Phase II Randomized Study of Cisplatin and Radiotherapy Versus Durvalumab and Radiotherapy in Intermediate-Risk HPV-Positive Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma
- Trial ID
- 2023-508853-13-00
- Protocol
- EORTC 1740-HNCG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to estimate the **efficacy** in terms of event-free survival of two treatment arms in patients with intermediate risk, HPV-positive, locally advanced **oropharyngeal squamous cell carcinoma** (LA-OSCC). The treatment arms being compared are: (A) radiotherapy (RT) combined with **cisplatin**, and (B) RT combined with **durvalumab** followed by adjuvant durvalumab. This objective is clinically relevant as it aims to determine the most effective treatment regimen for improving survival outcomes in this patient population.
Secondary objectives include:
- Assessing differences between treatment arms in the change in FACT-HN score from baseline to 36 months post-RT.
- Estimating and describing locoregional control (LRC), distant metastasis-free survival (DMFS), overall survival (OS), and the cost-effectiveness of the immunotherapy-based experimental treatment arm versus the standard of RT and cisplatin using the EQ-5D-5L, as well as cost utility and lost productivity.
- Estimating and describing toxicity, incidence of second cancer, dysphagia using the PSS-HN swallowing subscale and MDADI Global at 36 months from the end of RT, PRO-CTCAE at various time points, and radiation-related late toxicity at 3 months, 6 months, and 1 year from the end of RT for Arms A, B, and C.
Participants
The clinical trial involves a total of **155 participants** diagnosed with **Oropharyngeal Squamous Cell Carcinoma**. The study population includes both male and female subjects, aged 18 years and older, who are considered to be part of a vulnerable population. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of locoregionally advanced, intermediate-risk, nonmetastatic squamous cell carcinoma of the oropharynx, with a history of smoking as a relevant lifestyle consideration. The trial requires participants to have adequate organ and marrow function, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a body weight of more than 30 kg. Additionally, participants must be HPV-positive as determined by p16 immunohistochemical staining. The trial does not specify any particular dietary or physical activity requirements for participants. The selection process ensures that participants are suitable for the administration of the study treatments, which include radiotherapy, cisplatin, and durvalumab.
Plans and Procedures
The clinical trial is a **randomized**, **controlled**, Phase II study designed to evaluate the efficacy of two treatment arms in patients with intermediate risk, HPV-positive, locally advanced **oropharyngeal squamous cell carcinoma**. The trial involves the administration of radiotherapy combined with either **cisplatin** or **durvalumab**, followed by adjuvant durvalumab in one of the arms. The primary objective is to estimate event-free survival, with secondary endpoints including overall survival, loco-regional control, distant metastasis-free survival, toxicity, and quality of life. The trial is expected to conclude by June 2026, with recruitment having commenced in May 2018.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed carcinoma, HPV status, and adequate organ function. Following randomization, treatment is to commence within one week. The study includes regular follow-up visits to monitor treatment response and adverse events, with the end-of-study visit marking the completion of the trial protocol. The expected duration of participant involvement is up to seven weeks for the durvalumab arm and three weeks for the cisplatin arm, with additional follow-up as required.
Participants may be withdrawn from the study early due to reasons such as disease progression, unacceptable toxicity, or withdrawal of consent. The trial is conducted under strict adherence to ethical guidelines, ensuring that all participants provide informed consent prior to enrollment. The study is designed to maintain a double-blind approach where applicable, ensuring unbiased assessment of outcomes. The trial's methodology and design are structured to provide robust data on the comparative efficacy and safety of the treatment regimens under investigation.
Treatment
The clinical trial involves the administration of **Durvalumab**, marketed under the name **IMFINZI 50 mg/mL concentrate for solution for infusion**. This experimental medication is a **concentrate for solution for infusion** and is administered via **intravenous use**. The maximum daily dose of Durvalumab is 1500 mg, with a total maximum dose of 12 g over a treatment period of up to 7 weeks. Durvalumab is a protein-based therapeutic agent, specifically classified as a protein of other origin. The administration schedule and participant compliance are closely monitored to ensure adherence to the dosing regimen.
In addition to Durvalumab, the trial also includes the administration of **Cisplatin**, which serves as a comparator treatment. Cisplatin is also provided as a **concentrate for solution for infusion** and is administered intravenously. The maximum daily dose for Cisplatin is 100 mg/m², with a total maximum dose of 300 mg/m² over a treatment period of up to 3 weeks. Cisplatin is a chemical-based therapeutic agent. The administration of Cisplatin is conducted under strict compliance monitoring to ensure accurate dosing and adherence to the treatment protocol.
Both treatments are part of a randomized Phase II study comparing the efficacy of Cisplatin plus radiotherapy versus Durvalumab plus radiotherapy, followed by adjuvant Durvalumab, in patients with intermediate-risk, HPV-positive, locally advanced oropharyngeal squamous cell carcinoma. The study aims to estimate the efficacy in terms of event-free survival across the different treatment arms. Compliance with the dosing schedules and administration routes is rigorously monitored to maintain the integrity of the trial outcomes.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **event-free survival (EFS)**. This endpoint will evaluate the time from randomization to the occurrence of any event such as disease progression, recurrence, or death. Secondary endpoints include overall survival (OS), loco-regional control (LRC), distant metastasis-free survival (DMFS), toxicity, and quality of life. These parameters will provide a comprehensive evaluation of the treatment's impact on patients with intermediate risk, HPV-positive, locally advanced oropharyngeal squamous cell carcinoma (LA-OSCC).
