Temozolomide + SurVaxM for Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Roswell Park Cancer Institute

Must be taking: Somatostatin analogues

Must not be taking: Checkpoint inhibitors, Corticosteroids

Disqualifiers: Autoimmune disorder, HIV, Uncontrolled illness, 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

Compensation: Varies

Number of Visits: 29

Duration: Up to 1 year

132 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial allows patients to continue taking somatostatin analogues (SSA) while on study treatment. However, the protocol does not specify about other medications, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug Temozolomide in treating cancer?

Temozolomide has shown effectiveness in treating various types of brain tumors, such as gliomas and glioblastoma, and is being studied for other cancers like melanoma and mycosis fungoides. Its ability to damage cancer cell DNA makes it a promising option, especially in cases where the cancer cells have low levels of certain repair proteins. ^{1 2 3 4 5}

Is the combination of Temozolomide and SurVaxM generally safe for humans?

Temozolomide is generally well tolerated and safe, with common side effects like fatigue, nausea, and mild blood-related issues. However, severe blood-related problems like aplastic anemia have been rarely reported. ^{5 6 7 8 9}

What makes the drug Temozolomide + SurVaxM unique for cancer treatment?

Temozolomide is unique because it is an oral drug that can cross the blood-brain barrier, making it effective for brain tumors like glioblastoma, and it has a favorable safety profile compared to older treatments. SurVaxM is a novel cancer vaccine that targets survivin, a protein that helps cancer cells survive, potentially enhancing the effectiveness of Temozolomide. ^{3 5 8 10 11}

What is the purpose of this trial?

This phase II trial compares the safety and effect of temozolomide combined with survivin long peptide vaccine (SurVaxM) to temozolomide alone in patients with neuroendocrine tumors (NET) that has spread from where it first started (primary site) to other places in the body (metastatic) and is growing, spreading or getting worse (progressing). Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid and may kill tumor cells and slow down or stop tumor growth. Survivin, a protein, is expressed in 50% of patients that have neuroendocrine tumors and, is associated with poor outcomes. SVN53-67/M57-KLH peptide vaccine (SurVaxM) is a vaccine that has been shown to produce an immune system response against cancer cells that express a survivin and may block the growth of new tumor cells. Giving temozolomide with SurVaxM may kill more tumor cells in patients with progressing metastatic neuroendocrine tumors.

Research Team

Renuka V. Iyer

Principal Investigator

Roswell Park Cancer Institute

Eligibility Criteria

This trial is for patients with neuroendocrine tumors that have spread and are worsening. Participants should not have had prior treatment with temozolomide or the vaccine being tested, and must be able to undergo MRI or CT scans.

Inclusion Criteria

Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (obtained within 14 days prior to enrollment)

I can take care of myself with little help.

My neuroendocrine tumor tissue tests positive for survivin.

Exclusion Criteria

I have previously been treated with SurVaxM.

I am currently pregnant or breastfeeding.

I do not have any serious illnesses that my doctor thinks could make this treatment unsafe for me.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive temozolomide orally once daily on days 1-5. Treatment repeats every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients also receive SurVaxM with montanide ISA-51 subcutaneously and sargramostim subcutaneously once every 2 weeks for 4 doses.

Up to 1 year

Every 28 days, with additional visits every 2 weeks for SurVaxM administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days post-treatment.

4 weeks

1 visit (in-person) at 30 days post-treatment

Extension

Patients with clinical benefit after 4 doses of SurVaxM and remain free of tumor progression and unacceptable toxicity may receive 3 additional doses on weeks 24, 36, and 48.

Additional doses at weeks 24, 36, and 48

Treatment Details

Interventions

• SurVaxM
• Temozolomide

Trial Overview The study is testing if combining a drug called temozolomide with a new vaccine (SurVaxM) is more effective than using temozolomide alone in treating spreading neuroendocrine tumors. Patients will receive both treatments or just the drug.

