Peposertib + Radiation for Advanced Head and Neck Cancer

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

42 Participants Needed

Trial Summary

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.

What data supports the idea that Peposertib + Radiation for Advanced Head and Neck Cancer is an effective treatment?

The available research does not provide specific data on the effectiveness of Peposertib + Radiation for Advanced Head and Neck Cancer. Instead, it discusses other treatments like gefitinib, pembrolizumab, cetuximab, and tepotinib in combination with radiation or chemoradiation for similar conditions. These studies focus on the safety, feasibility, and potential benefits of these treatments, but do not mention Peposertib. Therefore, there is no direct evidence from the provided information to support the effectiveness of Peposertib + Radiation for this condition. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Peposertib in combination with radiation for advanced head and neck cancer?

The research on similar treatments, like the MET inhibitor tepotinib, shows that targeting specific pathways can enhance the effectiveness of radiation therapy in head and neck cancer by making cancer cells more sensitive to radiation. This suggests that Peposertib, which may work in a similar way, could potentially improve treatment outcomes when combined with radiation. ^{1 2 3 4 5}

What safety data exists for Peposertib + Radiation in head and neck cancer?

The provided research does not contain specific safety data for Peposertib (also known as M3814, MSC2490484A, nedisertib) combined with radiation for head and neck cancer. The studies focus on other treatments and combinations, such as gefitinib, panitumumab, linifanib, cetuximab, and olaparib, in combination with radiation or chemoradiation for head and neck cancer. Therefore, no relevant safety data for Peposertib + Radiation is available in the provided research. ^{1 4 6 7 8}

Is the drug Peposertib a promising treatment for advanced head and neck cancer?

The information provided does not directly address the effectiveness of Peposertib for advanced head and neck cancer. The articles focus on other drugs and treatments, so we can't determine if Peposertib is promising based on this data. ^{1 3 9 10 11}

What makes the drug Peposertib unique for treating advanced head and neck cancer?

Peposertib is unique because it is a DNA-PK inhibitor, which means it targets a specific enzyme involved in DNA repair, potentially enhancing the effectiveness of radiation therapy by preventing cancer cells from repairing the damage caused by radiation. ^{1 3 9 10 11}

What is the purpose of this trial?

This phase I trial investigates the side effects and best dose of peposertib when given together with radiation therapy in treating patients with head and neck cancer that has spread to other places in the body (advanced) who cannot take cisplatin. Peposertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. This trial aims to see whether adding peposertib to radiation therapy is safe and works well in treating patients with head and neck cancer.

Research Team

Maura L Gillison

Principal Investigator

NRG Oncology

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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 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]

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]

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]

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]

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 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]

References

1. United States 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. [2021]

2. England 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. [2021]

3. Germany 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. [2018]

4. United States 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. [2021]

5. United States 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. [2021]

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

Augmentation of radiation response by panitumumab in models of upper aerodigestive tract cancer. [2021]

7. England 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. [2022]

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

Combined EGFR1 and PARP1 Inhibition Enhances the Effect of Radiation in Head and Neck Squamous Cell Carcinoma Models. [2021]

9. United States 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. [2019]

10. Ireland 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. [2023]

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

Cetuximab, paclitaxel, carboplatin, and radiation for head and neck cancer: a toxicity analysis. [2015]