Abemaciclib + Temozolomide for Brain Cancer

Overseen By Sadhana Jackson, M.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors/inducers

Disqualifiers: Pregnancy, Severe renal impairment, others

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

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 34

17 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Diffuse midline gliomas are the most aggressive brain tumors of childhood and young adults. Most people with these tumors survive less than 2 years. Researchers want to see if an anticancer drug (abemaciclib) can help. Objective: To see if researchers can measure how much abemaciclib is in a person's brain tumor and brain fluid after they take the drug for a few days. Eligibility: People aged 18 to 39 with recurrent high-grade glioma or diffuse midline glioma. Design: Participants will be screened with: Medical history Physical exam Blood and urine tests Tests of heart function Imaging scans of the brain, with a contrast agent Screening tests will be repeated during the study. Participants will also have chest X-rays. Participants will take abemaciclib by mouth twice a day for 4 and a half days. Participants will undergo surgery. They will have either a tumor biopsy (a needle will be inserted to remove a small piece of tissue) or a surgical resection (part or all of the tumor will be removed). A small tube (catheter) will be placed in their brain for 48 hours to collect fluid samples. They will have a neurological exam every few hours while the tube is in place. Two days later, the tube will be removed without surgery. Participants will stay in the hospital for about 4 days for treatment. Based on the results of abemaciclib levels in the brain, participants may keep taking abemaciclib and another drug (temozolomide) by mouth until their cancer gets worse or they have bad side effects. While taking these two drugs, participants will come back to the clinic for follow-up routinely. They will be followed by the study for life.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot take medications that are strong or moderate CYP3A inhibitors or inducers. It's important to discuss your current medications with the study team to ensure there are no interactions.

What data supports the effectiveness of the drug Abemaciclib for brain cancer?

Abemaciclib has shown effectiveness in treating certain types of breast cancer and lung cancer by inhibiting specific proteins (CDK4/6) that help cancer cells grow. While this data is not directly about brain cancer, it suggests that Abemaciclib might have potential in treating other cancers by targeting similar pathways. ^{1 2 3 4 5}

Is Abemaciclib safe for use in humans?

Abemaciclib, also known as Verzenio, has been approved for treating certain types of breast cancer and is generally considered safe when used as directed. Common side effects include diarrhea, infections, and low white blood cell counts, but these are usually manageable. ^{4 6 7 8 9}

What makes the drug combination of Abemaciclib and Temozolomide unique for treating brain cancer?

The combination of Abemaciclib and Temozolomide is unique because Abemaciclib is a targeted therapy that inhibits specific proteins involved in cancer cell growth, while Temozolomide is an oral chemotherapy that works by damaging the DNA of cancer cells. This combination may offer a novel approach by potentially enhancing the effectiveness of treatment for brain cancer compared to using Temozolomide alone. ^{10 11 12 13 14}

Research Team

Sadhana Jackson, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for young adults aged 18 to 39 with recurrent high-grade glioma or diffuse midline glioma. They must have recovered from previous treatments, have good organ function, and not be pregnant. Participants should be able to swallow pills and avoid grapefruit during the study.

Inclusion Criteria

My high-grade brain tumor was confirmed by tests during surgery.

I can swallow pills.

Women considered to be of childbearing potential must have a negative pregnancy test within 7 days of the first dose of abemaciclib

Exclusion Criteria

I do not have any active infections.

I have a history of fainting due to heart issues, irregular heartbeats, or sudden cardiac arrest.

I have severe nausea and vomiting that could interfere with taking medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for medical history, physical exam, and imaging scans

Pre-operative Treatment

Participants take abemaciclib by mouth twice a day for 4.5 days before surgery

4.5 days

Inpatient stay for drug administration

Surgery and Microdialysis

Participants undergo surgery for tumor biopsy or resection, followed by microdialysis catheter placement for 48 hours

4 days

Inpatient stay for surgery and monitoring

Maintenance Therapy

Participants may continue abemaciclib and temozolomide therapy based on PK and PD findings

28-day cycles

Clinic visits every 28 days for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, with ongoing contact for survival

10 years post-enrollment

Follow-up every 6 months

Treatment Details

Interventions

• Abemaciclib

Trial Overview The trial tests if abemaciclib levels can be measured in brain tumors and fluid after intake. It involves taking abemaciclib orally, surgery for tumor biopsy or resection, and cerebral fluid collection via a catheter. If effective, participants may continue treatment with abemaciclib plus temozolomide.

Participant Groups

Group I: 1/Abemaciclib and microdialysis monitoring Experimental Treatment 4 Interventions

Abemaciclib orally BID for 4.5 days followed by resection or biopsy and microdialysis catheter placement with continuous monitoring for 48 hours post-operative and genomic sampling of tissue/blood; followed by abemaciclib+temozolomide maintenance therapy

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Interim results from the MONARCH3 study show that abemaciclib, a CDK4/6 inhibitor, is an effective first-line treatment for advanced ER-positive, HER2-negative breast cancer.

Patients receiving abemaciclib in combination with letrozole experienced significantly improved progression-free survival compared to those receiving a placebo with endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Abemaciclib Effective in ER+ Breast Cancer. [2019]

In a phase 1b study involving 50 patients with advanced non-small cell lung cancer (NSCLC), the combination of abemaciclib and pembrolizumab showed significant toxicity, with 80% of patients in cohort A and 76% in cohort B experiencing severe treatment-emergent adverse events.

