Peposertib + Radiation for Advanced Head and Neck Cancer

Not currently recruiting at 27 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Proton pump inhibitors

Disqualifiers: Metastatic disease, Prior malignancy, Organ transplant, others

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

Compensation: Varies

Number of Visits: 4

Duration: 7 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for advanced head and neck cancer. Researchers are testing a drug called peposertib combined with radiation to assess its safety and effectiveness for patients unable to use the common chemotherapy drug, cisplatin. Peposertib may inhibit cancer cell growth by blocking certain necessary enzymes. Individuals with metastatic head and neck cancer who cannot tolerate cisplatin might be suitable candidates for this study. As a Phase 1 trial, the research aims to understand how the treatment works in people, providing participants the opportunity to be among the first to receive this new treatment.

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

Yes, you may need to stop certain medications. The trial excludes participants who cannot discontinue proton pump inhibitors 5 days before treatment and those taking strong inhibitors, inducers, or sensitive substrates of specific enzymes (CYP3A4/5, CYP2C19, CYP2C9, CYP1A2, CYP2B6) before the study. Opioids are allowed, except methadone.

Will I have to stop taking my current medications?

The trial requires participants to stop taking proton pump inhibitors 5 days before treatment and any medications that are strong inhibitors, inducers, or sensitive substrates of certain liver enzymes (CYP3A4/5, CYP2C19, CYP2C9) before starting the study. Opioids are allowed, except for methadone.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown mixed safety results when combining peposertib with radiation therapy. In one study, this combination was unsafe for some patients with head and neck cancer. However, another study found that peposertib, when used with palliative radiation therapy, was well-tolerated at doses up to 200 mg once a day. This indicates that some patients managed the treatment without serious issues at that dose. It is important to note that this treatment remains under investigation. The goal is to determine the optimal dose and assess its safety for a broader patient population. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Peposertib is unique because it targets the DNA damage response in cancer cells, potentially enhancing the effectiveness of radiation therapy. Unlike traditional treatments for advanced head and neck cancer, which often rely solely on radiation or chemotherapy, peposertib is taken orally before each radiation session. This approach aims to make cancer cells more sensitive to radiation, potentially improving outcomes and reducing the chance of disease progression. Researchers are excited about peposertib because it offers a novel way to attack cancer cells, possibly leading to better survival rates and fewer side effects.

What evidence suggests that peposertib combined with radiation therapy might be an effective treatment for advanced head and neck cancer?

Research has shown that peposertib, a treatment in this trial, can effectively slow tumor growth when combined with radiation therapy. In studies with mice, this combination stopped tumor growth in various cancers, including head and neck cancer. Peposertib blocks an enzyme that tumor cells need to grow, enhancing the effectiveness of radiation in killing these cells. Although still in the early stages, this research suggests that the treatment could be promising for individuals with advanced head and neck cancer. ^{2 3 6 7 8}

Who Is on the Research Team?

Maura L Gillison

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

This trial is for adults with advanced head and neck cancer who can't take cisplatin. Participants must be HIV-positive on effective treatment, able to swallow tablets, willing to use contraception, have certain types of oropharynx cancer stages, measurable disease per RECIST 1.1 criteria, specific blood cell counts within range, and no history of distant metastatic disease.

Inclusion Criteria

I am HIV positive, on treatment, with undetectable viral load and CD4 count >= 200.

I am 70 or older with one or more serious health conditions.

My cancer is in the early to mid stages and located in my mouth, throat, or voice box.

Exclusion Criteria

I am not using proton pump inhibitors or can stop them 5 days before treatment.

I have had radiation in the same area where my current cancer is located.

My cancer has spread beyond the neck area.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive peposertib orally once daily and undergo IMRT daily Monday-Friday for 7 weeks

7 weeks

Daily visits (in-person) for radiation therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Every 3 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Peposertib

Trial Overview

The trial tests the safety and optimal dose of peposertib combined with intensity-modulated radiation therapy in patients with advanced head and neck cancer. It aims to determine if this combination is more effective than radiation alone for those unable to receive cisplatin.

How Is the Trial Designed?

Group I: Treatment (peposertib, IMRT) Experimental Treatment 6 Interventions

Beginning 60-90 minutes before each radiation treatment, patients receive peposertib PO QD and undergo IMRT daily Monday-Friday for 7 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or 18F-FDG PET/CT during screening and follow-up.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Published Research Related to This Trial

EGFR expression alone does not predict how well head and neck squamous cell carcinoma (HNSCC) patients will respond to the EGFR-inhibitor Cetuximab (C225) or its combination with radiotherapy, as shown in four different xenograft models.

The study found that changes in tumor proliferation were more closely linked to treatment response, suggesting that additional growth factor receptors and proliferation rates could serve as better predictive biomarkers for the efficacy of C225 combined with radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictive value of hypoxia, proliferation and tyrosine kinase receptors for EGFR-inhibition and radiotherapy sensitivity in head and neck cancer models. Stegeman, H., Kaanders, JH., van der Kogel, AJ., et al.[2023]

In a study involving 23 patients with locally advanced squamous cell head and neck cancer, daily gefitinib (250 or 500 mg) was found to be well tolerated when combined with radiation therapy, showing no dose-limiting toxicities in the initial treatment cohort.

