Immunotherapy +/− Targeted Therapy for Nasopharyngeal Cancer

Recruiting at 92 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticoagulants, Immunosuppressants

Disqualifiers: Autoimmune diseases, Active tumor bleeding, 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: 8

Duration: Up to 2 years

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests how well nivolumab and ipilimumab immunotherapy with or without cabozantinib works in treating patients with nasopharyngeal cancer that has come back (after a period of improvement) (recurrent), has spread from where it first started (primary site) to other places in the body (metastatic), or for which no treatment is currently available (incurable). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving immunotherapy with nivolumab and ipilimumab and targeted therapy with cabozantinib may help shrink and stabilize nasopharyngeal cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does prohibit certain medications like strong inhibitors or inducers of CYP3A4 and some anticoagulants. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination of Immunotherapy and Targeted Therapy for Nasopharyngeal Cancer?

While there is no direct data on the specific combination of Cabozantinib, Ipilimumab, and Nivolumab for nasopharyngeal cancer, similar treatments have shown promise. For example, Camrelizumab combined with apatinib, another immunotherapy and targeted therapy combination, showed promising results in patients with resistant nasopharyngeal cancer, with a significant portion of patients responding to the treatment. ^{1 2 3 4 5}

Is the combination of immunotherapy and targeted therapy safe for nasopharyngeal cancer?

The combination of immunotherapy drugs like nivolumab and targeted therapies has shown a manageable safety profile in clinical trials for nasopharyngeal cancer. Common side effects include mild to moderate issues like high blood pressure and skin reactions, but serious side effects are less common. Overall, these treatments are generally considered safe for use in humans. ^{1 4 6 7 8}

How is the drug combination of Cabozantinib S-malate, Ipilimumab, and Nivolumab unique for nasopharyngeal cancer?

This drug combination is unique because it combines immunotherapy (Ipilimumab and Nivolumab) with targeted therapy (Cabozantinib S-malate), which may offer a novel approach by enhancing the immune system's ability to fight cancer while also targeting specific cancer cell pathways, unlike traditional chemotherapy that is commonly used for nasopharyngeal cancer. ^{1 2 4 9 10}

Research Team

Glenn J. Hanna, MD

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

Adults (18+) with nasopharyngeal cancer that's returned, spread, or is incurable can join. They should have had no more than two prior treatments and not been on VEGFR targeted therapy. A good performance status (ECOG 0-2) and certain blood counts are required. The cancer must be measurable by scans or physical exam.

Inclusion Criteria

My eligibility is not affected by my smoking history or specific cancer markers.

I haven't taken steroids or immunosuppressants in the last 14 days.

I have a tumor that can be measured and hasn't been treated with radiation.

Exclusion Criteria

My tumor is not currently bleeding.

I haven't had any cancer except for skin cancer in the last 5 years.

I have a history of cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab and ipilimumab with or without cabozantinib. Cycles repeat every 28 days for up to 2 years.

Up to 2 years

Monthly visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 8-12 weeks until disease progression or new therapy, then every 6 months for up to 2 years.

Up to 2 years

Regular follow-up visits every 8-12 weeks, then every 6 months

Treatment Details

Interventions

• Cabozantinib S-malate
• Ipilimumab
• Nivolumab

Trial Overview The trial tests nivolumab and ipilimumab immunotherapy combined with cabozantinib against the same immunotherapy without cabozantinib to see if it helps control nasopharyngeal cancer better. These drugs may boost the immune system to fight cancer and block proteins that help cancer grow.

Participant Groups

Group I: Arm B (nivolumab, ipilimumab, cabozantinib) Experimental Treatment 6 Interventions

Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1 and cabozantinib S-malate PO daily on days 1-28 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients may continue with cabozantinib S-malate after 2 years per treating investigator. Patients undergo CT or MRI and collection of blood samples throughout the trial.

Group II: Arm A (nivolumab, ipilimumab) Active Control 5 Interventions

Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI and collection of blood samples throughout the trial.

