Combination Therapy for Head and Neck Cancer

Overseen By Tina Swartzlander

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Investigational agents, Immunosuppressants

Disqualifiers: Additional malignancy, Cell therapy, Organ transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination treatment for individuals with advanced head and neck cancer that has not responded to certain standard treatments. The researchers aim to determine if adding TBio-4101, a type of cell therapy, alongside existing drugs like pembrolizumab (an immunotherapy drug), can be safe and potentially effective. Participants will first undergo standard treatments, and if those prove ineffective, they will receive TBio-4101 followed by additional pembrolizumab. This trial is suitable for those with recurrent, metastatic head and neck cancer who have not previously received other cell therapies. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I need to stop my current medications to join the trial?

Yes, you need to stop any systemic therapy, including anti-cancer monoclonal antibodies, at least 3 weeks before the TIL harvest or apheresis. Also, you cannot be on chronic anti-coagulant therapy that can't be changed to one with a short half-life.

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

Research has shown that TBio-4101 is a treatment called tumor-infiltrating lymphocyte (TIL) therapy, which uses a patient's own immune cells to fight cancer. Detailed safety information for TBio-4101 remains limited, and some studies on similar treatments have been stopped, indicating the need for further research.

In contrast, aldesleukin (also known as IL-2) has been used for a long time. It can cause side effects, especially in high doses, such as low blood pressure and heart issues. However, low doses usually result in fewer serious side effects.

Pembrolizumab is a well-established treatment already approved for certain cancers. It is generally well tolerated, but some people might experience side effects like tiredness or a rash.

Overall, while researchers continue to study the safety of TBio-4101, aldesleukin and pembrolizumab have known safety records from their use in other treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for head and neck cancer because they offer a fresh approach compared to standard therapies like surgery, radiation, and chemotherapy. TBio-4101 is particularly intriguing because it involves an innovative method of using tumor-infiltrating lymphocytes (TILs) to boost the body's immune response against cancer. This method, combined with pembrolizumab and IL-2, aims to enhance the immune system's ability to target and destroy cancer cells more effectively. Additionally, pembrolizumab's role in this combination is to block a specific pathway (PD-1) that cancer cells use to hide from the immune system, potentially leading to better outcomes for patients who don't initially respond to standard treatments.

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

Research has shown that TBio-4101, a therapy using tumor-infiltrating lymphocytes (TILs), may help treat advanced solid cancers. Early results suggest this therapy could enhance the immune system's ability to locate and attack cancer cells. In this trial, participants who do not respond to initial treatment with pembrolizumab or pembrolizumab/platinum chemotherapy may transition to receive TBio-4101. Studies indicate that combining TBio-4101 with pembrolizumab might strengthen the body's ability to fight tumors.

Aldesleukin, also known as IL-2, is another treatment used in this trial. It has been used in cancer therapy to boost immune cell activity. Research has shown that IL-2 can significantly shrink tumors when combined with other treatments. Together, these therapies aim to provide new hope for patients who have not responded to previous treatments. ^{6 7 8 9 10}

Who Is on the Research Team?

Kedar Kirtane, MD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced head and neck squamous cell carcinoma (HNSCC) who have seen their cancer progress despite treatment with pembrolizumab or a combination of pembrolizumab and platinum-based chemotherapy.

Inclusion Criteria

I am willing and able to undergo a procedure to collect my blood cells.

The effects of TBio-4101 on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study drug administration.

I have a score of 1 or more for pembrolizumab treatment eligibility.

Exclusion Criteria

Participants who are receiving any other investigational agents.

Participants with a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the patient to participate, in the opinion of the treating Investigator.

I have not taken drugs like nivolumab or pembrolizumab before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

TIL Harvest/Standard of care Treatment

Participants undergo tumor harvest for TIL and receive 2 to 3 cycles of pembrolizumab or pembrolizumab/platinum chemotherapy

6-9 weeks

TBio-4101 Treatment

Participants receive TBio-4101 infusion, followed by IL-2 administration and pembrolizumab on specified days

Up to 2 years

Multiple visits for IL-2 and pembrolizumab administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Aldesleukin
• Cyclophosphamide
• Fludarabine
• Pembrolizumab
• Platinum based chemotherapy
• TBio-4101

Trial Overview The study tests TBio-4101, a type of tumor-infiltrating lymphocyte therapy, after chemo that reduces immune cells. It's followed by aldesleukin to boost the immune system and more pembrolizumab to help fight the cancer.

How Is the Trial Designed?

Group I: TIL Harvest/Standard of care Treatment Phase Experimental Treatment 2 Interventions

Participants will undergo tumor harvest for TIL and then receive 2 to 3 cycles of pembrolizumab or pembrolizumab/platinum chemotherapy (cisplatin or carboplatin / 5-FU) as per standard of care.

