Temozolomide + Capecitabine for Pancreatic Cancer

Not currently recruiting at 330 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Eastern Cooperative Oncology Group

Must be taking: Somatostatin analogues

Must not be taking: Temozolomide, Capecitabine, 5-FU, Coumadin

Disqualifiers: Small cell carcinoma, CNS metastases, 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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether temozolomide alone or combined with capecitabine is more effective for treating advanced pancreatic neuroendocrine tumors, a cancer affecting hormone-producing cells in the pancreas. Both drugs are chemotherapy agents designed to stop cancer cells from growing and spreading. Participants should have advanced or metastatic pancreatic neuroendocrine tumors that have worsened in the past year and must not have previously used temozolomide or capecitabine. This study aims to find more effective treatments for this type of cancer. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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

The trial does not specify if you need to stop taking your current medications, but you cannot be on Coumadin (a blood thinner) while on treatment. Other anticoagulants are allowed, and you must have stopped taking everolimus or sunitinib at least 4 weeks before joining the trial.

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

Research has shown that temozolomide is generally well-tolerated by patients. In studies, about 93.8% of patients experienced mild side effects, while 23.7% encountered more serious ones. These findings suggest that temozolomide has a known safety profile when used alone.

For the combination of temozolomide and capecitabine (CAPTEM), research has found it safe and effective for treating advanced neuroendocrine tumors. One study reported that 64% of patients experienced side effects, but the combination showed promise in improving survival rates. This combination has been widely studied, with evidence supporting its use and safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of temozolomide and capecitabine for pancreatic cancer because these drugs introduce a fresh approach to treatment. Unlike traditional options like gemcitabine or FOLFIRINOX, temozolomide is an oral chemotherapy that allows for more convenient dosing. The combination with capecitabine, another oral chemotherapy, provides a dual attack on cancer cells, potentially enhancing effectiveness while maintaining a patient-friendly delivery method. This approach could offer improved outcomes with potentially fewer hospital visits, making it an attractive option for both patients and healthcare providers.

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

Research has shown that using temozolomide and capecitabine together may help treat advanced pancreatic neuroendocrine tumors. In this trial, participants in Arm B will receive this combination, which studies have found can help patients live longer without disease progression. Reports have linked this combination to a high rate of disease control, with effectiveness reaching up to 77%. Meanwhile, participants in Arm A will receive temozolomide alone, which is also effective, with about 41.2% of patients experiencing tumor shrinkage or halted growth. These treatments target tumor cells, either killing them or stopping their growth and spread. ^{3 4 6 7 8}

Who Is on the Research Team?

Pamela Kunz

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for adults with advanced pancreatic neuroendocrine tumors who've had disease progression within the last year. They must have a life expectancy of at least 12 weeks, be able to swallow pills, and tolerate CT/MRI scans. Women of childbearing age must test negative for pregnancy and use contraception; men should also use contraception if their partner could become pregnant.

Inclusion Criteria

Date of last documented disease progression must be within 12 months from date of randomization

I stopped taking everolimus or sunitinib at least 4 weeks ago.

Your hemoglobin level is 9 grams per deciliter or higher.

Exclusion Criteria

Receiving any other investigational agents while on study treatment

I have previously been treated with temozolomide, dacarbazine, capecitabine, or 5-FU.

I am taking Coumadin or another blood thinner.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive temozolomide with or without capecitabine in 28-day cycles for up to 13 courses

12 months

Monthly visits for each treatment cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for 2 years, then every 6 months for 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Capecitabine
• Temozolomide

Trial Overview The study is testing whether temozolomide alone or combined with capecitabine is more effective in stopping tumor growth in patients with advanced pancreatic neuroendocrine tumors. It's a phase II trial where participants are randomly assigned to one of the two treatment groups.

How Is the Trial Designed?

Group I: Arm B (temozolomide and capecitabine) Experimental Treatment 2 Interventions

Patients receive capecitabine PO BID on days 1-14 and temozolomide PO QD on days 10-14. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (temozolomide) Experimental Treatment 1 Intervention

Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.

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?

Eastern Cooperative Oncology Group

Lead Sponsor

Trials

272

Recruited

153,000+

ECOG-ACRIN Cancer Research Group

Lead Sponsor

Trials

122

Recruited

160,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Combining temozolomide (TMZ) with O(6)-benzyl-guanine (BG) enhances the effectiveness of treatment in pancreatic tumors, particularly in cells with functional p53, as shown in studies using human and mouse cell lines.

