Evaluation of Durvalumab and Tremelimumab Combined with Stereotactic Body Radiotherapy in Metastatic Squamous Cell Carcinoma of Various Sites
- Trial ID
- 2024-514920-18-00
- Protocol
- CSET N°2016/2454
- Sponsor
- Institut Gustave Roussy
Trial statistics
Objectives
The primary objective of this study is to evaluate the **safety** of the combination of **Durvalumab** and **Tremelimumab** with stereotactic body radiotherapy (SBRT) in patients with metastatic squamous cell carcinoma of the head and neck, lung, esophagus, cervix, vagina, vulva, or anus. This evaluation is crucial to determine the feasibility of this combination therapy in a clinical setting, ensuring that it does not pose undue risk to patients. Additionally, the study aims to assess the abscopal response rate following treatment with this combination, which is significant for understanding the potential systemic effects of localized radiotherapy when combined with immunotherapy.
Secondary objectives include:
- Describing the clinical efficacy of the combination on both irradiated and non-irradiated lesions, which is important for understanding the broader therapeutic impact of the treatment beyond the targeted area.
- Evaluating the safety and tolerability of the combination therapy within six months after the completion of radiotherapy, providing insights into the longer-term safety profile of the treatment regimen.
Participants
The clinical trial involves a study population comprising **male and female** participants aged 18 years and older, diagnosed with **metastatic squamous cell carcinoma** of the head and neck, lung, esophagus, cervix, vagina, vulva, or anus. The total number of participants is not provided by the sponsor. Participants were selected based on their ability to safely undergo the protocol therapy, with adequate organ function and no significant comorbid conditions. Lifestyle considerations such as diet and physical activity are not specified. The trial includes individuals who are part of a vulnerable population, and all participants must have a histologically or cytologically confirmed diagnosis of the specified carcinoma types. The study requires that participants have at least one tumor lesion accessible to radiation therapy and another site that can be spared from radiation. Participants must not have a history of previous radiation therapy within the body area to be irradiated and must adhere to specified wash-out periods from prior treatments. The trial population is required to have a WHO performance status of 0-1 and must be affiliated with a social security system or be a beneficiary of the same.
Plans and Procedures
The clinical trial is designed to evaluate the safety and clinical activity of **durvalumab** and **tremelimumab** in combination with stereotactic body radiotherapy (SBRT) in patients with metastatic squamous cell carcinoma of the head and neck, lung, esophagus, cervix, vagina, vulva, or anus. This study is structured as a Phase I/II trial, incorporating a randomized, double-blind, controlled methodology to ensure robust and unbiased results. The trial is expected to span from June 2017 to May 2025, with participant involvement anticipated to last until the end of the study or until early termination criteria are met.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, organ function, and previous treatment history. Following successful screening, participants will be enrolled in the trial and will attend regular follow-up visits to monitor safety and efficacy outcomes. These visits will include assessments such as CT-SCAN evaluations and adverse event monitoring using CTCAE v4.03. The end-of-study visit will conclude the participant's involvement, where final evaluations will be conducted to assess the primary and secondary endpoints, including dose-limiting toxicities and response rates according to RECIST 1.1 and irRC criteria.
The expected length of participant involvement is contingent upon the study's progression and individual response to treatment. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, withdrawal of consent, or non-compliance with study protocols. Participants are required to adhere to specific wash-out periods from previous treatments and must meet all inclusion criteria to ensure the integrity and safety of the trial. The trial aims to provide valuable insights into the therapeutic potential of combining **durvalumab** and **tremelimumab** with SBRT in treating metastatic squamous cell carcinoma.
Treatment
The clinical trial involves the administration of two experimental medications, **Durvalumab** and **Tremelimumab**, both of which are of biological/biotechnological origin. **Durvalumab**, marketed under the name **IMFINZI**, is provided as a 50 mg/mL concentrate for solution for infusion. It is administered intravenously. The pharmaceutical form is a solution for infusion, and the active substance is classified as a protein of other origin. The administration schedule and dosage frequency are determined by the study protocol, ensuring adherence to safety and efficacy parameters. Participant compliance is monitored through regular assessments and documentation of infusion sessions.
**Tremelimumab**, marketed as **IMJUDO**, is available as a 20 mg/mL concentrate for solution for infusion. Similar to **Durvalumab**, it is administered intravenously. The pharmaceutical form is a sterile concentrate for solution for infusion, and the active substance is also a protein of other origin. The administration of **Tremelimumab** follows a specific dosing schedule as outlined in the clinical trial protocol, with compliance monitoring to ensure accurate adherence to the treatment regimen. Both medications are used in combination with stereotactic body radiotherapy (SBRT) to evaluate their safety and clinical activity in patients with metastatic squamous cell carcinoma of various anatomical sites.
Efficacy
Efficacy in the clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoints include the evaluation of dose-limiting toxicities during Phase I, assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, and the CT-SCAN evaluation outside the field of focal radiotherapy during Phase II. Secondary endpoints will involve assessments based on RECIST 1.1 and immune-related response criteria (irRC), as well as adverse events evaluated using CTCAE-V4.
The trial aims to evaluate the abscopal response rate following treatment with **Durvalumab** and **Tremelimumab** in combination with stereotactic body radiotherapy (SBRT) in patients with metastatic squamous cell carcinoma of the head and neck, lung, esophagus, cervix, vagina, vulva, or anus. The efficacy parameters will be measured and collected at specified timepoints throughout the trial, ensuring a comprehensive analysis of the treatment's impact on the disease.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or Female patients ≥18 years of age or older.
