Ibrutinib + Nivolumab/Cetuximab for Head and Neck Cancer

Overseen By Gerald Henderson

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Diego

Must not be taking: Immunosuppressants, Warfarin, CYP3A inhibitors

Disqualifiers: Nasopharyngeal carcinoma, CNS metastases, 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: Unknown

Duration: 28-day cycles, up to 3 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of two drug combinations for treating recurrent or metastatic head and neck cancer. Participants will receive either Ibrutinib with Cetuximab (a targeted therapy) or Ibrutinib with Nivolumab (an immunotherapy) to determine which combination is more effective in managing this cancer type. Individuals with squamous cell carcinoma of the head and neck, who cannot be cured with current treatments, may be suitable for this study. The trial aims to discover better treatment options for those facing recurring or spreading head and neck cancer. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does exclude those on certain treatments like strong CYP3A inhibitors and warfarin. It's best to discuss your current medications with the trial team to see if they might affect your eligibility.

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

Research has shown that the combination of Ibrutinib and Cetuximab has been studied before, though not in detail here. The FDA has already approved Ibrutinib for other conditions, indicating its safety is well understood. Cetuximab is often used to treat head and neck cancer, with established guidelines for its safe use.

For the combination of Ibrutinib and Nivolumab, studies have shown promising safety results. Specifically, one study found that this combination was well-tolerated by patients with certain blood cancers. While these findings come from different types of cancer, they offer some insight into potential safety.

This trial tests both combinations to evaluate their effectiveness together. Although specific safety data for this exact setup isn't mentioned, existing research suggests a reasonable level of safety based on past studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they bring a fresh approach to fighting head and neck cancer. Unlike the standard chemotherapy and radiation, Ibrutinib acts on a specific pathway that cancer cells use to grow and survive, potentially leading to more precise targeting of cancer cells. When combined with Cetuximab, which blocks a growth factor receptor, or Nivolumab, an immune checkpoint inhibitor that unleashes the body’s own immune system against cancer, these treatments could offer a more effective and potentially less toxic alternative to the current standard of care. This combination of targeted therapy and immunotherapy offers a double-pronged attack, aiming to both directly inhibit cancer growth and bolster the immune response against the tumor.

What evidence suggests that this trial's treatments could be effective for head and neck cancer?

This trial will compare two treatment combinations for head and neck cancer. Arm A involves the combination of Ibrutinib and Cetuximab. Research has shown that combining Ibrutinib with Cetuximab may enhance cancer treatments by making chemotherapy and radiotherapy more effective and helping to overcome resistance to some drugs. Five-year studies indicate that adding Cetuximab to radiation therapy significantly improved overall survival in patients with advanced head and neck cancer.

Arm B involves the combination of Ibrutinib and Nivolumab. This combination has shown potential in treating head and neck cancer. Clinical trials of Nivolumab alone have already demonstrated benefits for patients with previously treated squamous cell head and neck cancer. Early results suggest that using Ibrutinib with Nivolumab works similarly to using Ibrutinib alone, with a safety profile considered acceptable. These combinations are being studied to improve outcomes for patients with recurrent and metastatic head and neck cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

Kathryn Gold, MD

Principal Investigator

University of California San Diego, Moores Cancer Center

Are You a Good Fit for This Trial?

Adults with recurrent or metastatic head and neck squamous cell carcinoma not suitable for curative treatment. Participants must have known P16/HPV status, measurable tumor lesions, a life expectancy over 12 weeks, adequate organ function, and agree to use effective birth control. Exclusions include active central nervous system metastases, recent immunosuppressant therapy or live vaccines, prior specific cancer treatments, certain bleeding disorders or infections.

Inclusion Criteria

Ability and willingness to provide written informed consent

My liver and kidneys are working well.

Presence of measurable tumor lesions per RECIST criteria v1.1 by investigator review

Exclusion Criteria

Lactating or pregnant

I have been treated with an EGFR inhibitor for my cancer when it came back or spread.

I do not have an active autoimmune disease or a condition that prevents me from receiving PD-1 inhibitors.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Ibrutinib in combination with either Cetuximab or Nivolumab for recurrent/metastatic head and neck squamous cell carcinoma

28-day cycles, up to 3 years

Weekly visits for Cetuximab arm, biweekly visits for Nivolumab arm

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Ibrutinib
• Nivolumab

Trial Overview The trial is testing the effectiveness of Ibrutinib in combination with either Nivolumab or Cetuximab in treating advanced head and neck cancers. It's an open-label (patients know what they're getting), randomized (assigned by chance), phase II study to see which combination works better.

