Atezolizumab + Chemotherapy for Neuroendocrine Carcinoma

Recruiting at 275 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Glucocorticoids, Immunostimulatory agents

Disqualifiers: Autoimmune disease, Cardiovascular disease, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 21

189 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding atezolizumab, an immunotherapy drug, to standard chemotherapy can more effectively treat poorly differentiated extrapulmonary neuroendocrine cancer. The cancer may have spread from its original site to nearby tissues or other parts of the body. The trial aims to determine if this combination can slow cancer growth more effectively than chemotherapy alone. Individuals with this type of cancer, which cannot be surgically removed or has spread, might be suitable candidates.

As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval. It offers a chance to contribute to potentially groundbreaking advancements in cancer treatment.

Will I have to stop taking my current medications?

The trial requires participants to stop taking denosumab before joining and replace it with a bisphosphonate. If you are on active systemic therapy for another cancer, you may need to stop certain medications, like glucocorticoid-containing regimens, but hormonal therapies like darolutamide can be continued during chemotherapy. The protocol does not specify other medication restrictions, so it's best to discuss your current medications with the trial team.

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

Research has shown that atezolizumab, when combined with chemotherapy drugs like carboplatin or cisplatin and etoposide, is generally safe. Studies have found that patients usually tolerate this combination well. For instance, one study using real-world data confirmed the mix's effectiveness and safety. Another study supported the safety of this treatment in clinical settings.

Atezolizumab alone is also considered safe, with manageable side effects. Additionally, these drugs have been used together in other cancer treatments, suggesting they are recognized as safe in the medical field.

The current trial is in an advanced stage, indicating that earlier phases demonstrated the treatment's safety for testing in a larger group. This trial will closely monitor safety to ensure the treatment remains well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for neuroendocrine carcinoma because they combine the power of immunotherapy with traditional chemotherapy. Atezolizumab is an innovative immunotherapy drug that activates the body's immune system to target cancer cells, which is different from the usual approach of just attacking the cancer cells directly with chemotherapy. This combination aims to enhance the effectiveness of the treatment by not only trying to kill cancer cells with carboplatin, cisplatin, and etoposide but also by boosting the immune response against them. This dual approach could potentially improve outcomes compared to standard chemotherapy alone, making it a promising option for patients with this challenging condition.

What evidence suggests that this trial's treatments could be effective for neuroendocrine carcinoma?

Research shows that adding atezolizumab, a type of immunotherapy, to standard chemotherapy can enhance treatment for some cancers. Studies on extensive-stage small-cell lung cancer have demonstrated that this combination helps patients live longer and achieve better outcomes. In this trial, participants in Arm I and Arm II will receive atezolizumab along with the usual chemotherapy drugs, which include a platinum drug (such as carboplatin or cisplatin) and etoposide. Atezolizumab enables the immune system to find and attack cancer cells more effectively. Although direct data for poorly differentiated extrapulmonary neuroendocrine cancer is limited, positive results in similar cancers suggest potential benefits. Meanwhile, participants in Arm III will receive the chemotherapy regimen without atezolizumab, followed by observation. ^{4 5 6 7 8}

Who Is on the Research Team?

David B Zhen

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic extrapulmonary neuroendocrine carcinoma that's not eligible for surgery. They must have a good performance status, no prior treatments for advanced NEC (except possibly one cycle of specific chemo), and meet certain lab test criteria. People with symptomatic brain metastases, active cancers elsewhere, severe allergies to trial drugs, or certain medical conditions can't join.

Inclusion Criteria

My cancer can be seen and measured on scans according to specific criteria.

You can choose to have your biological samples stored for future research.

I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

Participants must not have history of known severe allergy, anaphylactic, or other hypersensitivity reactions to specific agents

I may have had one round of specific chemotherapy for my advanced cancer, but no other treatments.

I am not currently on treatment for another cancer, with some exceptions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Patients receive atezolizumab, carboplatin or cisplatin, and etoposide. Treatment repeats every 21 days for 4 cycles.

12 weeks

4 visits (in-person)

Maintenance Treatment

Patients receive atezolizumab every 21 days for up to 17 cycles.

51 weeks

17 visits (in-person)

Observation

Patients undergo observation for 1 year.

