Chemoradiotherapy vs Immunotherapy with Radiation for Oral Cancer

Recruiting at 25 trial locations

Overseen By Wendy Parulekar

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Canadian Cancer Trials Group

Must not be taking: Immunosuppressants, PD1/PD-L1 inhibitors

Disqualifiers: Other malignancies, Autoimmune disorders, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 41

129 Participants Needed

Trial Summary

What is the purpose of this trial?

Sometimes, cancer patients receive an initial treatment, followed by additional treatment to lower the chance of cancer coming back. The standard or usual treatment for this type of disease is initially having radiation therapy at the same time as chemotherapy (with a drug called cisplatin), with no additional therapy afterwards

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that you should not be on any other anti-cancer therapy or participate in other clinical studies during the trial. It's best to discuss your current medications with the trial team to ensure they don't interfere with the study treatments.

What data supports the effectiveness of the treatment for oral cancer?

Research shows that combining durvalumab, an immune therapy drug, with radiotherapy has shown promise in treating head and neck cancers, which are similar to oral cancers. Additionally, a case study reported a positive response in a patient with oral cancer using a similar combination of immune therapy and radiotherapy, suggesting potential effectiveness. ^{1 2 3 4 5}

Is the combination of chemoradiotherapy and immunotherapy with radiation generally safe for humans?

The combination of treatments like cisplatin and durvalumab has been studied for safety in various cancers. In one study, 45% of patients experienced severe side effects like anemia and stomatitis, but no treatment-related deaths occurred. Another study with durvalumab showed a high rate of severe side effects, but these were expected and manageable. ^{6 7 8 9 10}

How does the treatment of chemoradiotherapy vs immunotherapy with radiation for oral cancer differ from other treatments?

This treatment is unique because it combines immunotherapy (using durvalumab) with radiation, which can enhance the immune system's ability to fight cancer, unlike traditional chemoradiotherapy that primarily targets cancer cells directly. This approach leverages the immune-modulatory effects of radiation to potentially improve outcomes in patients who may not respond well to standard chemotherapy. ^{1 5 11 12 13}

Research Team

Anna Spreafico

Principal Investigator

UNH/Princess Margaret Cancer Centre, Toronto ON Canada

Khalil Sultanem

Principal Investigator

The Jewish General Hospital, Montreal QC, Canada

Eligibility Criteria

This trial is for adults with intermediate-risk HPV-positive oropharyngeal squamous cell carcinoma that hasn't spread. They must be in good physical condition, not have had certain previous cancer treatments, and agree to use effective contraception. People with a history of severe allergies to study drugs, other cancers (except some exceptions), autoimmune diseases, uncontrolled illnesses, or who are pregnant can't join.

Inclusion Criteria

I can care for myself and weigh more than 30 kg.

The following radiological investigations must be done within 8 weeks of randomization: CT or MRI of the neck (with PET-CT and head imaging as indicated); CT chest or x-ray, other radiology tests as clinically indicated

I can start treatment within a week of being chosen for the trial.

Exclusion Criteria

My heart's electrical activity (QTcF) is normal and I don't have a family history of long QT syndrome.

I have never had a severe immune reaction from treatments or been on strong immune-suppressing drugs recently.

I haven't taken strong immune-weakening meds in the last 28 days, except for small doses of steroids or specific treatments.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Concurrent Treatment

Participants receive either Cisplatin or Durvalumab concurrently with radiation therapy

7 weeks

35 visits (in-person, daily radiation sessions)

Adjuvant Treatment

Participants receive adjuvant Durvalumab or Durvalumab with Tremelimumab

24 weeks

6 visits (in-person, every 4 weeks)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• Cisplatin
• Durvalumab
• Radiation
• Tremelimumab

Trial Overview The study compares the effectiveness of cisplatin plus radiotherapy against durvalumab (an immunotherapy drug) plus radiotherapy followed by either more durvalumab or a combination of tremelimumab (another immunotherapy drug) and durvalumab in preventing cancer recurrence.

Participant Groups

Group I: Radiation/Durvalumab + Adjuvant Durvalumab/Tremelimumab Experimental Treatment 3 Interventions

ARM CLOSED TO ACCRUAL WITH AMENDMENT #1

Group II: Radiation/Durvalumab + Adjuvant Durvalumab Experimental Treatment 2 Interventions

All patients will receive standard fractionation radiation therapy (RT) scheme: 70 Gy in 35 fractions over 7 weeks (i.e. 2 Gy per fraction) Concurrent Phase: Durvalumab IV 1500 mg, days -7 and 22 (the second dose is given concurrently with RT). Adjuvant Phase (to start 4 weeks after completion of concurrent phase): Durvalumab IV 1500 mg q4 weekly for 6 doses.

Group III: Radiation/Cisplatin Active Control 2 Interventions

All patients will receive standard fractionation radiation therapy (RT) scheme: 70 Gy in 35 fractions over 7 weeks (i.e. 2 Gy per fraction) Cisplatin IV 100 mg/m2 days 1, 22, 43 concurrently with RT

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

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

Canadian Cancer Trials Group

Lead Sponsor

Trials

135

Recruited

70,300+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

In a phase 2 trial involving 90 patients with non-small-cell lung cancer resistant to PD-1/PD-L1 therapy, the combination of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) with radiotherapy did not show improved overall response rates compared to the therapy alone, leading to the trial's early termination due to futility.