How Is the Trial Designed?

Group I: Arm B: Ibrutinib + Nivolumab Experimental Treatment 2 Interventions

Ibrutinib 560mg PO daily (Imbruvica) PLUS Nivolumab 3mg/kg biweekly 28 day cycle

Group II: Arm A: Ibrutinib + Cetuximab Experimental Treatment 2 Interventions

Ibrutinib 560mg PO daily (Imbruvica) PLUS Cetuximab 400mg/m2 x 1 then 250 mg/m2 weekly 28 day cycle

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

Approved in United States as Erbitux for:

• Locally or regionally advanced squamous cell carcinoma of the head and neck
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer
• BRAF V600E mutation-positive metastatic colorectal cancer

Approved in European Union as Erbitux for:

• Squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

Pharmacyclics LLC.

Industry Sponsor

Trials

114

Recruited

13,800+

Dr. Maky Zanganeh

Pharmacyclics LLC.

Chief Executive Officer

Degree from Louis Pasteur University in Strasbourg, France; MBA from Schiller International University in France

Dr. Ellie Im

Pharmacyclics LLC.

Chief Medical Officer

MD from an unspecified institution

Published Research Related to This Trial

In a study of 99 head-and-neck cancer patients receiving simultaneous integrated boost intensity-modulated radiotherapy with cetuximab, 34% experienced severe dermatitis (Grade 3/4), significantly higher than the 3% in a control group treated with cisplatin.

There was a clear link between the radiation dose to the skin and the severity of dermatitis in patients receiving cetuximab, indicating that higher radiation exposure increases the risk of severe skin reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Grade 3/4 dermatitis in head and neck cancer patients treated with concurrent cetuximab and IMRT. Studer, G., Brown, M., Salgueiro, EB., et al.[2015]

Monoclonal antibodies like cetuximab work by promoting receptor endocytosis and activating the immune system to reduce tumor growth in head and neck squamous cell carcinoma (HNSCC).

Different strategies for targeting EGFR, including tyrosine kinase inhibitors and antisense approaches, have unique mechanisms of action, which could lead to more effective treatments and better patient selection for EGFR inhibition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma. Cassell, A., Grandis, JR.[2021]

The recommended phase II dose (RP2D) of ipilimumab, when added to standard cetuximab and radiotherapy for high-risk head and neck squamous carcinoma, is established at 1 mg/kg, demonstrating a tolerable safety profile with manageable adverse effects.

The combination treatment resulted in a promising 3-year disease-free survival and overall survival rate of 72%, indicating its efficacy without the need for cytotoxic chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Cetuximab, Radiotherapy, and Ipilimumab in Locally Advanced Head and Neck Cancer. Ferris, RL., Moskovitz, J., Kunning, S., et al.[2023]

In a study involving 201 patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, the two-drug regimen of cetuximab plus cisplatin (CetCis) demonstrated noninferior progression-free survival (PFS) compared to the three-drug regimen that included paclitaxel (CetCisPac), with median PFS of 6 months versus 7 months, respectively.

The CetCis regimen also showed a lower rate of grade 4 toxicities (14% compared to 33% in the CetCisPac group), indicating a potentially safer treatment option without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, phase 2 study of cetuximab plus cisplatin with or without paclitaxel for the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Bossi, P., Miceli, R., Locati, LD., et al.[2023]

Cetuximab, a monoclonal antibody targeting the EGFR, has been shown to improve survival rates when used alongside radiation therapy for patients with locally-advanced head and neck cancer, as demonstrated in a landmark study.

In recurrent and metastatic cases, cetuximab also enhances the effectiveness of chemotherapy, indicating its significant role in the treatment of squamous cell carcinoma of the head and neck, although further research is needed to optimize its use and identify the best patient candidates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of cetuximab in the management of head and neck cancers. Kabolizadeh, P., Kubicek, GJ., Heron, DE., et al.[2020]

Cétuximab, a monoclonal antibody targeting EGFR, has been shown to improve overall survival in patients with locally advanced head and neck cancer when used alongside radiotherapy, and is now reimbursed in Belgium under specific conditions.

In metastatic head and neck cancer, adding cétuximab to platinum-based chemotherapy has demonstrated improved overall survival compared to chemotherapy alone, marking a significant advancement in treatment options, although it is not yet available to Belgian patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Monoclonal antibodies for the treatment of head and neck cancer]. Sautois, B., Martin, M., Demez, P., et al.[2018]

Adding the EGFR inhibitor cetuximab to radiotherapy for locally advanced squamous cell carcinoma of the head and neck significantly improves clinical outcomes without increasing the toxicity associated with radiotherapy.