Group II: TBio-4101 Treatment Experimental Treatment 6 Interventions

Participants without radiographic response (progressive disease) after pembrolizumab or pembrolizumab/platinum chemotherapy, and who meet eligibility requirements, will transition to receive TBio-4101. Participants will receive TBio-4101 infusion and after completion of TBio-4101 infusion, IL-2 will be administered every 8 hours, for up to 6 doses. Finally, pembrolizumab will be administered on Day 14, Day 35, and Day 56 and Q6W (beginning Week 12) thereafter for up to 2 years until discontinuation.

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Turnstone Biologics, Corp.

Industry Sponsor

Trials

7

Recruited

120+

Published Research Related to This Trial

In a study of 139 patients with recurrent and metastatic head and neck squamous cell carcinoma, pembrolizumab monotherapy showed similar long-term survival rates compared to combination therapy with chemotherapy, with 2-year progression-free survival at 28.6% and overall survival at 41.8%.

Patients receiving pembrolizumab monotherapy who experienced adverse events had a better prognosis than those without adverse events, suggesting that monotherapy may be a safer and more effective long-term treatment option compared to combination therapy, which did not improve prognosis and could lead to more side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Monotherapy Versus Pembrolizumab Plus Chemotherapy in Patients With Head and Neck Squamous Cell Carcinoma. Matsuo, M., Masuda, M., Yamauchi, M., et al.[2023]

In a study of 38 patients with p16+ oropharyngeal squamous cell carcinoma, there was a 76% agreement in PD-L1 combined positive scores (CPS) between primary tumors and lymph node metastases, indicating variability in scoring between these specimens.

The interobserver agreement for CPS scoring was fair to substantial, suggesting that additional evaluations may be necessary to ensure accurate scoring, especially for patients who might benefit from immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma. Kaur, A., Kuchta, K., Watkin, W., et al.[2023]

In a phase 3 study involving 495 patients with recurrent or metastatic head-and-neck squamous cell carcinoma, pembrolizumab demonstrated a median overall survival of 8.4 months, compared to 6.9 months for standard-of-care treatments, indicating a significant improvement in survival rates.

Pembrolizumab was associated with fewer severe treatment-related adverse events (13%) compared to standard-of-care therapies (36%), suggesting a better safety profile for patients receiving pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Cohen, EEW., Soulières, D., Le Tourneau, C., et al.[2019]

In a phase III trial, pembrolizumab, a single-agent treatment, showed significant effectiveness in patients with head and neck tumors that had high PD-L1 expression, leading to deep and lasting responses.

This study highlights the potential of pembrolizumab as a first-line therapy for this specific group of cancer patients, suggesting a targeted approach based on PD-L1 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembro Ups Survival in PD-L1-positive HNSCC. [2019]

Pembrolizumab (KEYTRUDA) received accelerated FDA approval for treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) based on a study of 174 patients, showing an objective response rate of 16% and a duration of response ranging from 2.4 to 27.7 months.

The safety profile included serious adverse reactions such as pneumonia and respiratory failure, but the overall benefit-risk assessment was deemed acceptable, marking pembrolizumab as the first new treatment option for HNSCC since 2006.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy. Larkins, E., Blumenthal, GM., Yuan, W., et al.[2019]

Pembrolizumab, an immune checkpoint inhibitor, has been approved by the FDA for treating platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), offering a new option with potentially improved efficacy compared to traditional chemotherapy and EGFR inhibitors.

This review discusses the pharmacology and tolerability of pembrolizumab, emphasizing its mechanism of action by blocking the PD-1 receptor, which may enhance the immune response against HNSCC tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab and its use in the treatment of recurrent or metastatic head and neck cancer. Sheth, S., Weiss, J.[2019]

In a study involving 882 participants with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), pembrolizumab alone significantly improved overall survival compared to cetuximab with chemotherapy, especially in patients with high PD-L1 expression (CPS of 20 or more).

Pembrolizumab combined with chemotherapy also showed improved overall survival compared to cetuximab with chemotherapy across all populations, indicating that pembrolizumab is an effective first-line treatment option for HNSCC, particularly for those with PD-L1 positivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Burtness, B., Harrington, KJ., Greil, R., et al.[2021]

In a study involving 133 patients with locally advanced squamous cell carcinoma of the head and neck, pembrolizumab combined with radiotherapy did not show a significant improvement in locoregional control or survival compared to the standard treatment of cetuximab with radiotherapy.

However, patients receiving pembrolizumab experienced significantly lower toxicity, with only 74% reporting severe adverse events compared to 92% in the cetuximab group, suggesting it may be a safer option for patients unfit for high-dose cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial. Tao, Y., Biau, J., Sun, XS., et al.[2023]

In a study of 34 patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with PD-1 inhibitors, 29% experienced hyperprogression, where tumor growth accelerated during treatment.

Hyperprogression was significantly associated with regional recurrence, leading to shorter progression-free survival, but did not affect overall survival, highlighting the need for further research into the mechanisms behind this phenomenon.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Saâda-Bouzid, E., Defaucheux, C., Karabajakian, A., et al.[2022]

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