Cabozantinib S-malate is already approved in United States, European Union for the following indications:

Approved in United States as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Approved in United States as Cometriq for:

• Medullary thyroid cancer

Approved in European Union as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Camrelizumab, an anti-PD-1 antibody, shows promising safety and preliminary antitumor activity as a second-line treatment for recurrent or metastatic nasopharyngeal carcinoma, with 34% of patients responding to monotherapy and 91% responding when combined with gemcitabine and cisplatin.

The combination therapy had a manageable toxicity profile, with 87% of patients experiencing grade 3 or 4 adverse events, but no treatment-related deaths, indicating that camrelizumab could be a viable option for treatment-naive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Fang, W., Yang, Y., Ma, Y., et al.[2022]

In a study of 70 patients with recurrent or metastatic nasopharyngeal carcinoma, those treated with nimotuzumab (NTZ) plus chemotherapy had a significantly longer overall survival (48.6 months) compared to those receiving chemotherapy alone (25.6 months).

The addition of NTZ did not increase the toxicity of treatment, indicating that it is a safe and effective option for improving survival in patients with this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nimotuzumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone in patients with recurrent or metastatic nasopharyngeal carcinoma. Zhu, Y., Yang, S., Zhou, S., et al.[2022]

Nimotuzumab, an anti-EGFR monoclonal antibody, shows promise in improving outcomes for patients with nasopharyngeal carcinoma (NPC), which often has high EGFR expression associated with poor prognosis.

Combining nimotuzumab with induction chemotherapy, radiotherapy, or concurrent chemoradiotherapy has been shown to provide benefits for NPC patients, with manageable side effects reported in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nimotuzumab, an Anti-EGFR Monoclonal Antibody, in the Treatment of Nasopharyngeal Carcinoma. Liang, R., Yang, L., Zhu, X.[2021]

In a phase 2 trial involving 72 patients with refractory recurrent/metastatic nasopharyngeal carcinoma, the combination of camrelizumab and apatinib achieved an objective response rate of 65% in platinum-resistant patients and 34.3% in PD-1 inhibitor resistant patients, indicating promising efficacy.

The treatment was associated with a significant incidence of grade ≥ 3 treatment-related adverse events in 65.3% of patients, highlighting the need for careful monitoring of safety while also suggesting that high expression of certain biomarkers, like PD-L1 and B-cell-related genes, may predict better responses to the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Camrelizumab combined with apatinib in patients with first-line platinum-resistant or PD-1 inhibitor resistant recurrent/metastatic nasopharyngeal carcinoma: a single-arm, phase 2 trial. Yuan, L., Jia, GD., Lv, XF., et al.[2023]

In a study of 38 patients with advanced nasopharyngeal carcinoma, the combination of nimotuzumab and intensity-modulated radiotherapy (IMRT) resulted in high 3-year survival rates, including 92.8% for local recurrence-free survival and 87.5% for overall survival, indicating effective treatment outcomes.

The treatment was well-tolerated, with a notable absence of severe skin rash or infusion reactions, which are common with other similar therapies, and only 36.8% of patients experienced grade 3 radiation-induced mucositis, suggesting nimotuzumab does not significantly increase radiation-related toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience with combination of nimotuzumab and intensity-modulated radiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. Zhai, RP., Ying, HM., Kong, FF., et al.[2022]

In a comparison of anti-PD-1 drugs for recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), camrelizumab showed the highest objective response rate (34.1%) among second-line therapies, while first-line nivolumab achieved a 40% response rate, indicating its effectiveness in treating this cancer.

Nivolumab and pembrolizumab demonstrated the best safety profiles for managing adverse events, particularly for lower-grade side effects, while camrelizumab combined with chemotherapy resulted in a significantly higher response rate (90.9%) compared to chemotherapy alone (64.1%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from recent advances in landmark trials. Lv, JW., Li, JY., Luo, LN., et al.[2020]

In a phase II clinical trial involving 51 patients with relapsed and refractory nasopharyngeal carcinoma, apatinib demonstrated an overall response rate of 31.37%, indicating its potential effectiveness in treating this type of cancer.

