Paxalisib for Central Nervous System Lymphoma

Recruiting at 1 trial location

Overseen By Lakshmi Nayak, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Lakshmi Nayak

Must not be taking: mTOR/PI3K inhibitors, CYP3A4 inhibitors/inducers

Disqualifiers: Active systemic disease, Uncontrolled illness, Prior malignancy, others

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

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the drug Paxalisib can effectively treat primary central nervous system lymphoma (PCNSL), a type of brain cancer. The research aims to determine Paxalisib's effectiveness against this specific cancer and identify potential side effects. Suitable participants include those with a confirmed diagnosis of recurrent or hard-to-treat PCNSL and symptoms visible on an MRI scan. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot take strong CYP3A4 inhibitors or inducers, as they may affect the study drug. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is there any evidence suggesting that Paxalisib is likely to be safe for humans?

Research has shown that Paxalisib has been tested in patients with primary central nervous system lymphoma (PCNSL) and has yielded promising results. In these studies, most patients tolerated the treatment well. Some experienced side effects, but these were usually manageable. The FDA has granted Paxalisib special recognition for other conditions, indicating some confidence in its safety. While no treatment is without risk, current evidence supports the safe use of Paxalisib in humans, with careful monitoring during the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Paxalisib is unique because it targets the PI3K pathway, which plays a crucial role in the growth and survival of cancer cells, including those in central nervous system lymphoma. Unlike traditional treatments, such as chemotherapy and radiation, which have broad effects on the body, Paxalisib's targeted approach may lead to fewer side effects and more effective control of the disease. Researchers are excited about Paxalisib because its ability to penetrate the blood-brain barrier could offer a significant advantage in treating lymphomas located in the brain, potentially improving outcomes for patients with this challenging condition.

What evidence suggests that Paxalisib might be an effective treatment for primary central nervous system lymphoma?

In a previous study, Paxalisib showed positive effects in patients with relapsed or hard-to-treat primary central nervous system lymphoma (PCNSL). Some patients experienced tumor shrinkage, known as a partial response. Although specific data for Paxalisib in PCNSL is lacking, similar treatments have shown promising results. This trial tests Paxalisib to determine its effectiveness in treating PCNSL by blocking signals that enable cancer cell growth and survival. Research suggests that Paxalisib could be effective because it targets the processes that support cancer cell growth. ^{1 2 3 4 6}

Who Is on the Research Team?

Lakshmi Nayak

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with confirmed recurrent or refractory primary DLBCL CNS lymphoma, who have measurable disease on MRI and are stable after previous treatments, can join. They must be able to undergo MRI scans, have good organ function, use effective contraception if applicable, and not require high doses of steroids. Excluded are those with other active cancers or infections like HIV/Hepatitis B/C, allergy to Paxalisib components, uncontrolled illnesses or hypertension.

Inclusion Criteria

Participant must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care

Participant must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study

My MRI shows my disease is not responding to treatment and can be measured.

Exclusion Criteria

Concurrent participation in another therapeutic trial

My high blood pressure is not controlled despite taking medication.

I cannot swallow pills or have a stomach condition that affects medication absorption.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Paxalisib (GDC-0084) in 28-day cycles for up to 24 months

24 months

Monthly visits for treatment and evaluations

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Paxalisib

Trial Overview The trial is testing the effectiveness of a drug called Paxalisib (GDC-0084) for treating primary central nervous system lymphoma that has come back or hasn't responded to treatment. Participants will receive this oral medication under study conditions to see how well it works against their cancer.

How Is the Trial Designed?

Group I: PAXALISIB Experimental Treatment 1 Intervention

The research study procedures include: screening for eligibility and study treatment including evaluations and follow up visits. * Paxalisib (GDC-0084) * Each study treatment cycle lasts 28 days, up to 24 months.

Paxalisib is already approved in United States for the following indications:

Approved in United States as Paxalisib for:

• None approved; Orphan Drug Designation for glioblastoma, diffuse intrinsic pontine glioma, and atypical teratoid/rhabdoid tumors

Who Is Running the Clinical Trial?

Lakshmi Nayak

Lead Sponsor

Trials

1

Recruited

30+

Lakshmi Nayak, MD

Lead Sponsor

Trials

1

Recruited

30+

Kazia Therapeutics Limited

Industry Sponsor

Trials

12

Recruited

1,600+

Published Research Related to This Trial

High-dose methotrexate-based immunochemotherapy, such as R-MPV, shows a 70-75% complete response rate in newly diagnosed primary central nervous system lymphoma (PCNSL) patients, making it a preferred treatment over whole brain radiotherapy, which has significant neurotoxic effects, especially in the elderly.

Tirabrutinib, a second-generation BTK inhibitor, has demonstrated substantial effectiveness against relapsed/refractory PCNSL and was approved in Japan in 2020, highlighting the potential of targeting specific genetic mutations in treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Molecular pathogenesis and therapeutic development of primary central nervous system lymphoma: update and future perspectives]. Nagane, M.[2022]

In a study of 100 patients with primary central nervous system lymphoma, the combination of high-dose methotrexate and rituxan resulted in a higher complete remission rate (66% vs. 58%) compared to traditional treatment with high-dose methotrexate and whole brain radiotherapy.