Current chemoradiotherapy regimens, which are often platinum-based, have reached a limit in tolerable toxicity, highlighting the need for more effective and tolerable treatment options like cetuximab combined with radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab combined with radiotherapy: an alternative to chemoradiotherapy for patients with locally advanced squamous cell carcinomas of the head and neck? Bernier, J., Schneider, D.[2015]

Cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor, which plays a crucial role in the growth of various cancers.

It received accelerated approval from the US FDA in February 2004 for treating metastatic colorectal cancer based on positive tumor response rates observed in Phase II clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab. Goldberg, RM.[2020]

In a post-marketing surveillance study involving 2126 patients with metastatic colorectal cancer, cetuximab was found to be well tolerated, with a median treatment duration of 15.3 weeks and a high incidence of adverse reactions at 89.6%.

The most common adverse reactions included skin disorders (83.7%) and infusion reactions (5.7%), primarily occurring during the first administration, indicating that while side effects are common, they align with previous reports and suggest that cetuximab is clinically useful in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Japanese post-marketing surveillance of cetuximab (Erbitux®) in patients with metastatic colorectal cancer. Ishiguro, M., Watanabe, T., Yamaguchi, K., et al.[2022]

In a study of 32 head and neck squamous cell carcinoma (HNSCC) cell lines, researchers identified YAP1 amplification as a key factor associated with resistance to the EGFR-targeting antibody cetuximab, suggesting it could serve as a novel biomarker for treatment response.

The study demonstrated that higher levels of YAP1 not only correlated with cetuximab resistance but also that reducing YAP1 expression through RNA knockdown increased sensitivity to the drug, highlighting its potential role in guiding therapy decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer. Jerhammar, F., Johansson, AC., Ceder, R., et al.[2021]

The combination treatment of carboplatin, 5-FU, and cetuximab with intensity-modulated radiation therapy (IMRT) showed promising efficacy in treating locally advanced squamous cell carcinoma of the head and neck, with a complete response rate of 28.6% at the first follow-up and 92.9% thereafter.

While the treatment was associated with moderate toxicity, including significant skin reactions and mucositis, these side effects were manageable and resolved quickly, indicating that the regimen is feasible for routine clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiochemoimmunotherapy with intensity-modulated concomitant boost: interim analysis of the REACH trial. Jensen, AD., Krauss, J., Potthoff, K., et al.[2023]

Citations

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Trial of Ibrutinib Combined With Nivolumab or Cetuximab ... Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for ...

2. clinicaltrials.ucsd.edu clinicaltrials.ucsd.edu/trial/NCT03646461

Trial of Ibrutinib Combined With Nivolumab or Cetuximab to ... This is an open-label, randomized, phase II trial to test the efficacy of Ibrutinib in combination with either Nivolumab or Cetuximab in the treatment of ...

3. cdek.pharmacy.purdue.edu cdek.pharmacy.purdue.edu/trial/NCT03646461/

Trial | NCT03646461 This is an open-label, randomized, phase II trial to test the efficacy of Ibrutinib in combination with either Nivolumab or Cetuximab in the treatment of ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2376084/

Review of cetuximab in the treatment of squamous cell ... Available experimental data suggest that cetuximab may enhance chemotherapy and radiotherapy activity, reverse resistance to some anticancer drugs and has ...

5. news.bms.com news.bms.com/news/details/2008/ERBITUXR-Five-Year-Data-Show-Significant-Improvement-in-Overall-Survival-for-Patients-with-Locally-or-Regionally-Advanced-Head-and-Neck-Cancer/default.aspx

ERBITUX(R) Five-Year Data Show Significant ... These five-year data demonstrate that the addition of ERBITUX to radiation therapy resulted in a significant increase in median overall survival for patients ...

6. jnj.com jnj.com/media-center/press-releases/imbruvica-ibrutinib-combination-therapy-data-from-two-studies-and-long-term-integrated-analysis-presented-at-ash-2019-show-efficacy-and-safety-in-first-line-treatment-of-chronic-lymphocytic-leukemia

IMBRUVICA® (ibrutinib) Combination Therapy Data From ... IMBRUVICA in combination with rituximab versus fludarabine, cyclophosphamide and rituximab showed statistically significant difference in progression-free ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11925625/

Practical Consensus Guidelines on the Use of Cetuximab in ... These consensus guidelines represent how cetuximab should be used today in the management of HNSCC. Keywords: oral cancer, monoclonal antibody, EGFR, targeted ...