Tolinapant + Radiation for Head and Neck Cancer

Overseen By Nicole C Schmitt, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Emory University

Must not be taking: Antipsychotics, Antiarrhythmics, Antidepressants, others

Disqualifiers: Prior radiotherapy, Cardiovascular disease, HIV, others

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

Compensation: Varies

Number of Visits: 1

Duration: 7 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and side effects of combining tolinapant with radiation therapy for head and neck cancer. Tolinapant may stop tumor growth by blocking enzymes, while radiation uses high-energy x-rays to kill cancer cells. The study targets individuals with locally spread head and neck cancer who cannot use the chemotherapy drug cisplatin. Ideal candidates have not received previous treatment for their cancer and have conditions like hearing loss that make cisplatin unsuitable. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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 certain medications known to cause QT prolongation (a heart rhythm condition). It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research has shown that tolinapant is generally safe. In studies involving patients with relapsed or difficult-to-treat peripheral T-cell lymphoma, tolinapant alone demonstrated a promising response rate and was mostly well-tolerated, with most participants not experiencing severe side effects.

In early animal studies, combining tolinapant with radiation therapy halted tumor growth and improved survival. This combination was tested in people unable to use the common cancer drug cisplatin. Although this trial remains in the early stages, initial results are encouraging regarding the safety of using tolinapant with radiation.

Early-phase trials focus on safety, so researchers closely monitor for any side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for head and neck cancer, which typically involve surgery, chemotherapy, and radiation, tolinapant offers a different approach by enhancing the effects of radiation therapy. Tolinapant is an oral medication that targets and inhibits proteins that help cancer cells survive, potentially making them more sensitive to radiation. Researchers are excited because this combination could improve treatment effectiveness and reduce resistance, potentially leading to better outcomes for patients with this type of cancer.

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

In this trial, participants will receive a combination of tolinapant and radiation therapy to evaluate its effectiveness in controlling tumors in head and neck cancer. Research has shown that tolinapant, when used with radiation therapy, may control tumors more effectively. Tolinapant blocks certain enzymes that cancer cells need to grow. Combined with the tumor-killing effects of radiation, it may lead to better outcomes. Early trials in other types of cancer have shown promising results in shrinking tumors and improving survival rates. ^{1 2 3 4 5}

Who Is on the Research Team?

Nicole C Schmitt, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

Adults with previously untreated, locally advanced head and neck cancer who cannot receive cisplatin. They must be in good physical condition (ECOG ≤1), have acceptable organ function, no severe hearing loss or neuropathy, and not be pregnant or breastfeeding. Participants need to use effective contraception and cannot have a history of significant mental illness or substance abuse.

Inclusion Criteria

I have a confirmed diagnosis of head and neck cancer that hasn't been treated yet, and I can't receive cisplatin with my radiation.

I cannot receive cisplatin due to my age or other health conditions.

Evidence of informed consent indicating awareness of study details

Exclusion Criteria

Receiving any other investigational agents or device within 21 days before study drugs

History of allergic reactions to compounds similar to tolinapant

I have had radiation therapy to my head or neck.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tolinapant orally and undergo radiation therapy for a total of 35 fractions over 7 weeks

7 weeks

Weekly visits for radiation therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Follow-up visits at 1, 3, 6, 12, and 24 months

What Are the Treatments Tested in This Trial?

Interventions

• Radiation Therapy
• Tolinapant

Trial Overview The trial is testing the combination of a new drug called Tolinapant with radiation therapy against head and neck cancers that can't be treated with cisplatin. The goal is to see if this combo is safe and more effective at killing cancer cells than standard treatments.

How Is the Trial Designed?

Group I: Treatment (tolinapant, radiation therapy) Experimental Treatment 2 Interventions

Patients undergo standard of care radiation therapy for a total of 35 fractions over 7 weeks and receive tolinapant PO daily for 7 days during weeks 1, 3, 5, and 7 of radiation therapy in the absence of disease progression or unacceptable toxicity.

Radiation Therapy is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in United States as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Canada as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Japan as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in China as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Switzerland as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Astex Pharmaceuticals, Inc.

Industry Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Published Research Related to This Trial

Induction therapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) before chemoradiotherapy significantly increased the rate of complete radiologic response (CR) in patients with locally advanced squamous cell carcinoma of the head and neck, achieving a CR rate of 50% compared to 21.2% for chemoradiotherapy alone.

