Atezolizumab + Chemotherapy for Neuroendocrine Carcinoma

Recruiting in Palo Alto (17 mi)

+244 other locations

Overseen by David B Zhen

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Glucocorticoids, Immunostimulatory agents

Disqualifiers: Autoimmune disease, Cardiovascular disease, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new treatment combining an immune-boosting drug with standard chemotherapy for patients with a specific type of aggressive cancer that has spread. The goal is to help the immune system fight the cancer and use chemotherapy to kill cancer cells.

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.

What data supports the effectiveness of the drug combination Atezolizumab, Carboplatin, Cisplatin, and Etoposide for treating neuroendocrine carcinoma?

Research shows that immune checkpoint inhibitors like Atezolizumab, when combined with chemotherapy drugs such as Carboplatin and Etoposide, have shown promising results in treating neuroendocrine neoplasms, with combination regimens generally performing better than single-drug treatments. ^{1 2 3 4 5}

Is the combination of Atezolizumab and chemotherapy safe for humans?

The research highlights that chemotherapy drugs like carboplatin and cisplatin can cause nausea and vomiting, which are common side effects. However, these side effects can be managed with antiemetic (anti-nausea) medications, suggesting that while the treatment has side effects, they are generally manageable. ^{6 7 8 9 10}

How is the drug Atezolizumab + Chemotherapy unique for treating neuroendocrine carcinoma?

This treatment combines Atezolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with chemotherapy drugs like Carboplatin, Cisplatin, and Etoposide, which are standard for neuroendocrine carcinoma. The combination aims to enhance the effectiveness of chemotherapy by also engaging the immune system, offering a novel approach compared to traditional chemotherapy alone. ^{1 2 3 11 12}

Research Team

David B Zhen

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

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 am 18 years old or older.

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.

Trial Timeline

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

Treatment Details

Interventions

• Atezolizumab (Monoclonal Antibodies)
• Carboplatin (Alkylating agents)
• Cisplatin (Alkylating agents)
• Etoposide (Anti-tumor antibiotic)

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.

Participant Groups

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.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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 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 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]

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]

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]

References

1. United States 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. [2015]

2. England pubmed.ncbi.nlm.nih.gov

Future therapeutic strategies in the treatment of extrapulmonary neuroendocrine carcinoma: a review. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Activity and Safety of Immune Checkpoint Inhibitors in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis. [2021]

4. Switzerland 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. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Post first-line dacarbazine or temozolomide in neuroendocrine carcinoma. [2022]

6. England 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. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Delayed nausea and vomiting from carboplatin doublet chemotherapy. [2018]

8. England pubmed.ncbi.nlm.nih.gov

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

9. Germany pubmed.ncbi.nlm.nih.gov

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

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

Prevention of Nausea and Vomiting in Patients Undergoing Oral Anticancer Therapies for Solid Tumors. [2018]

11. Switzerland 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. [2023]

12. England 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. [2021]