Targeted Therapy for Brain Cancer

Not currently recruiting at 501 trial locations

Overseen By Priscilla Brastianos, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Alliance for Clinical Trials in Oncology

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Uncontrolled diabetes, HIV, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 8

Duration: Up to 5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well genetic testing can guide treatment for patients with brain cancer that originated elsewhere and spread to the brain. It targets patients with specific gene mutations, such as NTRK, ROS1, CDK, PI3K, or KRAS G12C. The trial uses medications aimed at these mutations, potentially stopping tumor growth by blocking enzymes that aid cell growth. People with brain tumors featuring these genetic changes, who have not responded to other treatments, might be suitable for this study. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to benefit from targeted therapies.

Will I have to stop taking my current medications?

The trial requires a washout period for certain medications. You must stop chemotherapy at least 14 days before joining the study, and for the abemaciclib arm, a 21-day washout is needed. If you're on strong CYP3A4 inhibitors or inducers, you must stop them 14 days before starting the trial. For the entrectinib arm, you cannot use certain stomach acid medications.

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

Previous studies have generally shown that abemaciclib is well-tolerated. Some patients experienced side effects, but these were mostly manageable. Common side effects included fatigue and diarrhea.

Research on entrectinib has shown promising safety results. For patients with brain tumors, it proved effective without causing many serious side effects. Some patients reported mild to moderate side effects, such as dizziness and nausea.

Paxalisib has also undergone safety studies. The most common side effects included high blood sugar and skin rash. However, these were similar to those of other medications, and many patients managed the treatment well.

Overall, these treatments have been tested in patients with brain tumors and have shown reasonable safety. However, like any treatment, they may have some side effects, and the experience can vary from person to person. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these investigational treatments for brain cancer because they offer novel, targeted approaches that differ from traditional chemotherapy and radiation. Abemaciclib specifically targets CDK gene mutations, potentially stopping cancer cell growth more effectively. Entrectinib is designed for those with NTRK/ROS1 gene mutations, zeroing in on specific cancer-driving proteins. Paxalisib targets the PI3K pathway, which is often involved in cancer cell survival, offering a new avenue for those with PI3K gene mutations. Lastly, adagrasib focuses on the KRAS G12C mutation, a notoriously difficult target, potentially providing a breakthrough for patients with this mutation. These drugs represent a shift toward more personalized and precise cancer treatments.

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

Research shows that abemaciclib, available to participants in Arm I of this trial, can penetrate the brain and slow tumor growth by blocking proteins called CDK 4 and CDK 6. Studies suggest it may halt the growth of high-grade gliomas, a type of brain tumor, and even shrink them in some cases. Entrectinib, offered in Arm III, has demonstrated a 61.2% success rate in patients with brain tumors, particularly those with NTRK or ROS1 gene changes. For paxalisib, studied in Arm II, research indicates it can cross into the brain and has improved survival rates in patients with glioblastoma, a severe brain cancer. These treatments target specific genetic changes, potentially stopping tumor cells from growing. ^{1 2 5 6 7}

Who Is on the Research Team?

Priscilla Brastianos, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for patients with solid tumors that have spread to the brain, who can undergo MRI scans and haven't had recent surgery or chemotherapy. They must not be pregnant or nursing, have no uncontrolled medical issues, and not be on certain drugs affecting liver enzymes. Participants need confirmed metastatic disease in the brain from a solid tumor with specific gene alterations (NTRK, ROS1, KRAS G12C, CDK pathway or PI3K pathway) and meet other health criteria.

Inclusion Criteria

I haven't had chemotherapy in the last 14 days.

I am not on any strong medication that affects liver enzyme levels.

You can get an MRI with a special dye called contrast.

Exclusion Criteria

I meet the specific health requirements for the ABEMACICLIB trial arm.

To join the ADAGRASIB (MRTX849) arm, you need to meet specific requirements related to your blood, heart health, medications, and medical history. If you are a woman able to have children, you also need to use contraception.