When gefitinib was used alongside chemoradiotherapy, there were some serious side effects, such as grade 4 diarrhea and neutropenic fever, but overall, the treatment was manageable, with most patients experiencing only mild side effects like skin rash and diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of gefitinib in combination with radiation or chemoradiation for patients with locally advanced squamous cell head and neck cancer. Chen, C., Kane, M., Song, J., et al.[2021]

The Phase III trial KEYNOTE-412 is designed to evaluate the efficacy and safety of pembrolizumab, an immune checkpoint inhibitor, when used alongside chemoradiation therapy (CRT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Previous Phase Ib studies have indicated that combining pembrolizumab with CRT is safe and feasible, supporting its potential use in this larger trial to improve treatment outcomes for patients with locally advanced HNSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Machiels, JP., Tao, Y., Burtness, B., et al.[2021]

In a study of advanced head and neck squamous cell carcinoma (HNSCC), MET receptor was found to be highly expressed in 62.4% of primary tumors and 53.6% of lymph node metastases, correlating with poorer disease control.

The MET inhibitor tepotinib showed potential as a radiosensitizer, enhancing the effectiveness of radiotherapy by increasing DNA damage and cell death in cancer cells, particularly when combined with radiation in certain models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the MET Receptor Tyrosine Kinase as a Strategy for Radiosensitization in Locoregionally Advanced Head and Neck Squamous Cell Carcinoma. Nisa, L., Francica, P., Giger, R., et al.[2021]

In a pilot Phase I study involving 10 patients with locally advanced head-and-neck squamous cell carcinoma, the maximum tolerated dose of gefitinib combined with paclitaxel and radiation therapy was determined to be 250 mg/day of gefitinib and 36 mg/m² of paclitaxel weekly for 6 weeks.

Despite some patients achieving complete or partial responses, the addition of gefitinib did not significantly enhance treatment efficacy compared to paclitaxel and radiation alone, and it was associated with prolonged stomatitis, indicating potential safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular and clinical responses in a pilot study of gefitinib with paclitaxel and radiation in locally advanced head-and-neck cancer. Van Waes, C., Allen, CT., Citrin, D., et al.[2021]

In a study of 16 patients with locally advanced head and neck cancer, the combination of the PARP inhibitor olaparib (at a recommended dose of 25 mg twice daily), cetuximab, and radiation therapy was well tolerated, showing promising response rates and reduced radiation dermatitis.

The two-year overall survival rate was 72%, indicating that this treatment regimen may be effective for high-risk patients, although continued smoking during therapy was linked to higher recurrence rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final Report of a Phase I Trial of Olaparib with Cetuximab and Radiation for Heavy Smoker Patients with Locally Advanced Head and Neck Cancer. Karam, SD., Reddy, K., Blatchford, PJ., et al.[2019]

Panitumumab enhances the effectiveness of radiation therapy in treating head-and-neck squamous cell carcinoma and non-small-cell lung cancer, increasing radiosensitivity and promoting DNA damage in cancer cells.

In animal models, the combination of panitumumab and radiation therapy showed superior tumor control compared to either treatment alone, suggesting a promising approach for future clinical trials in epithelial tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmentation of radiation response by panitumumab in models of upper aerodigestive tract cancer. Kruser, TJ., Armstrong, EA., Ghia, AJ., et al.[2021]

The combination of linifanib, a multi-receptor tyrosine kinase inhibitor, and veliparib, a PARP inhibitor, significantly enhances the cytotoxic effects on Head and Neck Squamous Cell Carcinoma (HNSCC) cells, leading to increased cell growth inhibition and apoptosis.

This combination treatment results in greater DNA damage, as indicated by increased double strand breaks and reduced expression of the DNA repair protein Rad51, suggesting a potential new therapeutic strategy for improving outcomes in HNSCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Linifanib (ABT-869), enhances cytotoxicity with poly (ADP-ribose) polymerase inhibitor, veliparib (ABT-888), in head and neck carcinoma cells. Hsu, HW., de Necochea-Campion, R., Williams, V., et al.[2022]

In a phase II trial involving 74 patients with advanced squamous cell carcinoma of the head and neck, the combination of cetuximab, cisplatin, and hyperfractionated accelerated radiotherapy resulted in a 2-year progression-free survival rate of 45% and a complete remission rate of 35%.

Despite the promising results, the study found significant toxicity, with severe side effects like mucositis and dysphagia occurring in over half of the patients, and a parallel study indicated that this enhanced therapy did not provide a survival advantage over standard chemoradiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperfractionated accelerated radiation therapy plus cetuximab plus cisplatin chemotherapy in locally advanced inoperable squamous cell carcinoma of the head and neck : Final 5‑year results of a phase II study. Kuhnt, T., Schreiber, A., Pirnasch, A., et al.[2018]

In a study involving 32 patients with advanced head and neck cancer, the addition of cetuximab to a treatment regimen of paclitaxel, carboplatin, and radiation was found to increase dermatologic toxicities, with 44% experiencing grade 3 radiation dermatitis.

Despite the increased skin toxicity, the combination treatment did not lead to higher mucosal toxicity compared to previous studies, suggesting that while cetuximab may enhance side effects, it does not worsen certain other adverse effects associated with cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab, paclitaxel, carboplatin, and radiation for head and neck cancer: a toxicity analysis. Birnbaum, A., Dipetrillo, T., Rathore, R., et al.[2015]

A combination of EGFR inhibitor cetuximab and PARP1 inhibitor olaparib with radiation therapy significantly enhances DNA damage and tumor control in head and neck squamous cell carcinoma (HNSCC) compared to standard treatments, as shown in a proof-of-concept study using Detroit562 HNSCC cells.

This study suggests that combining biologically-based therapies could optimize radiosensitization in HNSCC, potentially improving treatment outcomes for patients with this challenging cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined EGFR1 and PARP1 Inhibition Enhances the Effect of Radiation in Head and Neck Squamous Cell Carcinoma Models. Frederick, BA., Gupta, R., Atilano-Roque, A., et al.[2021]

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Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg once daily as tablet with each RT fraction.