PCI-24781 + Temozolomide for Recurrent Brain Cancer

Overseen By Michaela K Savine, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Nebraska

Must not be taking: Enzyme-inducing antiepileptics, Valproic acid

Disqualifiers: Cardiovascular disease, Active malignancy, HIV, others

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

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

Compensation: Varies

Number of Visits: 28

Duration: Up to 25 months

24 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications, including some antiepileptic drugs and specific medications like amiodarone, clarithromycin, and methadone, among others. If you are on these medications, you must discontinue or switch them before enrolling in the study.

What data supports the effectiveness of the drug temozolomide for recurrent brain cancer?

Temozolomide has shown effectiveness in treating various types of brain tumors, including glioblastoma multiforme and anaplastic astrocytoma, and is being studied for other brain cancers. It is known for its ability to treat malignant gliomas and has been used successfully in combination with other treatments. ^{1 2 3 4 5}

Is the combination of PCI-24781 and Temozolomide safe for humans?

Temozolomide has been shown to have mild to moderate side effects like fatigue, nausea, and low blood cell counts, with severe effects being rare. Safety data for PCI-24781 specifically is not provided, but Temozolomide's safety profile is generally acceptable in humans. ^{1 6 7 8 9}

What makes the drug Temozolomide unique for treating recurrent brain cancer?

Temozolomide is unique because it is an alkylating agent that works by adding a chemical group to the DNA of cancer cells, which can help stop their growth. It has shown effectiveness in treating various types of brain tumors, including gliomas and pituitary carcinomas, and is often used when other treatments have failed. ^{1 3 10 11 12}

What is the purpose of this trial?

Glioblastoma (GBM), WHO grade IV glioma, represents the majority of adult malignant primary brain tumors, with an incidence of 2-3 per 100,000 person-years. The survival for GBM has increased in the last decade but is still low with a median survival of 15-18 months. Recurrence after initial standard therapy, radiation therapy and chemotherapy with temozolomide, few options are available. Even with further therapy, median progression free survival at 6 months after first relapse (PFS-6) is only 15%. Similarly, anaplastic astrocytoma and anaplastic oligodendroglioma, grade III gliomas, once recurrent after radiation therapy and first-line chemotherapy, have identical therapeutic options and poor outcomes with PFS-6 of 31%. Temozolomide (TMZ) has a favorable side effect profile and is available orally, however, cytotoxicity occurs. Metronomic temozolomide at low doses on a continuous schedule, have demonstrated better survival in studies. This study will determine the recommended dose and the side effects of PCI-24781/Abexinostat with metronomic temozolomide.

Research Team

Nicole A Shonka, MD

Principal Investigator

University of Nebraska

Eligibility Criteria

This trial is for adults over 19 with recurrent high-grade glioma who've had prior radiation and temozolomide treatment. They must have good liver, kidney, and bone marrow function, not be pregnant or nursing, and agree to use birth control. Excluded are those with certain heart conditions, other active cancers (except some skin/prostate), specific infections or systemic illnesses that could affect safety.

Inclusion Criteria

I have recovered from side effects of previous cancer treatments.

I've had radiation and temozolomide treatment for my cancer.

I am 19 years old or older.

Exclusion Criteria

Baseline ECG showing QTc interval prolongation

I have recently used specific medications or therapies.

Lactating or pregnant

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive PCI-24781/Abexinostat and metronomic temozolomide in 28-day cycles until disease progression or intolerance

Up to 25 months

Regular visits every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

Extension

Participants with stable or responsive disease may continue therapy until intolerance or progressive disease

Long-term

Treatment Details

Interventions

• PCI 24781
• Temozolomide

Trial Overview The study tests the combination of a drug called PCI-24781 with low-dose Temozolomide in patients whose brain cancer has returned. It aims to find the safest dose of this combo and assess its side effects in treating high-grade gliomas like astrocytoma or glioblastoma.

Participant Groups

Group I: Single arm Experimental Treatment 2 Interventions

Participants will receive a combination of PCI-24781/Abexinostat and temozolomide: loading dose of PCI-24781/Abexinostat prior to the start of Cycle 1, PCI-24781/Abexinostat by mouth twice a day starting 7 days prior to Cycle 1, Day 1 and ending 4 days prior to Cycle 1, Day 1. Participants will continue taking PCI-24781/Abexinostat on days 1 - 4, 8 - 11, and 15 - 18 of each 28 day cycle, starting with Cycle 1, Day 1. The initial dose level is 60 mg of PCI-2478/Abexinostat by mouth twice daily. The dose level may be escalated based on results of interim data analysis. Participants will additionally initiate metronomic temozolomide on Cycle 1, Day 1 at a dose of 50 mg/m2, taken by mouth twice daily and continue the PCI-24781/Abexinostat and metronomic temozolomide regimen until disease progression or intolerance.

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

Approved in European Union as Temodal for:

• Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment
• Children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy

Approved in United States as Temodar for:

• Newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment
• Newly diagnosed or refractory anaplastic astrocytoma

Who Is Running the Clinical Trial?

University of Nebraska

Lead Sponsor

Trials

563

Recruited

1,147,000+

Xynomic Pharmaceuticals, Inc.

Industry Sponsor

Trials

11

Recruited

1,200+

Findings from Research

In a phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., et al.[2022]

In a study involving 831 patients across 21 French hospitals, temozolomide (TMZ) prescriptions were found to conform to the French summary of product characteristics (SPC) in 51.9% of cases, indicating a moderate level of adherence to official guidelines.

