Xevinapant + Chemoradiation for Head and Neck Cancer

Overseen By Clinical Trials Intake

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Chicago

Must not be taking: Prohibited medications

Disqualifiers: Metastatic disease, Unknown primary, others

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

Compensation: Varies

Number of Visits: 6

42 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that patients taking prohibited medications or those requiring close monitoring are excluded, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination of Xevinapant, Carboplatin, and Paclitaxel with radiation therapy for head and neck cancer?

Research shows that the combination of paclitaxel and carboplatin, along with radiation therapy, has been effective in treating advanced head and neck cancer, with some patients achieving complete or partial responses. This combination has shown promise in improving survival and preserving organ function compared to radiotherapy alone. ^{1 2 3 4 5}

Is the combination of Xevinapant, Carboplatin, Paclitaxel, and radiation therapy safe for humans?

Carboplatin and Paclitaxel, when used with radiation therapy, have been studied in head and neck cancer patients and are generally considered safe, with common side effects including nausea, vomiting, and low blood cell counts. No severe kidney or nerve damage was observed in these studies. ^{1 4 6 7 8}

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

Xevinapant is unique because it is a first-in-class drug that blocks proteins preventing cancer cell death, making cancer cells more sensitive to chemotherapy and radiotherapy. This approach has shown superior effectiveness compared to standard treatments in clinical trials for head and neck cancer. ^{9 10 11 12 13}

What is the purpose of this trial?

The goal of this clinical trial is to determine the best safe dose of xevinapant that can be given in combination with chemotherapy and radiation in patients with head and neck cancer. Up to 4 doses of xevinapant will be tested in the dose escalation portion of the study. After the best safe dose is found during escalation, an additional group of participants will be enrolled at that dose to learn more about the treatment combination (dose expansion). The main question\[s\] it aims to answer are: * what is the maximum safe dose that can be given * what dose should be used in subsequent (phase 2) trials Participants will receive xevinapant in combination with paclitaxel and carboplatin chemotherapy and radiation. Treatment will be given in 3-week cycles for 3 cycles.

Research Team

Ari Rosenberg, MD

Principal Investigator

University of Chicago

Eligibility Criteria

This trial is for adults with certain types of head and neck squamous cell carcinoma who cannot use cisplatin. They must have a specific stage of cancer, measurable disease, good organ function, and agree to contraception. Excluded are those with distant metastasis, prior chemo or radiotherapy for the same cancer within 3 years, severe health issues like recent heart attacks or active infections, pregnant women, and those on certain medications.

Inclusion Criteria

Hemoglobin >= 9.0 g/dL

Total bilirubin <= 1.5 x upper limit of normal (ULN) (except patients with Gilbert Syndrome who can have total bilirubin < 3.0 mg/dL)

Absolute neutrophil count (ANC) >= 1,500 cells/mm3

Exclusion Criteria

I have not received any live vaccines in the last 28 days.

I've had radiation in the same area as my current cancer.

I have had a heart attack in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive up to 4 doses of xevinapant to determine the maximum safe dose in combination with chemotherapy and radiation

9 weeks

Weekly visits for 3 cycles

Dose Expansion

Participants receive the best safe dose of xevinapant determined during escalation, in combination with chemotherapy and radiation

9 weeks

Weekly visits for 3 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Carboplatin
• Paclitaxel
• Radiation Therapy
• Xevinapant

Trial Overview The study tests different doses of Xevinapant combined with chemotherapy (Paclitaxel and Carboplatin) and radiation therapy in patients with head and neck cancer. It aims to find the maximum safe dose for future phase 2 trials. Participants will undergo treatment cycles lasting three weeks each for a total of three cycles.

Participant Groups

Group I: Escalation Group Dose Level 2 Experimental Treatment 4 Interventions

Participants assigned to this cohort will receive xevinapant 200 mg for 2 out of every 3 weeks (Daily on days 1-14 of a 21-day cycle). They will also receive carboplatin and paclitaxel weekly for 7 doses with radiation (chemoRT). An additional 3 cycles of xevinapant will be given after completion of chemoRT.