Patients receiving TPF followed by chemoradiotherapy also experienced longer median progression-free survival (30.4 months vs. 19.7 months) and overall survival (39.6 months vs. 33.3 months) without an increase in toxic effects, indicating that TPF is both effective and safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study. Paccagnella, A., Ghi, MG., Loreggian, L., et al.[2020]

In a study of 98 nasopharynx cancer patients treated with a combination of helical tomotherapy (HT) and intensity-modulated proton therapy (IMPT), the combination therapy resulted in significantly lower rates of grade ≥2 mucositis compared to HT alone (45.7% vs 69.8%).

The combination therapy (HT/IMPT) showed comparable early oncologic outcomes with no significant differences in locoregional or distant failures, suggesting that it may provide a safer treatment option with reduced acute toxicity for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early clinical outcomes of helical tomotherapy/intensity-modulated proton therapy combination in nasopharynx cancer. Park, SG., Ahn, YC., Oh, D., et al.[2021]

Methotrexate and cisplatin are still the standard chemotherapy agents for patients with recurrent head and neck cancer, but neoadjuvant chemotherapy lacks firm evidence for improving survival, though it may help with organ preservation.

Concomitant chemoradiotherapy has shown proven benefits in randomized trials, and while there are promising results from protracted radiation schedules, these need further confirmation through additional randomized studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy and integrated treatment approaches in head and neck cancer. Vokes, EE.[2019]

Recent innovations in radiation therapy for head and neck squamous cell carcinoma focus on intensity-modulated radiation therapy (IMRT), which aims to reduce long-term side effects while effectively targeting tumors.

Emerging technologies such as adaptive treatment, dose painting, and proton therapy are being evaluated for their potential to improve treatment outcomes and minimize toxicity in patients with head and neck cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The management of head and neck tumors with high technology radiation therapy. Mendez, LC., Moraes, FY., Poon, I., et al.[2016]

Combination therapies for head and neck cancer, including agents like cisplatin and 5-fluorouracil, have shown improved response rates but no significant survival advantage over monotherapy.

Docetaxel has demonstrated promising response rates of 23-42% as a monotherapy and up to 100% when combined with cisplatin and 5-FU, leading to a phase III trial to evaluate its effectiveness in standard neoadjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The chemotherapy of head and neck cancer. de Mulder, PH.[2019]

Intensity Modulated Radiation Therapy (IMRT) combined with Image Guided Radiation Therapy (IGRT) enhances treatment for head and neck cancer by improving tumor coverage while minimizing damage to normal tissues, leading to similar tumor control rates with less toxicity compared to conventional methods.

In the context of systemic therapy, platinum-based radiochemotherapy remains the standard treatment, and early evidence suggests that adding Cetuximab to cisplatin-based therapy does not provide additional benefits in primary treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current strategies in radiotherapy of head and neck cancer. Pütz, M., Wenz, F.[2021]

In a study of 56 patients with head and neck cancer, the addition of amifostine to radiochemotherapy significantly reduced acute xerostomia (dry mouth) and showed a trend towards reducing mucositis (inflammation of the mucous membranes).

While amifostine improved certain side effects of radiation treatment, it did not significantly affect overall performance status or other side effects like skin reactions and hair loss, suggesting its specific protective role for salivary glands and oral mucosa.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase III trial of postoperative radiochemotherapy +/- amifostine in head and neck cancer. Is there evidence for radioprotection? Vacha, P., Fehlauer, F., Mahlmann, B., et al.[2013]

A 47-year-old female patient with breast cancer experienced severe nausea and vomiting despite being treated with ondansetron during radiotherapy, which is typically used to prevent these symptoms.

Switching to granisetron and aprepitant successfully alleviated her nausea and prevented further vomiting, suggesting that this combination may be an effective alternative for patients who do not respond to standard antiemetic treatments for radiotherapy-induced nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of granisetron and aprepitant in a patient who failed ondansetron in the prophylaxis of radiation induced nausea and vomiting: a case report. Rowbottom, L., Pasetka, M., McDonald, R., et al.[2022]

Both MV-kV and CBCT imaging modalities produced similar setup error measurements for head-and-neck cancer patients, indicating that either method can be effectively used for image-guided radiation therapy.

