination can improve treatment outcomes for this aggressive brain cancer. Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumors.

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.

What data supports the idea that Pamiparib + Standard Care for Glioblastoma is an effective treatment?

The available research does not provide specific data on the effectiveness of Pamiparib combined with standard care for glioblastoma. Instead, it focuses on other drugs and treatments like buparlisib and iniparib, which are being tested for glioblastoma. There is also a study on Pamiparib's presence in human plasma and brain tumors, but it does not discuss its effectiveness for glioblastoma. Therefore, there is no direct evidence from the provided information to support the effectiveness of Pamiparib + Standard Care for glioblastoma. ^{1 2 3 4 5}

What safety data exists for Pamiparib and standard care in glioblastoma treatment?

The research indicates that Pamiparib, a PARP inhibitor, has been evaluated for its safety and efficacy in combination with temozolomide (TMZ) for brain tumors. Pamiparib shows strong anti-tumor synergy with TMZ and improved penetration across the blood-brain barrier. It has been tested in clinical trials, such as NCT03150862, for its potential in treating brain tumors. Additionally, a Phase I trial of Veliparib, another PARP inhibitor, with standard radiation and TMZ in glioblastoma patients was conducted to determine safety and maximum tolerated dose, suggesting a similar approach could be applicable to Pamiparib. ^{3 6 7 8 9}

Is the drug Pamiparib a promising treatment for glioblastoma?

Yes, Pamiparib is a promising drug for glioblastoma because it can effectively target brain tumors, works well with another cancer drug called temozolomide, and can cross the blood-brain barrier to reach the tumor. ^{2 3 8 10 11}

Research Team

Nader Sanai, MD

Principal Investigator

Director, Ivy Brain Tumor Center

Eligibility Criteria

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.

Treatment Details

Interventions

• Olaparib (PARP Inhibitor)
• Pamiparib (PARP Inhibitor)
• Radiation therapy (Radiation)

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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 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]

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]

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]

References

1. United States 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. [2020]

2. England 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. [2023]

3. England 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. [2021]

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

Phase II Study of Iniparib with Concurrent Chemoradiation in Patients with Newly Diagnosed Glioblastoma. [2020]

5. 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]

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

Phase II trial of dacomitinib, a pan-human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification. [2022]

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

Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627). [2019]

8. 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]

9. United States 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). [2023]

10. Netherlands 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. [2023]

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

PARP inhibition restores extrinsic apoptotic sensitivity in glioblastoma. [2018]