Living outside the US

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive targeted therapy based on genetic mutations (e.g., abemaciclib, paxalisib, entrectinib, or adagrasib) in 28-day cycles

Up to 5 years

Monthly visits for treatment cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 8 weeks for 2 years, then every 3 months for years 3-4, and every 6 months thereafter

What Are the Treatments Tested in This Trial?

Interventions

• Abemaciclib
• Entrectinib
• paxalisib

Trial Overview The trial tests if genetic testing can guide treatment using targeted medications like abemaciclib, paxalisib, entrectinib and adagrasib for brain metastases from solid tumors. These drugs aim to block enzymes needed by tumor cells to grow by focusing on mutations found in genes related to cancer progression.

How Is the Trial Designed?

Group I: Arm IV (KRAS G12C mutation) Experimental Treatment 1 Intervention

Patients receive adagrasib (MRTX849) PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm III (NTRK/ROS1 gene mutation) Experimental Treatment 1 Intervention

Patients receive entrectinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group III: Arm II (PI3K gene mutation) Experimental Treatment 1 Intervention

Patients receive PI3K inhibitor paxalisib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group IV: Arm I (CDK gene mutation) Experimental Treatment 1 Intervention

Patients receive abemaciclib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Abemaciclib is already approved in United States, European Union for the following indications:

Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Who Is Running the Clinical Trial?

Alliance for Clinical Trials in Oncology

Lead Sponsor

Trials

521

Recruited

224,000+

Mirati Therapeutics Inc.

Industry Sponsor

Trials

73

Recruited

8,900+

Dr. Charles M. Baum

Mirati Therapeutics Inc.

Chief Executive Officer since 2023

MD, PhD

Dr. Joseph Leveque

Mirati Therapeutics Inc.

Chief Medical Officer since 2021

MD

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Kazia Therapeutics Limited

Industry Sponsor

Trials

12

Recruited

1,600+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

Lazertinib, a new EGFR tyrosine kinase inhibitor, is being tested as a first-line treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutations and brain metastases, with a total of 75 patients participating in this phase II trial.

The trial aims to evaluate lazertinib's efficacy in improving progression-free survival and intracranial progression-free survival, potentially offering better outcomes than existing treatments due to its higher selectivity and ability to penetrate the blood-brain barrier.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of lazertinib for symptomatic or asymptomatic brain metastases in treatment-naive patients with advanced EGFR mutation-positive non-small cell lung cancer: Protocol of an open-label, single-arm phase II trial. Lee, B., Ji, W., Lee, JC., et al.[2023]

Dovitinib, an oral multi-tyrosine kinase inhibitor, was found to be safe for patients with recurrent glioblastoma, with only 16.7% of adverse events classified as severe (grade 3) toxicity, primarily involving liver and blood-related issues.

The trial showed a progression-free survival rate of 16.7% at 6 months, indicating some efficacy, but this was not linked to the presence of the FGFR-TACC gene fusion in tumors, suggesting that further personalized trials are needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of dovitinib (TKI258) in recurrent glioblastoma. Schäfer, N., Gielen, GH., Kebir, S., et al.[2018]

In a study of 393 patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC), lazertinib significantly improved median intracranial progression-free survival to 28.2 months compared to 8.4 months for gefitinib, indicating its superior efficacy in patients with central nervous system (CNS) metastases.

Lazertinib also showed a higher intracranial objective response rate (94% vs. 73% for gefitinib) among patients with measurable CNS lesions, suggesting it may provide more durable responses, while tolerability was similar to that observed in the overall study population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central Nervous System Outcomes of Lazertinib Versus Gefitinib in EGFR-Mutated Advanced NSCLC: A LASER301 Subset Analysis. Soo, RA., Cho, BC., Kim, JH., et al.[2023]

In a phase 0 trial involving 10 patients with brain metastases or recurrent glioblastoma, ceritinib was well-tolerated with no dose-limiting toxicities observed, indicating a favorable safety profile.