Participant Groups

Group I: PART 1 (temozolomide, SurVaxM) Experimental Treatment 7 Interventions

Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity and can be continued at investigators discretion at end of treatment. Patients also receive SurVaxM with montanide ISA-51 SC and sargramostim SC once every 2 weeks for 4 doses. Patients with clinical benefit after 4 doses of SurVaxM and remain free of tumor progression and unacceptable toxicity may receive 3 additional doses on weeks 24, 36, and 48. Additionally, patients undergo blood sample collection, CT scans or MRI scans throughout study.

Group II: ARM II (temozolomide, SurVaxM) Experimental Treatment 7 Interventions

Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days until disease progression or unacceptable toxicity and can be continued at investigators discretion at end of treatment. Patients also receive SurVaxM with Montanide ISA-51 SC and sargramostim SC once every 2 weeks for 4 doses. Patients with clinical benefit after 4 doses of SurVaxM and remain free of tumor progression and unacceptable toxicity may receive 3 additional doses on weeks 24, 36, and 48. Additionally, patients undergo blood sample collection, CT scans or MRI scans throughout study.

Group III: ARM I (temozolomide) Experimental Treatment 4 Interventions

Patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days until disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT scans or MRI scans throughout study.

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

Approved in United States as SurVaxM for:

• None approved yet; under investigation for glioblastoma, malignant gliomas, neuroendocrine tumors, multiple myeloma, medulloblastoma, high-grade glioma, ependymoma, and diffuse intrinsic pontine glioma

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

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]

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 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]

Temozolomide (TMZ) is an effective oral anticancer drug for treating newly diagnosed glioblastoma and shows comparable efficacy to dacarbazine for metastatic melanoma, making it a promising option for various cancers.

Resistance to TMZ is a common challenge that limits its effectiveness, prompting ongoing research into combination therapies with DNA repair inhibitors and other treatments to enhance its efficacy and overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent approaches to improve the antitumor efficacy of temozolomide. Tentori, L., Graziani, G.[2019]

In a phase II trial involving 26 patients with advanced mycosis fungoides/Sézary syndrome, temozolomide (TMZ) showed an overall response rate of 27%, with 8% achieving complete remission and 19% partial remission, indicating its potential efficacy in this patient population.

Despite the low levels of MGMT in malignant CD4(+) T cells, which suggested sensitivity to TMZ, the study found that pretreatment levels of MGMT and mismatch repair proteins did not predict treatment response, indicating that other resistance mechanisms may be at play.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins. Querfeld, C., Rosen, ST., Guitart, J., et al.[2021]

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]

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]

In a phase I trial involving 38 patients with advanced solid tumors, the combination of intravenous methoxyamine (MX) and oral temozolomide (TMZ) was found to be safe, with no dose-limiting toxicities observed, allowing for a maximum tolerated dose of TMZ at 200 mg/m² daily for 5 days alongside MX at 150 mg/m² on day 1.

The trial showed that while there were some grade 3 and 4 adverse events, the combination therapy resulted in a partial response in one patient and prolonged stable disease in six others, suggesting potential efficacy in certain tumor types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors. Eads, JR., Krishnamurthi, SS., Saltzman, J., et al.[2022]

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]

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 a promising drug for combination therapies due to its ability to cross the blood-brain barrier, good safety profile, and effectiveness against solid tumors like malignant glioma, especially when combined with carmustine or irinotecan.

Studies indicate that administering carmustine before temozolomide results in lower toxicity and a higher maximum tolerated dose, while the combination of temozolomide followed by irinotecan shows greater effectiveness than either drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with other cytotoxic agents. Prados, M.[2019]

References

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

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

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

Future directions for temozolomide therapy. [2019]

3. 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]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Recent approaches to improve the antitumor efficacy of temozolomide. [2019]

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

Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins. [2021]

6. England pubmed.ncbi.nlm.nih.gov

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

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

Hematologic adverse events associated with temozolomide. [2018]

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

Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. [2018]

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

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

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

Temozolomide in combination with other cytotoxic agents. [2019]