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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach for treating neuroendocrine tumors (NETs) that have spread and are worsening. It combines temozolomide, a chemotherapy drug that can damage cancer cells, with SurVaxM, a vaccine designed to boost the immune system against these cells. Researchers aim to determine if this combination is more effective than temozolomide alone. This trial may suit individuals with NETs that are worsening despite prior treatment. Participants should have a tumor that tests positive for a protein called survivin. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research shows that the combination of temozolomide and SurVaxM is generally safe and well-tolerated by patients. One study found that patients taking this combination did not experience serious side effects from SurVaxM, meaning it did not cause severe health problems. Another source highlights SurVaxM's strong safety record, allowing patients to maintain their quality of life. This means they can continue daily activities without major disruptions from side effects. Overall, evidence suggests that this treatment combination is safe for use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Temozolomide and SurVaxM because it offers a novel approach to treating cancer. Unlike traditional therapies that primarily target cancer cells directly, SurVaxM works as a vaccine to stimulate the immune system to recognize and attack cancer cells, which could potentially lead to improved control of the disease. Additionally, Temozolomide is a well-known chemotherapy drug that helps in slowing down tumor growth, and when paired with SurVaxM, it may enhance the overall effectiveness of the treatment. This combination aims to provide a more targeted and potentially less toxic treatment option compared to standard chemotherapies.

What evidence suggests that temozolomide combined with SurVaxM might be an effective treatment for metastatic neuroendocrine tumors?

Research has shown that using temozolomide with the SurVaxM vaccine, the combination studied in this trial, may help treat worsening metastatic neuroendocrine tumors. In a past study with this combination, patients lived without their cancer worsening for an average of 11.4 months and lived overall for an average of 25.9 months. Additionally, 95.2% of patients did not experience cancer progression six months after diagnosis. Temozolomide damages the DNA of cancer cells, while SurVaxM helps the immune system attack cancer cells with a protein called survivin, often found in these tumors. Together, these treatments might improve tumor control. ^{3 6 7 8 9}

Who Is on the Research Team?

Renuka V. Iyer

Principal Investigator

Roswell Park Cancer Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: (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.

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

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 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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9995096/

Phase IIa Study of SurVaxM Plus Adjuvant Temozolomide ... Measured from first SurVaxM dose, median progression-free survival was 11.4 months and median overall survival was 25.9 months. Patients ...

2. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.22.00996

Phase IIa Study of SurVaxM Plus Adjuvant Temozolomide ... Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point) ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11275351/

Temozolomide (TMZ) in the Treatment of Glioblastoma ... Prolonged TMZ therapy (>6 cycles) may result in improved survival of patients with GBM without increasing the frequency of hematologic side ...

4. ecog-acrin.org ecog-acrin.org/press-release-adding-the-chemotherapy-pill-temozolomide-to-radiation-therapy-improves-survival-in-adult-patients-with-glioma-a-slow-growing-type-of-brain-cancer/

Clinical trial finds that adding the chemotherapy pill ... “We found that the 10-year survival rate was 70% with the combined treatment with temozolomide chemotherapy and radiation, compared to 47% with ...

5. physicianresources.roswellpark.org physicianresources.roswellpark.org/news/roswell-park-announces-positive-progress-in-clinical-trial-of-novel-immunotherapy-survaxm

Roswell Park Announces Positive Progress in Clinical ... “SurVaxM continues to show promise as a treatment option for patients with glioblastoma when paired with standard-of-care chemotherapy and ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36521103/

Phase IIa Study of SurVaxM Plus Adjuvant Temozolomide for ... Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point) ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.22.00996

Phase IIa Study of SurVaxM Plus Adjuvant Temozolomide ... Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point) ...

8. appliedclinicaltrialsonline.com appliedclinicaltrialsonline.com/view/survaxm-promise-glioblastoma-survive-trial

SurVaxM Shows Continued Promise in Glioblastoma as ... Results from the study, shared by Roswell Park in December 2022, demonstrated that 60 of 63 evaluable patients were progression-free six months ...

9. mimivax.com mimivax.com/wp-content/uploads/2022/06/Ciesielski-ASCO-2022_Final.pdf

Final data from the Phase 2a single arm trial of SurVaxM ... Immunological responses to SurVaxM were also assessed. RESULTS: SurVaxM plus TMZ was well-tolerated with no serious adverse events attributable to SurVaxM.