The targeted treatment group also experienced significantly longer median progression-free survival (28 months) compared to the traditional treatment group (11 months), indicating that the methotrexate and rituxan combination is not only effective but also has fewer adverse reactions, making it a safer option, especially for elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Curative Efficacy of High Dose MTX Combined with Rituxan for Treatment Primary CNS Lymphoma]. Mou, K., Gu, WW., Gu, CH., et al.[2018]

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma that primarily affects the brain and spinal cord, with treatment typically involving high-dose methotrexate-based chemotherapy, which can lead to cognitive impairment in elderly patients.

The prognosis for PCNSL has improved significantly, with a median overall survival of 26 months and a 5-year survival rate of 31%, particularly in younger patients and those with better performance status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lymphomas of Central Nervous System. Yokogami, K., Azuma, M., Takeshima, H., et al.[2023]

Whole-exome sequencing of 36 primary central nervous system lymphoma (PCNSL) patients revealed that MYD88 mutations were present in 67% of cases, indicating a common genetic alteration that may play a role in the disease's development.

The study found that CD79b mutations were linked to better progression-free and overall survival, suggesting that these mutations could be important biomarkers for patient prognosis and treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MYD88 L265P mutation and CDKN2A loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas. Nayyar, N., White, MD., Gill, CM., et al.[2022]

In a study of 5 patients with refractory or relapsed primary central nervous system lymphoma (PCNSL), tirabrutinib demonstrated a 100% response rate, indicating its potential as an effective treatment for those who cannot tolerate standard therapies.

Despite some manageable adverse reactions, tirabrutinib was well-tolerated, and the median survival for patients was 8 months, suggesting it could be a promising alternative for improving outcomes in difficult-to-treat PCNSL cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience With Tirabrutinib in the Treatment of Primary Central Nervous System Lymphoma that Is Difficult to Treat With Standard Treatment. Yoshioka, H., Okuda, T., Nakao, T., et al.[2022]

In a study of 85 patients with primary central nervous system lymphoma (PCNSL) treated with the R-MPV regimen, the treatment showed a high tumor control rate with 5-year progression-free and overall survival rates of 61.6% and 69.9%, respectively.

The CD79B Y196 mutation was identified as a significant predictive marker for a favorable response to R-MPV, indicating that patients with this mutation had prolonged survival, while this association was not seen in patients treated with high-dose methotrexate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD79B Y196 mutation is a potent predictive marker for favorable response to R-MPV in primary central nervous system lymphoma. Yamaguchi, J., Ohka, F., Lushun, C., et al.[2023]

Ibrutinib showed promising efficacy in treating relapsed/refractory primary and secondary central nervous system lymphomas, with an objective response rate of 58% and a complete response rate of 55% among 33 patients studied.

The treatment resulted in a median progression-free survival of 3.1 months for primary CNS lymphoma and 10.2 months for secondary CNS lymphoma, with only one case of invasive fungal infection reported, indicating a favorable safety profile despite concurrent steroid use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience. Lewis, KL., Chin, CK., Manos, K., et al.[2021]

In a study of 128 patients with primary central nervous system lymphoma (PCNSL), combining high-dose methotrexate (MTX) with Gamma Knife radiosurgery (GKRS) significantly improved median survival rates from 26.8 months to 47.6 months compared to MTX alone.

GKRS was found to be a safe and non-invasive treatment option that led to complete tumor responses in all lesions evaluated within 6.3 weeks, suggesting it enhances tumor control and reduces complications when used alongside MTX.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary Central Nervous System Lymphoma (PCNSL): Analysis of Treatment by Gamma Knife Radiosurgery and Chemotherapy in a Prospective, Observational Study. Alvarez-Pinzon, AM., Wolf, AL., Swedberg, H., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04906096

Paxalisib (GDC-0084) In Recurrent Or Refractory PCNSL This is an open-label, phase 2 study to determine the efficacy of Paxalisib (GDC-0084) in 25 patients with recurrent or refractory primary central nervous ...

2. targetedonc.com targetedonc.com/view/preliminary-clinical-activity-observed-with-paxalisib-in-r-r-pcnsl

Preliminary Clinical Activity Observed With Paxalisib in R/R ... Clinical activity has been seen in patients with relapsed/refractory (R/R) primary central nervous system lymphoma (PCNSL), including partial responses and ...

3. withpower.com withpower.com/trial/phase-3-lymphoma-non-hodgkin-5-2021-588d2

Paxalisib for Central Nervous System Lymphoma While there is no direct data on Paxalisib for central nervous system lymphoma, similar treatments like ibrutinib have shown encouraging results, with a 58% ...

4. aging.networkofcare.org aging.networkofcare.org/sanmateo/CommunityResources/ClinicalTrials/Detail/NCT04906096?keyword=%22Central%20Nervous%20System%20Lymphoma%22

Paxalisib (GDC-0084) In Recurrent Or Refractory PCNSL This is an open-label, phase 2 study to determine the efficacy of Paxalisib (GDC-0084) in 25 patients with recurrent or refractory primary central nervous ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12126982/

Novel Therapies in Primary Central Nervous System Lymphoma In this review, we focus on the biology of PCNSL and novel chemotherapeutics, including targeted and immunotherapeutic agents as well as cellular therapies.

6. rarediseaseadvisor.com rarediseaseadvisor.com/therapies/primary-central-nervous-system-lymphoma-experimental-therapies/

Primary Central Nervous System Lymphoma (PCNSL) Paxalisib was granted Orphan Drug designation for glioblastoma by the FDA in February 2018 and Fast Track designation for glioblastoma and solid ...