Temozolomide + Veliparib for Small Cell Lung Cancer

Not currently recruiting at 17 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: PARP-inhibitors, Temozolomide

Disqualifiers: Leptomeningeal involvement, Active seizures, 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: 8

Duration: 4 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether temozolomide, a drug that damages cancer cell DNA, is more effective alone or with an additional drug, veliparib, which prevents cancer cells from repairing themselves. It focuses on individuals with small cell lung cancer that either returned after treatment or did not respond to previous treatments. Participants must have undergone chemotherapy and still have measurable cancer. This study may suit those whose cancer has returned or worsened despite earlier chemotherapy. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on other investigational agents or certain HIV medications. It's best to discuss your specific medications with the trial team.

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

Research has shown that the combination of temozolomide and veliparib has been tested for safety and tolerability. In earlier studies, most patients managed the treatment well. These studies examined side effects and patient responses to the combination, finding that most side effects were mild to moderate. Common side effects included nausea and low blood cell counts, typical for cancer treatments. This suggests the treatment is generally safe. However, individual experiences can differ, so discussing potential risks with a healthcare provider before joining a trial is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Temozolomide and Veliparib for small cell lung cancer because this combination targets the cancer cells in a unique way. While most treatments for this condition, like chemotherapy, attack rapidly dividing cells in general, Veliparib is a PARP inhibitor that specifically interferes with cancer cells' ability to repair their DNA, making them more vulnerable to Temozolomide, which damages DNA. This combination could potentially enhance the effectiveness of treatment and offer a new option for patients who might not respond well to traditional therapies.

What evidence suggests that this trial's treatments could be effective for small cell lung cancer?

Research has shown that using temozolomide with veliparib may help treat small cell lung cancer that has recurred or isn't responding to other treatments. In this trial, one group of participants will receive the combination of temozolomide and veliparib. Studies have found that patients with certain markers, such as SLFN11, experienced longer periods without cancer progression and improved overall survival when treated with this combination. Temozolomide damages the DNA in cancer cells, which they need to grow. Veliparib inhibits proteins that repair this DNA damage, making the cancer cells more sensitive to temozolomide. This combination targets cancer cells more effectively than temozolomide alone, particularly in patients with specific genetic markers. ^{1 2 4 6 7}

Who Is on the Research Team?

Charles M Rudin

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with small cell lung cancer that has come back or isn't responding to treatment. They should have had one prior chemotherapy and responded for more than 60 days, or not responded well, or need a third-line therapy. Participants must be relatively active (ECOG <=1), may have stable brain metastases, measurable disease on CT scans, adequate blood counts, and normal bilirubin levels.

Inclusion Criteria

My small cell lung cancer diagnosis has been confirmed with lab tests.

I am mostly active and can care for myself.

My cancer did not respond to first-line treatment or worsened quickly after treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive veliparib or placebo with temozolomide in 28-day cycles

4 months

Monthly visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

8-12 weeks

Follow-up visits every 8-12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Temozolomide
• Veliparib

Trial Overview The study is testing the effectiveness of temozolomide alone versus combined with veliparib in treating relapsed/refractory small cell lung cancer. Temozolomide damages DNA inside cancer cells while veliparib blocks proteins needed for DNA repair which might enhance temozolomide's effects.

How Is the Trial Designed?

Group I: Arm I (veliparib and temozolomide) Experimental Treatment 3 Interventions

Patients receive veliparib PO BID on days 1-7 and temozolomide PO on days 1-5.

Group II: Arm II (placebo and temozolomide) Active Control 3 Interventions

Patients receive placebo PO BID on days 1-7 and temozolomide as in Arm I.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 combined with olaparib shows promise as a treatment option for patients with small-cell lung cancer who have progressive disease after standard etoposide and platinum-based therapy.

The study emphasizes the use of co-clinical trials with patient-derived xenografts to enhance biomarker discovery, potentially leading to more personalized and effective treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide plus PARP Inhibition in Small-Cell Lung Cancer: Could Patient-Derived Xenografts Accelerate Discovery of Biomarker Candidates? Pacheco, JM., Byers, LA.[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]

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) has been established as an effective treatment for primary brain tumors like glioblastoma and oligodendroglioma, and it has also shown efficacy in melanoma, with multiple studies supporting its use as both a monotherapy and adjuvant chemotherapy.

Recent clinical trials suggest that TMZ may be beneficial in treating a variety of other cancers, including brain metastases, lymphomas, and neuroendocrine tumors, indicating its potential as a versatile cancer treatment beyond its formal indications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and unusual indications: review of literature. Tatar, Z., Thivat, E., Planchat, E., et al.[2022]

In a phase I trial involving 29 children with recurrent brain tumors, the combination of veliparib and temozolomide was found to be well tolerated, with established recommended phase II doses of 25 mg/m² for veliparib and 135 mg/m² for temozolomide.

While no objective responses were observed, 4 patients maintained stable disease for over 6 months, indicating potential efficacy in this challenging population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: a pediatric brain tumor consortium report. Su, JM., Thompson, P., Adesina, A., et al.[2021]

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 the only anticancer drug proven to improve survival in glioblastoma when used with radiotherapy, showing high concentrations in brain tumors and cerebrospinal fluid, which enhances its effectiveness.

Molecular markers like MGMT promoter methylation can predict better responses to TMZ treatment, but side effects such as myelosuppression and nausea are common, necessitating precautions like prophylaxis against Pneumocystis carinii pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. Shinoura, N., Yamada, R., Tabei, Y., et al.[2018]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6085179/

Randomized, Double-Blind, Phase II Study of ... SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/veliparib, suggesting a promising biomarker of PARP-inhibitor sensitivity in ...

2. ascopubs.org ascopubs.org/doi/abs/10.1200/jco.2018.77.7672

Journal of Clinical Oncology SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/veliparib, suggesting a promising biomarker of PARP- ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01638546

NCT01638546 | Temozolomide With or Without Veliparib in ... This randomized phase II trial studies how well temozolomide with or without veliparib works in treating patients with small cell lung cancer that has ...

4. tlcr.amegroups.org tlcr.amegroups.org/article/view/26238/html

SLFN11 predicts response to veliparib and temozolomide in ... Sleep better on combination therapy: SLFN11 predicts response to veliparib and temozolomide in recurrent small cell lung cancer.

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29906251/

Randomized, Double-Blind, Phase II Study of Temozolomide ... This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS ...

6. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2018.77.7672

Randomized, Double-Blind, Phase II Study of ... Secondary objectives included overall response rate (ORR), overall survival (OS), and safety and tolerability of veliparib with TMZ. Exploratory ...

7. pure.johnshopkins.edu pure.johnshopkins.edu/en/publications/randomized-double-blind-phase-ii-study-of-temozolomide-in-combina

Randomized, double-blind, phase II study of temozolomide ... Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or ...