MV-kV imaging was significantly faster and delivered a lower radiation dose (6.88 mGy) compared to CBCT (17.2 mGy), suggesting it could be a suitable alternative when reduced imaging time is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Setup margin for head-and-neck cancer patients receiving 2D-2D and 3D image-guided intensity-modulated radiation therapy]. Kovács, P., Szita, E., Schvarcz, K., et al.[2018]

Intensity Modulated Proton Therapy (IMPT) provided better target coverage for recurrent nasopharyngeal carcinoma (rNPC) compared to Intensity Modulated Radiotherapy (IMRT), achieving higher coverage percentages for both the gross tumor volume and clinical target volume.

While IMPT showed advantages in sparing critical neurological organs, it also resulted in higher maximum doses to the internal carotid artery and nasopharyngeal mucosa, indicating a need for careful monitoring of potential complications when using this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dosimetric comparison of intensity modulated radiotherapy and intensity modulated proton therapy in the treatment of recurrent nasopharyngeal carcinoma. Hung, HM., Chan, OCM., Mak, CH., et al.[2022]

Intensity-modulated radiation therapy (IMRT) has improved the efficacy of treating head and neck squamous cell carcinomas (HNSCC) by allowing for precise targeting of tumors while protecting surrounding healthy tissues.

Despite being traditionally considered low risk for causing nausea and vomiting, recent studies suggest that IMRT may actually increase the incidence of radiation-induced nausea and vomiting (RINV), highlighting the need for further research to understand this side effect better.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation-induced nausea and vomiting in head and neck cancer: Is it something worth considering in the intensity modulated radiotherapy era? "A narrative review". Paiar, F., Cristaudo, A., Gonnelli, A., et al.[2021]

Radiation-induced nausea and vomiting (RINV) affects a significant number of patients undergoing radiotherapy, with antiemetic drugs like 5-HT3 receptor antagonists being the most commonly prescribed to manage these symptoms.

Research at a palliative outpatient radiotherapy clinic has explored various antiemetic strategies, including new drug types and combinations, which may lead to improved management of RINV and inform future clinical guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolution of antiemetic studies for radiation-induced nausea and vomiting within an outpatient palliative radiotherapy clinic. McKenzie, E., Chan, D., Parsafar, S., et al.[2021]

Intensity-modulated radiation therapy (IMRT) is becoming increasingly popular for treating head and neck cancers, showing promising preliminary results in improving tumor coverage and disease control.

IMRT aims to reduce radiation toxicity while effectively targeting tumors, prompting oncologists to reconsider traditional treatment practices and explore new therapeutic approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Target coverage for head and neck cancers treated with IMRT: review of clinical experiences. Garden, AS., Morrison, WH., Rosenthal, DI., et al.[2018]

5-HT3-receptor antagonists are recommended for preventing radiation-induced nausea and vomiting (RINV) in cancer patients undergoing moderately or highly emetogenic radiotherapy, showing both efficacy and safety in randomized trials.

When selecting antiemetic treatments, healthcare providers should consider patient-specific factors such as age, renal or hepatic impairment, and potential drug interactions to minimize complications and enhance patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment implications for radiation-induced nausea and vomiting in specific patient groups. Horiot, JC., Aapro, M.[2007]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11162013/

Dose escalation of tolinapant (ASTX660) in combination with ... Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival.

2. astx.com astx.com/wp-content/uploads/2022/06/2022_ASTX660_Oral_EHA_abst-S217_Michot-final-website.pdf

preliminary analysis of the phase ii study using TOLINAPANT (ASTX660) MONOTHERAPY IN 98 PERIPHERAL T-. CELL LYMPHOMA ... HNSCC = Head and Neck Squamous Cell Carcinoma, DLBCL = Diffuse Large B cell Lymphoma ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05245682

Study Details | NCT05245682 | Tolinapant and Radiation ... Tolinapant 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 ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/31/14/2910/763500/Early-Phase-Trial-of-IAP-Antagonist-Tolinapant-and

Early-Phase Trial of IAP Antagonist Tolinapant and Definitive ... Our prior preclinical work in head and neck cancer models showed that when the IAP antagonist tolinapant was added to RT, local tumor control was enhanced, and ...

5. onclive.com onclive.com/view/tolinapant-displays-encouraging-activity-and-safety-in-relapsed-refractory-ptcl-ctcl

Tolinapant Displays Encouraging Activity and Safety in ... Single-agent tolinapant (ASTX660) generated promising response rates with a manageable safety profile in patients with relapsed/refractory peripheral T-cell ...