52 weeks

Regular monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Carboplatin
• Cisplatin
• Etoposide

Trial Overview

The study compares standard chemotherapy (cisplatin/carboplatin and etoposide) alone versus adding the immunotherapy drug Atezolizumab to it in treating poorly differentiated neuroendocrine cancer outside the lung. It also looks at whether continuing Atezolizumab after initial treatment is beneficial.

How Is the Trial Designed?

Group I: Arm II (atezolizumab, platinum drug, etoposide, observation) Experimental Treatment 8 Interventions

During induction phase, patients receive atezolizumab IV over 30-60 minutes on day 1 of each cycle, carboplatin IV over 30 minutes or cisplatin IV over 60 minutes on day 1 of each cycle, and etoposide IV on days 1-3 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo observation for 1 year. Patients also undergo CT scan and/or MRI throughout the trial and blood sample collection on study.

Group II: Arm I (atezolizumab, platinum drug, etoposide) Experimental Treatment 7 Interventions

During induction phase, patients receive atezolizumab IV over 30-60 minutes on day 1 of each cycle, carboplatin IV over 30 minutes or cisplatin IV over 60 minutes on day 1 of each cycle, and etoposide IV on days 1-3 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. During maintenance phase, patients receive atezolizumab IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan and/or MRI throughout the trial and blood sample collection on study.

Group III: Arm III (platinum drug, etoposide, observation) Active Control 7 Interventions

During induction phase, patients receive carboplatin IV over 30 minutes or cisplatin IV over 60 minutes on day 1 of each cycle and etoposide IV on days 1-3 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo observation for 1 year. Patients also undergo CT scan and/or MRI throughout the trial and blood sample collection on study.

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

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

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

This phase II study is the first to evaluate the combination of the anti-PD-1 antibody camrelizumab with standard chemotherapy in patients with advanced gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC), aiming to improve treatment outcomes for this aggressive cancer.

The primary goal of the study is to assess the 6-month progression-free survival rate, which will help determine the effectiveness and safety of this new treatment strategy compared to traditional chemotherapy regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line treatment of camrelizumab combined with chemotherapy in advanced gastroenteropancreatic neuroendocrine carcinoma: Study protocol for a prospective, multicenter, phase II study. Li, X., Ma, Q., Chang, C., et al.[2022]

In a study of 105 patients receiving carboplatin chemotherapy, 30% experienced moderate to severe delayed nausea and vomiting (CINV) after the first treatment cycle, highlighting a significant issue even with standard antiemetic prophylaxis.

The incidence of delayed CINV decreased in subsequent cycles, dropping to around 12.8% to 16% by Cycle 3, indicating that patients may adapt over time, but 20% still required additional antiemetics after Cycle 1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delayed nausea and vomiting from carboplatin doublet chemotherapy. Waqar, SN., Mann, J., Baggstrom, MQ., et al.[2018]

The combination of netupitant and palonosetron (NEPA) effectively prevents chemotherapy-induced nausea and vomiting in patients receiving moderately to highly emetogenic chemotherapy, as shown in clinical trials.

NEPA is well tolerated and offers a convenient single oral capsule option, which may enhance adherence to treatment guidelines for managing chemotherapy-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of oral fixed-dose combination netupitant and palonosetron (NEPA) for the treatment of chemotherapy-induced nausea and vomiting. Lorusso, V., Karthaus, M., Aapro, M.[2018]

In a study involving 30 cancer patients receiving chemotherapy, the antiemetic Alizapride significantly reduced the incidence of severe nausea from 50% to 24% by day 3.

Alizapride also increased the percentage of patients who did not experience vomiting to 77% until day 5, supporting its effectiveness as an antiemetic in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Alizapride in the treatment of vomiting induced by cytostatic agents]. Bierbaum, HG.[2012]

In a phase II trial involving 78 patients with advanced poorly differentiated neuroendocrine carcinomas, the chemotherapy regimen of paclitaxel, carboplatin, and etoposide resulted in a 53% major response rate, with 15% achieving complete responses and some remaining disease-free for up to 66 months.