- Histologically or cytologically proven metastatic squamous cell carcinoma (from head and neck, oesophagus, lung, cervix, vagina, vulva or anus) with the following features: Previously treated with at least one prior regimen (chemotherapy, signal transduction inhibitors or radiotherapy) To be treated with radiotherapy at primary tumor site or metastatic site or menacing metastatic site. o The sites of metastases allowed are: soft tissue, peripheral lung, and liver. o Patients with brain and bone metastasis to be treated with radiotherapy are not allowed. Patients with asymptomatic brain metastasis can be included o The total tumor volume to be irradiated must not exceed 400 cc.
- At least one tumor lesion must be accessible to radiation therapy and at least another tumor site can be spared from radiation therapy (unirradiated site).
- At least one unirradiated and one irradiated tumor site must be accessible to tumor biopsy.
- Known availability of an archived block
- The irradiated and unirradiated tumor sites must be mesurable as per RECIST 1.1
- Patients must have no history of previous radiation therapy within the body area to be irradiated.
- Minimal wash-out periods from previous treatments to C1D1 must be Any investigational agent > 4 weeks Bevacizumab > 6 weeks Chemotherapy > 4 weeks TKI > 4 weeks RANK ligand agonists > 6 weeks Immunosuppressive medication > 28 days, with the exceptions of intranasal, topical, and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceeding 10 mg/day of prednisone, or an equivalent corticosteroid Live attenuated vaccination > 30 days
- WHO 0-1, Performance Status ECOG of 0-1
- Patients must have adequate organ function defined as follows: Absolute neutrophil count of ≥ 1500/mm3, Platelet count≥ 100,000/mm3, Hemoglobin > 9 g/dL, Bilirubin ≤ 1.5 times the institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. Serum ALT and AST ≤2.5 ULN (or if liver metastases are present must be ≤ 5x ULN) Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance (see formula in section 4.1).
- Patients must be free of significant comorbid conditions that would preclude safe administration or completion of protocol therapy.
- Female patients must either be of non-reproductive potential (ie, post-menopausal ≥ 12 months with no menses without an alternative medical cause OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry (within 72 hours before study drug start)
- Fertile men with a female partner of childbearing potential must agree to use male codom plus spermicide and childbearing potential women must have agreed to use at least one highly effective contraceptive method during treatment on this trial and for up to 180 days after the last of dose of Durvalumab + Tremelimumab or 90 days after the last dose of Durvalumab monotherapy, whichever is the longer period
- Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol
- Patients must be affiliated to a social security system or beneficiary of the same
Exclusion Criteria
- Any situation where the irradiation of the target site would imply re-irradiation of a formerly irradiated tumor site.
- Patients with any concurrent severe and/or uncontrolled disease which could compromise participation in the study including: Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia’s Correction Active or prior documented autoimmune disease within the past 2 years. Of note, patient with vitiligo, Grave’s disease or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Patients with type 1 diabetes or hypothyroiditism stable under treatment or not requiring systemic treatment are eligible. Active or prior documented inflammatory bowel disease (eg Crohn’s disease, ulcerative colitis) History of primary immunodeficiency Severe chronic or acute infection such as chronic HBV, HCV and HIV1, 2 infection, active tuberculosis infection Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity or active non-infectious pneumonitis History of allogenic organ transplant Uncontrolled diabetes, Prior history of active bleeding diathesis or patients taking an oral vitamin K antagonist (except low-dose Coumadin (warfarin sodium)) Symptomatic congestive heart failure, Uncontrolled hypertension, Unstable angina pectoris Cardiac arrhythmia Active peptic ulcer disease or gastritis, Any psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent Active secondary malignancy unless the malignancy is not expected to interfere with the evaluation of safety and is approved by the sponsor. Examples of the latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, and isolated elevation of prostate-specific antigen. Patients with a completely treated prior malignancy and no evidence of disease for ≥ 2 years are eligible. Chronic treatment with corticosteroids or another immunosuppressant
- Patients with tumors that invade major vessels, as shown unequivocally by imaging studies
- Patients with central lung metastasis (i.e within 2 cm from hilum) that are cavitary as shown unequivocally by imaging studies
- Patients with a history of gross hemoptysis (bright red blood of ½ teaspoon or more per episode of coughing) ≤ 3 months prior enrolment
- Major surgery within the last 4 weeks prior to entering the study
- Persisting significant toxicities related to prior treatments i.e. ≥ Grade 2 AE according to CTCAE V4.03 except alopecia and biological values defined in inclusion criteria I10.
- Current or planned use of forbidden concomitant medications : Any investigational anticancer therapy not specified in this protocol Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of hormones for noncancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable. Immunosuppressive medications including, but not limited to systemic corticosteroids at doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the management of investigational product-related AEs or in subjects with contrast allergies is acceptable. In addition, use of topical, inhaled and intranasal corticosteroids is permitted. Live attenuated vaccines within 90 days of Durvalumab dosing or within 180 days of Durvalumab and Tremelimumab dosing. Inactivated vaccines, such as the injectable influenza vaccine, are authorized.
- Any prior Grade ≥ 3 irAE while receiving previous immunotherapy agent or any unresolved irAE > Grade 1.
- Prior exposure to any anti-PD-1 or anti-PD-L1 or anti-CTLA4 antibody
- Known allergy or hypersensitivity to humanized antibodies
- Pregnant or breastfeeding women
- Persons deprived of their freedom or under guardianship, or for whom it would be impossible to undergo the medical follow-up required by the trial, for geographic, social or psychological reasons
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 20 Jun 2017 | 61 |
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 |
|---|---|---|---|---|---|---|
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD6651398 |
IMJUDO 20 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION (STERILE CONCENTRATE). | INTRAVENOUS USE | — | — | PRD10239824 |