Despite ceritinib's high binding to plasma proteins and tumor tissues, the unbound drug concentrations in the brain were insufficient to effectively modulate its intended targets, suggesting limited efficacy in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 0 Trial of Ceritinib in Patients with Brain Metastases and Recurrent Glioblastoma. Mehta, S., Fiorelli, R., Bao, X., et al.[2023]

Osimertinib, an EGFR-tyrosine kinase inhibitor, shows potential efficacy in treating recurrent malignant gliomas (MG) with EGFR alterations, as evidenced by one patient achieving a partial response and two others maintaining stable disease among six patients reviewed.

The treatment was generally well-tolerated, with a manageable safety profile, although some patients experienced mild side effects like thrombocytopenia and grade 1 diarrhea, indicating that osimertinib may be a beneficial option for select patients with recurrent MG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Experience using Osimertinib in Patients with Recurrent Malignant Gliomas Containing EGFR Alterations. Abousaud, M., Faroqui, NM., Lesser, G., et al.[2023]

Oral targeted agents, including BRAF inhibitors and various receptor inhibitors, show potential in treating brain metastases, but there is a lack of comprehensive data on their effectiveness in this specific area.

Many patients with brain metastases are excluded from clinical trials, leading to a significant gap in research and documentation of the intracranial activity of these therapies, highlighting the need for more focused investigations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Targeted Therapies and Central Nervous System (CNS) Metastases. Gabay, MP., Wirth, SM., Stachnik, JM., et al.[2022]

Voxtalisib, when combined with temozolomide (TMZ), was found to have a favorable safety profile, with maximum tolerated doses identified as 90 mg once daily and 40 mg twice daily, and common side effects including nausea and fatigue.

The treatment showed moderate inhibition of the PI3K/mTOR pathway and resulted in a partial response in 4% of patients, with 68% experiencing stable disease, indicating some potential efficacy in treating high-grade gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma. Wen, PY., Omuro, A., Ahluwalia, MS., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02981940

A Study of Abemaciclib in Recurrent Glioblastoma In laboratory studies, Abemaciclib was able to enter the brain, stop CDK 4 and CDK 6 from making cells, and slow growth of mice Glioblastoma. In this research ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7650442/

A PHASE II PLATFORM TRIAL USING BAYESIAN ... Preliminary analysis suggests that abemaciclib increases PFS compared to control. Updated toxicity, PFS and survival data and potential genomic biomarker ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-01113

Abemaciclib for the Treatment of Patients with Recurrent ... Giving abemaciclib to patients with recurrent high grade gliomas may prevent high grade gliomas from growing, slow down their growth, or possibly shrink them.

4. aacrjournals.org aacrjournals.org/clincancerres/article/26/20/5310/82934/A-Phase-II-Study-of-Abemaciclib-in-Patients-with

A Phase II Study of Abemaciclib in Patients with Brain ... In a phase I study, abemaciclib achieved unbound cerebrospinal fluid (CSF) concentrations similar to time-matched plasma concentrations in patients with ...

5. academic.oup.com academic.oup.com/oncolo/article/30/8/oyae274/7825842

Real-world outcomes in patients with brain metastases ... This article describes patient characteristics, treatment patterns, and real-world outcomes of abemaciclib-treated patients with brain ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32694159/

A Phase II Study of Abemaciclib in Patients with Brain ... This study did not meet its primary endpoint. Abemaciclib was associated with an iCBR of 24% in patients with heavily pretreated HR + ...

7. trials.braintumor.org trials.braintumor.org/trials/NCT03220646

Abemaciclib (LY2835219) in Patients With Recurrent Primary ... Abemaciclib (LY2835219) in Patients With Recurrent Primary Brain Tumors. Study Purpose. The purpose of this study is to test any good and bad effects of a study ...