The treatment was generally well-tolerated, with most adverse events being mild to moderate, including hypertension and proteinuria, and there were no treatment-related deaths, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apatinib, a novel VEGFR-2 tyrosine kinase inhibitor, for relapsed and refractory nasopharyngeal carcinoma: data from an open-label, single-arm, exploratory study. Li, L., Kong, F., Zhang, L., et al.[2023]

In a phase II study involving 36 patients with recurrent or metastatic nasopharyngeal carcinoma (NPC), the combination of nivolumab and gemcitabine demonstrated a promising objective response rate of 36.1% and a high disease control rate of 97.2%.

The treatment showed a median progression-free survival of 13.8 months with manageable safety, as only 2.8% of patients experienced grade ≥3 treatment-related adverse events like hypertension and anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Nivolumab plus Gemcitabine in Patients with Recurrent or Metastatic Nasopharyngeal Carcinoma (KCSG HN17-11). Jung, HA., Park, KU., Cho, S., et al.[2022]

In a study of 26 nasopharyngeal carcinoma (NPC) cases, PD-L1 was expressed in 46.2% of cases, and its expression was significantly associated with advanced tumor stages, indicating it may serve as a prognostic marker.

CTLA-4 was found in 88.4% of NPC cases and its high expression correlated with worse overall survival and disease progression, suggesting that targeting both PD-L1 and CTLA-4 could be a promising immunotherapy approach for NPC, particularly in EBV-associated cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of Immune Checkpoint Regulators, Cytotoxic T-Lymphocyte Antigen-4, and Programmed Death-Ligand 1 in Epstein-Barr Virus-associated Nasopharyngeal Carcinoma. Ahmed, MM., Gebriel, MG., Morad, EA., et al.[2022]

In a study of 114 newly diagnosed nasopharyngeal carcinoma (NPC) patients, 69% expressed PD-L1, indicating a potential target for immunotherapy, especially in EBV-positive cases, which were prevalent (96%).

Despite the high expression of PD-L1 in NPC tumors, there was no correlation found between PD-L1 levels, CD8+ tumor-infiltrating lymphocytes, or patient survival, suggesting that PD-L1 expression alone may not be a reliable prognostic marker.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of PD-L1 and PD-1 Expression and CD8+ Tumor-infiltrating Lymphocyte in Epstein-Barr Virus-associated Nasopharyngeal Carcinoma. Larbcharoensub, N., Mahaprom, K., Jiarpinitnun, C., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. [2022]

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

Nimotuzumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone in patients with recurrent or metastatic nasopharyngeal carcinoma. [2022]

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

Nimotuzumab, an Anti-EGFR Monoclonal Antibody, in the Treatment of Nasopharyngeal Carcinoma. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Camrelizumab combined with apatinib in patients with first-line platinum-resistant or PD-1 inhibitor resistant recurrent/metastatic nasopharyngeal carcinoma: a single-arm, phase 2 trial. [2023]

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

Experience with combination of nimotuzumab and intensity-modulated radiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. [2022]

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

Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from recent advances in landmark trials. [2020]

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

Apatinib, a novel VEGFR-2 tyrosine kinase inhibitor, for relapsed and refractory nasopharyngeal carcinoma: data from an open-label, single-arm, exploratory study. [2023]

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

A Phase II Study of Nivolumab plus Gemcitabine in Patients with Recurrent or Metastatic Nasopharyngeal Carcinoma (KCSG HN17-11). [2022]

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

Expression of Immune Checkpoint Regulators, Cytotoxic T-Lymphocyte Antigen-4, and Programmed Death-Ligand 1 in Epstein-Barr Virus-associated Nasopharyngeal Carcinoma. [2022]

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

Characterization of PD-L1 and PD-1 Expression and CD8+ Tumor-infiltrating Lymphocyte in Epstein-Barr Virus-associated Nasopharyngeal Carcinoma. [2022]