The treatment demonstrated moderate toxicity, primarily myelosuppression, and showed no significant efficacy advantages over standard platinum/etoposide regimens, suggesting that similar treatment strategies used for small-cell lung cancer may be appropriate for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research Network Study. Hainsworth, JD., Spigel, DR., Litchy, S., et al.[2015]

In a study involving 29 patients with metastatic high-grade neuroendocrine neoplasms (G3NENs), Pembrolizumab showed limited efficacy as only 3.4% of patients had an objective response, and the overall disease control rate was 24.1%.

Pembrolizumab was well tolerated, with only 9 instances of grade 3 adverse events and no grade 4 events, indicating it can be safely administered to this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials. Vijayvergia, N., Dasari, A., Deng, M., et al.[2021]

Immune-checkpoint inhibitors (ICIs) show promising efficacy in treating neuroendocrine neoplasms (NENs), with an overall response rate of 10% and a disease control rate of 42% based on a systematic review of 636 patients.

Combination therapies using ICIs, such as nivolumab + ipilimumab and atezolizumab + bevacizumab, demonstrated superior effectiveness compared to single-agent treatments, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity and Safety of Immune Checkpoint Inhibitors in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis. Bongiovanni, A., Maiorano, BA., Azzali, I., et al.[2021]

In a study of 27 patients with metastatic neuroendocrine carcinomas, both dacarbazine and temozolomide were found to provide a median progression-free survival of 3.0 months after first-line chemotherapy, indicating they can be effective second-line treatments.

Approximately 44% of patients experienced clinical responses and about 33% had morphological responses, with a median overall survival of 7.2 months, while the toxicity levels were consistent with expectations for these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post first-line dacarbazine or temozolomide in neuroendocrine carcinoma. Couronne, T., Girot, P., Hadoux, J., et al.[2022]

In a study of 104 patients with neuroendocrine carcinoma, both carboplatin and etoposide (CE) and cisplatin and etoposide (PE) showed comparable efficacy in terms of response rates and survival times, with no significant differences between the two treatments.

However, the PE group experienced a higher incidence of renal dysfunction compared to the CE group, indicating that while both treatments are effective, CE may be safer regarding kidney health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of efficacy and safety between carboplatin-etoposide and cisplatin-etoposide combination therapy in patients with advanced neuroendocrine carcinoma, retrospective study. Imai, H., Saijo, K., Kawamura, Y., et al.[2023]

Chemotherapy-induced nausea and vomiting (CINV) remains a significant issue, especially with oral antineoplastic agents, where evidence for effective antiemetic regimens is limited and often based on empirical data.

This review highlights the need for standardized antiemetic regimens for oral chemotherapy, proposing specific strategies for managing CINV based on the emetogenic risk of the agents used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of Nausea and Vomiting in Patients Undergoing Oral Anticancer Therapies for Solid Tumors. Costa, AL., Abreu, C., Pacheco, TR., et al.[2018]

In a study involving 413 chemotherapy-naïve patients, NEPA, a combination of netupitant and palonosetron, was found to be safe and well-tolerated, with a low incidence of adverse events such as constipation (3.6%) and headache (1.0%).

NEPA demonstrated high efficacy in preventing chemotherapy-induced nausea and vomiting, achieving a complete response rate of 81% in the first cycle, which was maintained over multiple cycles of highly and moderately emetogenic chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Gralla, RJ., Bosnjak, SM., Hontsa, A., et al.[2023]

Neuroendocrine carcinomas (NECs), particularly extrapulmonary poorly differentiated NECs (EP-PD-NECs), are aggressive tumors with poor prognosis, often treated similarly to small-cell lung cancer using platinum-etoposide as first-line therapy, but second-line treatment options remain unclear.

Recent advancements in understanding the genetic mutations associated with EP-PD-NEC have led to the exploration of targeted therapies and immune checkpoint inhibitors, showing promise in clinical trials, though further research is needed to optimize treatment based on tumor characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future therapeutic strategies in the treatment of extrapulmonary neuroendocrine carcinoma: a review. Robinson, MD., Livesey, D., Hubner, RA., et al.[2023]

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This is a phase IIIB, single-arm, single-country, multicenter study of the safety and efficacy of atezolizumab in combination with carboplatin plus etoposide