Group II: Escalation Group Dose Level 1 Experimental Treatment 4 Interventions

Participants assigned to this cohort will receive xevinapant 150 mg for 2 out of every 3 weeks (Daily on days 1-14 of a 21-day cycle). They will also receive carboplatin and paclitaxel weekly for 7 doses with radiation (chemoRT). An additional 3 cycles of xevinapant will be given after completion of chemoRT.

Group III: Escalation Group Dose Level 0 Experimental Treatment 4 Interventions

Participants assigned to this cohort will receive xevinapant 100 mg for 2 out of every 3 weeks (Daily on days 1-14 of a 21-day cycle). They will also receive carboplatin and paclitaxel weekly for 7 doses with radiation (chemoRT). An additional 3 cycles of xevinapant will be given after completion of chemoRT.

Group IV: Escalation Group Dose Level -1 Experimental Treatment 4 Interventions

Participants assigned to this cohort will receive xevinapant 50 mg for 2 out of every 3 weeks (Daily on days 1-14 of a 21-day cycle). They will also receive carboplatin and paclitaxel weekly for 7 doses with radiation (chemoRT). An additional 3 cycles of xevinapant will be given after completion of chemoRT.

Group V: Dose Expansion Experimental Treatment 4 Interventions

Participants assigned to this cohort will receive xevinapant at the dose found during escalation phase of study for 2 out of every 3 weeks (Daily on days 1-14 of a 21-day cycle). They will also receive carboplatin and paclitaxel weekly for 7 doses with radiation (chemoRT). An additional 3 cycles of xevinapant will be given after completion of chemoRT.

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

EMD Serono

Industry Sponsor

Trials

147

Recruited

27,800+

Dr. Shepard

EMD Serono

Chief Medical Officer since 2021

MD from University of Cincinnati Medical School, Fellowships in Hematology and Oncology at University of Chicago Hospitals and Clinics

Miguel Fernández Alcalde

EMD Serono

Chief Executive Officer

Bachelor's Degree in Pharmacy from the University Complutense in Madrid, MBA from the University of Alcalá de Henares, Master's Degree in Management from IESE Business School

Findings from Research

In a phase I trial involving 33 patients with advanced head and neck cancer, the combination of paclitaxel and carboplatin demonstrated a 54% overall response rate, with 27% achieving complete responses, indicating significant efficacy in treating this patient population.

The maximum tolerated dose of paclitaxel was determined to be between 230 and 265 mg/m2, with manageable side effects, primarily grade 3/4 neutropenia and thrombocytopenia, suggesting that this treatment can be safely administered while potentially enhancing organ preservation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel and carboplatin in head and neck cancer. Dunphy, F., Boyd, J., Dunleavy, T.[2015]

Higher T and N stages in head and neck cancer are associated with lower rates of complete local control and survival, highlighting the need for improved treatment strategies.

Combined-modality treatments, such as induction chemotherapy followed by radiotherapy, show promise in enhancing survival and preserving organ function compared to aggressive surgery or radiotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined modalities in the treatment of head and neck cancers. Aisner, J., Hiponia, D., Conley, B., et al.[2015]

In a study of 49 patients with recurrent or metastatic head and neck cancer, the combination of paclitaxel and carboplatin showed a 57% overall response rate in patients with nasopharyngeal cancer, indicating significant efficacy for this specific type of cancer.

The treatment was generally well tolerated, with only low rates of severe toxicities, suggesting it can be safely administered as an outpatient therapy, although its effectiveness was only moderate in non-nasopharyngeal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel by three-hour infusion and carboplatin in advanced carcinoma of nasopharynx and other sites of the head and neck. A phase II study conducted by the Hellenic Cooperative Oncology Group. Fountzilas, G., Skarlos, D., Athanassiades, A., et al.[2022]

In a phase II study involving 24 heavily pretreated patients with advanced head and neck cancer, the combination of paclitaxel and carboplatin resulted in an overall response rate of 39%, with 17% achieving a complete response and 22% a partial response.

The treatment was generally tolerable, although 79% of patients experienced neurotoxicity, and some had significant neutropenia, indicating that while effective, careful monitoring of side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of paclitaxel and carboplatin combination in heavily pretreated patients with head and neck cancers. Stathopoulos, GP., Rigatos, S., Papakostas, P., et al.[2019]

In a phase II trial involving 25 patients with advanced head and neck cancer, carboplatin demonstrated clinical activity, with 24% of patients achieving an objective response, including two complete responses.