The study revealed high conformity (91.5%) to the prescription guidebook, with specific adherence rates of 62% for newly diagnosed glioblastoma patients receiving combined treatment with radiotherapy, 72% for maintenance therapy, and 66% for patients with progressive disease, highlighting the overall compliance in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter prospective observational study of the conformity of temozolomide prescriptions in France. Tilleul, P., Brignone, M., Hassani, Y., et al.[2018]

In a phase II trial involving 38 patients with recurrent oligodendroglial tumors, temozolomide (TMZ) demonstrated a high response rate, with 52.6% of patients showing a complete or partial response, indicating its efficacy as a first-line chemotherapy.

TMZ was generally well tolerated, with hematologic side effects being the most common, and only one patient discontinuing treatment due to toxicity, suggesting a favorable safety profile for chemotherapy-naive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. van den Bent, MJ., Taphoorn, MJ., Brandes, AA., et al.[2022]

Temozolomide (TMZ) is shown to be more cost-effective than the traditional PCV treatment for glioblastoma multiforme (GBM), with costs of €2367 per extra life-month and €32,471 per quality-adjusted life-year (QALY).

The analysis indicates that TMZ has a high probability (over 60%) of being the most cost-effective treatment option at various willingness-to-pay thresholds, especially when considering quality of life improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic evaluation of temozolomide in the treatment of recurrent glioblastoma multiforme. Martikainen, JA., Kivioja, A., Hallinen, T., et al.[2018]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

The study confirmed that the generic temozolomide capsules (TOZ039) are bioequivalent to the brand Temodal® capsules, with pharmacokinetic parameters falling within the acceptable range for both 20-mg and 100-mg doses in 29 patients with brain tumors.

The treatment was found to be safe, with no treatment-related severe adverse events or mortality reported, although 82.8% of patients experienced some adverse effects, highlighting the importance of monitoring patient responses during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. Hu, C., Lin, Q., Liu, C., et al.[2021]

Temozolomide (TMZ) is an effective DNA-methylating agent with nearly 100% oral bioavailability, allowing it to cross the blood-brain barrier and be rapidly absorbed, making it a promising treatment for brain tumors.

While TMZ shows limited effectiveness against pediatric brain tumors on its own, combining it with other treatments and assessing the methylation status of specific genes may enhance its efficacy and should be explored in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of temozolomide in pediatric brain tumors. Barone, G., Maurizi, P., Tamburrini, G., et al.[2022]

In a retrospective study of 117 adult patients with recurrent gliomas treated with temozolomide (TMZ) under a compassionate use program, the overall objective response rate was 29%, with 34% achieving disease stabilization, indicating that TMZ is effective in this setting.

The treatment was generally well-tolerated, with mild toxicity; however, thrombocytopenia was the most common serious side effect, occurring in 17% of patients, particularly at higher starting doses, highlighting the importance of monitoring for adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide for the treatment of recurrent supratentorial glioma: results of a compassionate use program in Belgium. Everaert, E., Neyns, B., Joosens, E., et al.[2022]

Temozolomide (TMZ) is generally safe with mild to moderate side effects, but this case report highlights a rare instance of severe aplastic anemia (AA) in a 68-year-old female patient following treatment for glioblastoma, indicating a potential serious risk associated with the drug.

The patient's AA was managed successfully with supportive care, including platelet transfusions and growth factor treatment, and her blood counts returned to normal within 38 days, emphasizing the importance of monitoring blood parameters during and after TMZ treatment to detect such rare toxicities early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. Gilbar, PJ., Pokharel, K., Mangos, HM.[2022]

Temozolomide (TMZ) was effective in treating a 42-year-old man with an aggressive ACTH-secreting pituitary carcinoma, leading to over a 90% reduction in tumor size after four cycles of treatment.

The treatment was well tolerated overall, with only a temporary severe drop in platelet count (grade 4 thrombocytopenia), and the patient has remained alive 17 months after starting TMZ therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced shrinkage of a pituitary carcinoma causing Cushing's disease--report of a case and literature review. Curtò, L., Torre, ML., Ferraù, F., et al.[2021]

In a study of 32 patients with recurrent high-grade gliomas who had previously failed PCV chemotherapy, temozolomide showed limited efficacy as a second-line treatment, with only 7 patients experiencing clinical improvement.

The median survival for patients treated with temozolomide was 4 months, and 28% were alive at 6 months, indicating that while it may provide some benefit, the overall response rate was low and not influenced by factors like age or previous treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide as second-line chemotherapy for relapsed gliomas. Trent, S., Kong, A., Short, SC., et al.[2019]

The TMZ-resistant glioma cell line SF188/TR showed a 6-fold resistance to temozolomide and cross-resistance to various other anticancer agents, indicating a significant challenge in treating resistant tumors.

Increased activity of the enzyme alkylguanine alkyltransferase (AGT) was identified as a primary mechanism of resistance to TMZ, while changes in the balance of pro-apoptotic and anti-apoptotic proteins contributed to broader cross-resistance to other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Ma, J., Murphy, M., O'Dwyer, PJ., et al.[2022]

References

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

Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]

2. England pubmed.ncbi.nlm.nih.gov

A multicenter prospective observational study of the conformity of temozolomide prescriptions in France. [2018]

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

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. [2022]

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

Economic evaluation of temozolomide in the treatment of recurrent glioblastoma multiforme. [2018]

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

Future directions for temozolomide therapy. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Role of temozolomide in pediatric brain tumors. [2022]

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

Temozolomide for the treatment of recurrent supratentorial glioma: results of a compassionate use program in Belgium. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. [2022]

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

Temozolomide-induced shrinkage of a pituitary carcinoma causing Cushing's disease--report of a case and literature review. [2021]

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

Temozolomide as second-line chemotherapy for relapsed gliomas. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. [2022]