The presence of p53 not only triggers apoptosis by delaying the cell cycle but also aids in cell death through the activation of mismatch repair mechanisms, indicating a complex role of p53 in the response to chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of cell cycle checkpoints and p53 function on the toxicity of temozolomide in human pancreatic cancer cells. Gupta, S., Sathishkumar, S., Ahmed, MM.[2021]

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]

In a study of 30 patients with metastatic pancreatic endocrine carcinomas, the combination of capecitabine and temozolomide resulted in a remarkable 70% objective response rate and a median progression-free survival of 18 months.

The treatment showed a high two-year survival rate of 92% with only 12% of patients experiencing severe adverse events, indicating a favorable safety profile compared to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Strosberg, JR., Fine, RL., Choi, J., et al.[2022]

A review of 5,127 reports on temozolomide (TMZ) revealed 112 cases of major hematologic adverse events (HAEs), with a significant number of these cases leading to death, highlighting the serious risks associated with this medication.

Aplastic anemia (AA) and leukemia were the most common major HAEs linked to TMZ, indicating a unique toxicity profile compared to other alkylating agents, and suggesting that patients should be informed about these risks, especially since AA can develop after a short duration of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematologic adverse events associated with temozolomide. Villano, JL., Letarte, N., Yu, JM., et al.[2018]

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 oral treatment for malignant gliomas, providing significant survival benefits while being generally well tolerated by patients.

While most side effects of TMZ are mild to moderate, there is a risk of severe hematologic adverse events, such as myelodysplastic syndrome and aplastic anemia, which have been documented in the literature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. Scaringi, C., De Sanctis, V., Minniti, G., et al.[2018]

In a study involving 16 patients with advanced pancreatic adenocarcinoma, oral temozolomide at a dose of 200 mg/m2/day for 5 days showed no effective responses, with all 15 evaluable patients experiencing disease progression within 2 months.

While the treatment was associated with some hematological toxicity, including grade 3 neutropenia and thrombocytopenia in 3 patients, other side effects were relatively mild, indicating that temozolomide is not an effective option for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of temozolomide in advanced untreated pancreatic cancer. Moore, MJ., Feld, R., Hedley, D., et al.[2022]

Temozolomide (TMZ), a treatment for malignant glioma, can lead to therapy-induced myelodysplasia (T-MDS) in patients, with a cumulative dose threshold of approximately 18,000 to 20,000 mg/sq m identified as a risk factor.

Despite its effectiveness, TMZ is considered potentially leukemogenic, similar to other alkylating agents, highlighting the need for careful monitoring during long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced myelodysplasia. Natelson, EA., Pyatt, D.[2020]

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]

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]

Citations

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Randomized Study of Temozolomide or ... The combination of capecitabine/temozolomide was associated with a significant improvement in PFS compared with temozolomide alone in patients ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10860315/

Efficacy and safety of temozolomide-based regimens in ... The quantitative analyses showed a pooled objective response rate (ORR) of 41.2% (95% confidence interval, CI, of 32.4%-50.6%), disease control ...

3. academic.oup.com academic.oup.com/oncolo/article/28/10/875/7263101

Efficacy of Capecitabine and Temozolomide Regimen in ... First-line CAPTEM treatment appeared more effective, with a median PFS of 16.1 months and a median OS of 105.8 months (median PFS 16.1, 7.9, and ...

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Randomized Study of Temozolomide or ... - PubMed 022). In the final analysis (May 2021), the median overall survival was 53.8 months for temozolomide and 58.7 months for capecitabine/ ...

5. nature.com nature.com/articles/s41416-023-02462-0

Phase II study of everolimus and temozolomide as first-line ... The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering ...

6. esmoopen.com esmoopen.com/article/S2059-7029(24)00771-3/fulltext

a multicenter, open-label, single-arm, phase II trial This study shows that metronomic temozolomide has an encouraging efficacy and safety profile as a second-line treatment in poorly differentiated ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2589537022003972

Articles S-1/temozolomide versus ... The results of the phase II STEM trial confirm that S-1 plus temozolomide, with or without thalidomide, is a well-tolerated regimen for patients with ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38347461/

Efficacy and safety of temozolomide-based regimens in ... Regarding safety, the results showed that the pooled rates of nonserious AEs and serious AEs were 93.8% (95% CI of 88.3%-96.8%) and 23.7% (95% ...