The trial involves two treatment arms: (A) radiotherapy (RT) combined with cisplatin, and (B) RT combined with durvalumab followed by adjuvant durvalumab. Efficacy assessments will be conducted at specified intervals throughout the study duration, with the primary focus on event-free survival. The collection and analysis of data will be performed using validated methods to ensure accuracy and reliability. The trial is designed to provide robust evidence on the efficacy of the treatment regimens in improving patient outcomes in this specific cancer population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically and/or cytologically confirmed (primary lesion or regional lymph nodes) squamous cell carcinoma of the oropharynx (OSCC) which is locoregionally advanced, intermediate risk and nonmetastatic (M0) as defined by the following (UICC/AJCC 8th Edition staging): • T1-2 N1 (smoking ≥ 10 pack years); • T3 N0-N1 (smoking ≥ 10 pack years); • T1-3 N2 (any smoking hx).
- Human papillomavirus (HPV)-related as determined by positive p16 immunohistochemical staining on any tumour specimens. Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of the tumour cells. Local testing is acceptable; testing will not be done centrally in real-time.
- Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see Appendix I) and a body weight of > 30 kg.
- Must be ≥ 18 years of age.
- 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.
- Women/men of childbearing potential must have agreed to use a highly effective contraceptive method while on study. Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception during the study and for 3 months after taking the last dose of durvalumab or up to 6 months after the last dose of chemoradiotherapy. Men, who wish to become fathers in the future, should ask for advice regarding cryoconservation of their sperm prior to treatment.
- Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation. The pregnancy test (urine or serum) is to be repeated/ renewed every month during protocol treatment, at the end of protocol treatment and for 3 months after taking the last dose of durvalumab or up to 6 months after the last dose of chemoradiotherapy.
- Patient must consent to provision of, and investigator(s) must confirm location and commit to obtain a representation of formalin fixed paraffin block of non-cytology tissue samples.
- Patient must consent to provision of samples of blood, saliva and oropharyngeal swab.
- Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life and health economics questionnaires in the languages provided.
- Patients must be accessible for treatment and follow-up.
- In accordance with CCTG policy, protocol treatment (cisplatin/RT or durvalumab) is to begin within 1 week of randomization.
- The patient is not receiving anti-cancer therapy in a concurrent clinical study and the patient agrees not to participate in other clinical studies during their participation in this trial while on study treatment.
- Adequate normal organ and marrow function as defined in the protocol (must be done within 14 days prior to randomization).
- Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.
- Patients must be assessed by a radiation oncologist and medical oncologist and deemed suitable for study participation including administration of radiotherapy, cisplatin and durvalumab as outlined in the protocol.
Exclusion Criteria
- Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years.
- Current history of other non-OSCC malignancies of the head and neck.
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, or an anti-CTLA4, including tremelimumab.
- Any previous cisplatin or carboplatin chemotherapy.
- Any previous induction chemotherapy for current SCCHN.
- Any previous surgical treatment of the current cancer (except for a diagnostic biopsy) and no major surgery within 28 days prior to randomization.
- Any previous radiation to the head and neck region that would result in overlap of fields for the current study.
- History of allergic or hypersensitivity reactions to any study drug or their excipients.
- Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 msec in screening ECG measured using standard institutional method or history of familial long QT syndrome.
- History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of randomization* or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy or grade ≥ 3 infusion reaction.
- Current or prior use of immunosuppressive medication within 28 days of study entry, with the exceptions of intranasal and inhaled corticosteroids or systemic chronic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Corticosteroids used on study for anti-emetic purpose are allowed. Corticosteroids as premedication for hypersensitivity reactions (e.g. computed tomography [CT] scan premedication) are allowed.
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease (e.g. colitis or Crohn's disease), diverticulitis with the exception of diverticulosis, celiac disease (controlled by diet alone) or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of treatment. There are exceptions in the protocol.
- Patients with active or uncontrolled intercurrent illness including, but not limited to: • cardiac dysfunction (symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia); • active peptic ulcer disease or gastritis; • active bleeding diatheses; • psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent; • known history of previous clinical diagnosis of tuberculosis; • known active human immunodeficiency virus infection (positive HIV 1/2 antibodies). HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible; • known active hepatitis B infection (positive HBV surface antigen (HBsAg). • known active hepatitis C infection.
- History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline CT scan.
- Receipt of live attenuated vaccination (examples include, but are not limited to, vaccines for measles, mumps, and rubella, live attenuated influenza vaccine (nasal), chicken pox vaccine, oral polio vaccine, rotavirus vaccine, yellow fever vaccine, BCG vaccine, typhoid vaccine and typhus vaccine) within 30 days prior to randomization.
- Pregnant or lactating women.
- Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy.
- Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 28 May 2018 | 13 |
 Italy | Not Recruiting | 28 May 2018 | 1 |
 Spain | Not Recruiting | 28 May 2018 | 11 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CISPLATIN | Test | — | INTRAVENOUS | 100 | 3 | SUB07483MIG |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1500 | 7 | PRD6651398 |