The drug was generally well-tolerated, with mild side effects such as nausea, vomiting, and myelosuppression, and no significant renal or neurologic toxicity reported, suggesting it may be a safe treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin, an active drug in advanced head and neck cancer. de Andres Basauri, L., Lopez Pousa, A., Alba, E., et al.[2013]

In a study of 25 patients with locally advanced squamous cell carcinoma of the head and neck who were ineligible for cisplatin, concurrent treatment with carboplatin and radiotherapy resulted in a 70% complete response rate and a median progression-free survival of 42.7 months.

The treatment was generally well-tolerated, with significant toxicities including oral mucositis (56%) and thrombocytopenia (34%), suggesting that carboplatin could be a viable alternative for patients unable to receive cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of concurrent carboplatin plus radiotherapy for locally advanced head and neck cancer patients ineligible for treatment with cisplatin. Hamauchi, S., Yokota, T., Onozawa, Y., et al.[2018]

In a study of 160 patients with advanced oropharyngeal squamous cell carcinoma treated with carboplatin, paclitaxel, and radiation over 10 years, the overall survival rates were 81.7% at 3 years and 70.7% at 5 years, indicating effective treatment outcomes.

The treatment demonstrated an acceptable side effect profile, with the most common adverse effect being acute dysphagia (75.25%), and only 11.9% of patients experiencing significant hematologic toxicities, suggesting carboplatin may be a safer alternative to cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival outcomes in patients with oropharyngeal cancer treated with carboplatin/paclitaxel and concurrent radiotherapy. Roskies, M., Kay-Rivest, E., Mascarella, MA., et al.[2018]

The combination of paclitaxel, carboplatin, and external beam radiotherapy resulted in a high overall clinical response rate of 91% in 43 patients with advanced head and neck cancer, with 65% achieving a complete response.

Despite the promising efficacy, the treatment caused severe mucositis in 90% of patients, leading to hospitalization for 31%, highlighting significant toxicity concerns associated with this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent chemoradiotherapy with weekly paclitaxel and carboplatin for locally advanced head and neck cancer: Long-term follow-up of a Brown University Oncology Group Phase II Study (HN-53). Chougule, PB., Akhtar, MS., Rathore, R., et al.[2015]

References

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

Paclitaxel and carboplatin in head and neck cancer. [2015]

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

Combined modalities in the treatment of head and neck cancers. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Long-term outcomes with concurrent carboplatin, paclitaxel and radiation therapy for locally advanced, inoperable head and neck cancer. [2020]

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

Paclitaxel by three-hour infusion and carboplatin in advanced carcinoma of nasopharynx and other sites of the head and neck. A phase II study conducted by the Hellenic Cooperative Oncology Group. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Effectiveness of paclitaxel and carboplatin combination in heavily pretreated patients with head and neck cancers. [2019]

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

Carboplatin, an active drug in advanced head and neck cancer. [2013]

7. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of concurrent carboplatin plus radiotherapy for locally advanced head and neck cancer patients ineligible for treatment with cisplatin. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Survival outcomes in patients with oropharyngeal cancer treated with carboplatin/paclitaxel and concurrent radiotherapy. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Extended follow-up of a phase 2 trial of xevinapant plus chemoradiotherapy in high-risk locally advanced squamous cell carcinoma of the head and neck: a randomised clinical trial. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Xevinapant or placebo plus chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck: TrilynX phase III study design. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Long-term results from a clinical study of xevinapant plus chemoradiotherapy in people with high-risk locally advanced squamous cell carcinoma of the head and neck: a plain language summary. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy of Carboplatin/Paclitaxel-Based Radiochemotherapy in Locally Advanced Squamous Cell Carcinoma of Head and Neck. [2019]

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

Concurrent chemoradiotherapy with weekly paclitaxel and carboplatin for locally advanced head and neck cancer: Long-term follow-up of a Brown University Oncology Group Phase II Study (HN-53). [2015]