The most common serious adverse events were manageable, but one patient in the low-dose radiotherapy group died from respiratory failure potentially related to the treatment, highlighting the need for careful monitoring in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial. Schoenfeld, JD., Giobbie-Hurder, A., Ranasinghe, S., et al.[2023]

In a phase 3 study of 713 patients with stage III non-small-cell lung cancer, durvalumab significantly improved progression-free survival compared to placebo, with a median of 16.8 months versus 5.6 months, respectively.

Durvalumab also showed a higher response rate (28.4% vs. 16.0%) and longer median time to death or distant metastasis (23.2 months vs. 14.6 months), while safety profiles were similar between durvalumab and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. Antonia, SJ., Villegas, A., Daniel, D., et al.[2022]

In a study involving 10 patients receiving palliative radiotherapy (RT) combined with durvalumab, the treatment was well tolerated, with only 50% experiencing mild to moderate adverse events, primarily G2 mucositis, and no severe adverse events reported.

The treatment showed promising efficacy, with a 60% objective response rate in evaluable lesions and a significant decrease in tumor growth rate after RT, indicating that durvalumab combined with RT may effectively reduce tumor size in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial. Levy, A., Massard, C., Soria, JC., et al.[2022]

In a trial involving 20 patients with recurrent/metastatic oral squamous cell carcinoma, the combination of camrelizumab with docetaxel and cisplatin showed a median overall survival of 14.4 months and an overall response rate of 40%, indicating promising efficacy.

The treatment was generally well tolerated, with 45% of patients experiencing grade ≥ 3 treatment-related adverse events, the most common being anemia and stomatitis, but no treatment-related deaths occurred.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of camrelizumab with docetaxel and cisplatin for the first line treatment in recurrent/metastatic oral squamous cell carcinoma. Ju, H., Wei, D., Wu, Y., et al.[2023]

In a safety run-in phase of the DURIGAST PRODIGE 59 study involving 11 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, 63.6% experienced significant adverse events, primarily neutropenia, indicating a notable safety concern with the treatment combination.

The combination of FOLFIRI with Durvalumab and/or Tremelimumab showed an expected safety profile, allowing progression to the randomized phase II study, although careful monitoring for serious adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. Evrard, C., Aparicio, T., Soularue, E., et al.[2022]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

In a study of 107 patients with stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT) and intensity-modulated radiotherapy (IMRT), the median progression-free survival (PFS) was 20.7 months, indicating effective treatment outcomes.

Factors associated with longer PFS included a favorable response to CCRT, a radiation dose of 62 Gy or more, and having stage IIIA NSCLC, while shorter durations of durvalumab treatment and lower radiation doses were linked to increased mortality risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy profiles of concurrent chemoradiotherapy with intensity-modulated radiotherapy followed by durvalumab in patients with unresectable stage III non-small cell lung cancer: A multicenter retrospective cohort study. Takeda, Y., Kusaba, Y., Tsukita, Y., et al.[2022]

In a phase II study involving 29 patients with locally advanced head and neck squamous cell carcinoma who were ineligible for cisplatin, the combination of pembrolizumab and radiotherapy showed promising efficacy, with a 24-month progression-free survival rate of 71%.

The treatment was generally well-tolerated, although a significant number of patients experienced grade 3/4 lymphopenia (58.6%), indicating the need for monitoring immune cell changes during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication. Weiss, J., Sheth, S., Deal, AM., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial. [2023]

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

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. [2022]

3. China pubmed.ncbi.nlm.nih.gov

Response to nivolumab combining radiotherapy and nimotuzumab in metastatic oral squamous cell carcinoma patient with strong PD-L1 expression: a case report. [2022]

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

Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial. [2022]

5. Ireland pubmed.ncbi.nlm.nih.gov

Anti PD-L1 DUrvalumab combined with Cetuximab and RadiOtherapy in locally advanced squamous cell carcinoma of the head and neck: A phase I/II study (DUCRO). [2023]

6. China pubmed.ncbi.nlm.nih.gov

A pilot study of camrelizumab with docetaxel and cisplatin for the first line treatment in recurrent/metastatic oral squamous cell carcinoma. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. [2022]

8. Brazil pubmed.ncbi.nlm.nih.gov

Oral ulcers and sarcoid-like reaction in lymph nodes after cemiplimab therapy for locally advanced cutaneous squamous cell carcinoma: a case report. [2022]

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

Anti-epidermal growth factor receptor targeted therapy-associated ulcerations. [2023]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

11. Ireland pubmed.ncbi.nlm.nih.gov

The efficacy profiles of concurrent chemoradiotherapy with intensity-modulated radiotherapy followed by durvalumab in patients with unresectable stage III non-small cell lung cancer: A multicenter retrospective cohort study. [2022]

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

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication. [2023]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Synergies Radiotherapy-Immunotherapy in Head and Neck Cancers. A New Concept for Radiotherapy Target Volumes-"Immunological Dose Painting". [2021]