Despite some antitumor activity, including a disease control rate of 56% in cohort A and 64% in cohort B, the overall risk-benefit profile of this combination therapy does not support further investigation in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib in Combination With Pembrolizumab for Stage IV KRAS-Mutant or Squamous NSCLC: A Phase 1b Study. Pujol, JL., Vansteenkiste, J., Paz-Ares Rodríguez, L., et al.[2022]

Abemaciclib has demonstrated promising clinical activity in patients with relapsed mesothelioma that is deficient in the p16ink4A protein, suggesting it may be an effective treatment option for this specific cancer type.

The findings indicate a potential new therapeutic avenue for mesothelioma patients, particularly those whose tumors lack the p16ink4A protein, which is often associated with tumor suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDK4/6 Inhibition Shows Clinical Activity in p16ink4A-Deficient Mesothelioma. [2022]

In a phase III trial, abemaciclib combined with endocrine therapy significantly reduced the risk of breast cancer recurrence in patients with hormone receptor positive (HR+), HER2-negative, node-positive early breast cancer, regardless of prior chemotherapy or tumor characteristics.

The combination treatment was generally well-tolerated, with manageable side effects such as diarrhea, infections, and neutropenia, making it a valuable option for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. Fung, S., Blair, HA.[2023]

In patients with hormone receptor-positive, HER2-negative metastatic breast cancer who progressed on palbociclib, those without CDK4/6 inhibitor resistance mutations (CDKi-R[-]) had a median progression-free survival (PFS) of 7.0 months on abemaciclib, compared to just 3.5 months for those with mutations (CDKi-R[+]), indicating that the presence of these mutations significantly impacts treatment efficacy.

This study is the first to identify a genomic panel that may help predict sensitivity to abemaciclib in patients with ESR1 mutations after progression on palbociclib, suggesting that further research could refine this panel to better guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression. Brett, JO., Dubash, TD., Johnson, GN., et al.[2023]

In a study involving 19 children with recurrent BRAFV600E mutant brain tumors, vemurafenib was found to have promising anti-tumor activity, with 1 complete response and 5 partial responses observed among the patients.

The recommended phase 2 dose (RP2D) was established at 550 mg/m2 twice daily, with manageable side effects including rash and fever, indicating that vemurafenib can be safely administered to pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002). Nicolaides, T., Nazemi, KJ., Crawford, J., et al.[2021]

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]

Abemaciclib is an oral medication that inhibits cyclin-dependent kinases 4 and 6, specifically approved in the USA for treating advanced or metastatic breast cancer that is hormone receptor-positive and HER2-negative.

It is effective both as a combination therapy with fulvestrant for patients who have progressed after endocrine therapy and as a standalone treatment for those who have also undergone chemotherapy, highlighting its role in advanced cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: First Global Approval. Kim, ES.[2019]

In a Phase I clinical trial involving 24 patients with brain metastases from breast cancer, the combination of temozolomide and capecitabine demonstrated significant antitumor activity, achieving an 18% objective response rate with 1 complete and 3 partial responses.

The treatment was well-tolerated, with fatigue and nausea being the most common side effects, and it showed potential for maintaining or improving neurocognitive function in patients with stable disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. Rivera, E., Meyers, C., Groves, M., et al.[2018]

The combination of temozolomide and radiation therapy is safe and well tolerated in patients with newly diagnosed glioblastoma, with only mild to moderate nonhematologic toxicities observed during treatment.

Patients treated with this regimen had a median survival of 16 months, with 58% surviving at one year and 31% at two years, indicating that this treatment may effectively prolong survival, especially in younger patients and those who had surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. Stupp, R., Dietrich, PY., Ostermann Kraljevic, S., et al.[2022]

Nuclear Factor I A (NFIA) is significantly upregulated in glioblastoma (GBM) cells that are resistant to temozolomide (TMZ), and its elevated expression is linked to poorer outcomes in glioma patients, particularly those with GBM.

Suppressing NFIA reduces GBM cell proliferation and resistance to TMZ, indicating that targeting the NFIA-NF-kB signaling pathway could be a promising new therapeutic strategy for treating TMZ-resistant GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nuclear factor I A promotes temozolomide resistance in glioblastoma via activation of nuclear factor κB pathway. Yu, X., Wang, M., Zuo, J., 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]

Temodar is a promising new drug for treating brain tumors and other cancers, currently being researched for its effectiveness against solid tumors, glioblastoma multiforme, and metastatic melanoma.

It offers adult patients with anaplastic astrocytoma a convenient treatment option with minimal side effects, providing hope for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temodar offers promise for treating astrocytomas. Armstrong, T., Hancock, C.[2018]

In a phase II clinical trial involving 21 patients with newly diagnosed glioblastoma multiforme (GBM), the combination of temozolomide (TMZ) with radiotherapy resulted in a one-year survival rate of 58% and a median survival time of 15.7 months, indicating its efficacy in extending survival.

The treatment regimen was well-tolerated, with only mild to moderate non-hematological side effects and minimal severe hematological toxicity, suggesting that TMZ has a favorable safety profile compared to traditional chemotherapy agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. Lanzetta, G., Campanella, C., Rozzi, A., et al.[2018]

References

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

First-Line Abemaciclib Effective in ER+ Breast Cancer. [2019]

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

Abemaciclib in Combination With Pembrolizumab for Stage IV KRAS-Mutant or Squamous NSCLC: A Phase 1b Study. [2022]

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

CDK4/6 Inhibition Shows Clinical Activity in p16ink4A-Deficient Mesothelioma. [2022]

4. France pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. [2023]

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

A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression. [2023]

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

Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002). [2021]

7. 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]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Abemaciclib: First Global Approval. [2019]

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

Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. [2018]

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

Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Nuclear factor I A promotes temozolomide resistance in glioblastoma via activation of nuclear factor κB pathway. [2019]

12. 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]

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

Temodar offers promise for treating astrocytomas. [2018]

14. Greece pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. [2018]