Evaluation of Thoracic Radiotherapy and Durvalumab in Elderly/Frail Patients with Unresectable Stage III Non-Small Cell Lung Cancer Unfit for Chemotherapy

Trial ID: 2024-513948-28-00
Protocol: TRADE-hypo
Sponsor: Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

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Diseases & Conditions

Non-small cell lung cancer stage III Non-small cell lung cancer stage IIIA Non-small cell lung cancer stage IIIB

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of either conventionally fractionated or hypofractionated thoracic radiotherapy in combination with **durvalumab** in patients with unresectable stage III **NSCLC** (Non–small-cell lung cancer) who are not suitable for chemotherapy. Additionally, the study aims to investigate the efficacies of these radiotherapy fractionation modes in combination with durvalumab, focusing on response rates in this patient population. This is clinically relevant as it addresses the treatment options for a vulnerable group of patients who are unable to undergo standard chemotherapy, potentially improving their therapeutic outcomes.

The secondary objective is to determine further parameters for efficacy, safety, and quality of life in both treatment arms. This will provide a comprehensive understanding of the treatment's impact beyond the primary endpoints, offering insights into its overall benefit-risk profile.

Participants

The clinical trial involves participants diagnosed with **unresectable stage III non-small-cell lung cancer (NSCLC)**. The study population includes both male and female subjects, aged 18 years and older, with a focus on those who are not suitable for chemotherapy. Participants are required to have a histologically documented diagnosis of the condition and must meet specific health criteria, such as adequate bone marrow, renal, and hepatic function, as well as a life expectancy of at least 12 weeks. The trial includes individuals with a performance status of 2 on the ECOG scale or those aged 70 years and older. The selection process involves a multi-disciplinary tumor board or consultation with relevant specialists to determine the non-feasibility of sequential chemo-radiotherapy. The sponsor has not provided information regarding the total number of participants. The trial population is characterized by a willingness to comply with the study protocol, including hospital visits and follow-up examinations. Participants' lifestyle considerations, such as diet and physical activity, are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and efficacy of thoracic radiotherapy in combination with **durvalumab** for patients with unresectable stage III non-small-cell lung cancer (NSCLC) who are not suitable for chemotherapy. This is a randomized, open-label, multicenter, phase II trial with a safety stop-and-go lead-in phase. The trial aims to assess the response rates and treatment-related toxicities, with a primary endpoint focusing on the occurrence of treatment-related pneumonitis grade ≥ 3 and objective response according to RECIST 1.1 criteria. Secondary endpoints include the occurrence of treatment-related adverse events (AEs) and serious adverse events (SAEs), progression-free survival (PFS), overall survival (OS), and quality of life (QoL) assessments.

The trial is expected to run from May 29, 2020, to December 31, 2025. Participants will be involved for a maximum treatment period of 12 months, with the possibility of early termination if they experience significant adverse events or fail to comply with the study protocol. The study visits will include an initial screening visit to confirm eligibility based on criteria such as adequate bone marrow, renal, and hepatic function, and a histologically documented diagnosis of unresectable stage III NSCLC. Follow-up visits will be scheduled to monitor treatment response and safety, with an end-of-study visit to assess the final outcomes and any long-term effects of the treatment.

Participants must be at least 18 years old, have a life expectancy of at least 12 weeks, and meet specific pulmonary function criteria. The trial will exclude individuals who do not meet these criteria or who are unable to comply with the study requirements. The investigational product, **IMFINZI** (durvalumab), will be administered as a concentrate for solution for infusion via intravenous use, with a maximum daily dose of 1500 mg and a total dose not exceeding 19500 mg over the treatment period. The trial will not include a pediatric formulation, and the product is not classified as an orphan drug.

Treatment

The clinical trial involves the administration of **durvalumab**, marketed under the name IMFINZI, which is a **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, and it is administered via the **intravenous route**. The concentration of the solution is 50 mg/mL. The maximum daily dose of durvalumab is 1500 mg, with a total maximum dose of 19500 mg over the course of the treatment. The maximum treatment period is 12 months. Durvalumab is a protein-based therapeutic agent, specifically classified as "Protein - Other". The product is manufactured by AstraZeneca AB and is not a pediatric formulation.

In this study, durvalumab is combined with thoracic radiotherapy, which is administered in either a conventionally fractionated or hypofractionated manner. The primary objective of the trial is to evaluate the safety and tolerability of these radiotherapy regimens in combination with durvalumab in patients with unresectable stage III non-small cell lung cancer (NSCLC) who are not suitable for chemotherapy. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the **objective response** of patients with unresectable stage III non-small cell lung cancer (NSCLC) to the treatment regimen. The primary efficacy endpoint is defined by the objective response according to RECIST 1.1 criteria. This involves measuring the size of tumors at specified intervals to determine the response rate to the combination of thoracic radiotherapy and durvalumab. Secondary efficacy endpoints include progression-free survival (PFS), duration of clinical benefit (including complete response, partial response, and stable disease), metastasis-free survival (MFS), overall survival (OS), and quality of life (QoL) as measured by the FACT-L scale. Additionally, descriptive subgroup analyses will be conducted to evaluate efficacy in relation to PD-L1 expression levels.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Fully-informed written consent and locally required authorization (European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
Age ≥ 18 years.
Histologically documented diagnosis of unresectable stage III NSCLC
Non-feasibility of sequential chemo-/radiotherapy as determined by the site’s multi-disciplinary tumor board; if there is no tumor board, then this decision will be made by the investigator in consultation with a radiation oncologist, if the investigator is not a radiation oncologist; or by the investigator in consultation with an oncologist, if the investigator is not an oncologist.
Fulfills at least one of the following criteria: - Performance status (PS) 2 (ECOG scale) / - ECOG 1 and CCI ≥ 1 / - Age ≥ 70 years
Must have a life expectancy of at least 12 weeks.
FEV1 ≥ 40% (Best/Soll)
DLCO or DLCO/VA (Hb-corrected, if available) ≥ 40% (Best/Soll)
FVC or VC ≥ 70% (Best/Soll)
At least one measurable site of disease as defined by RECIST 1.1 criteria.
Adequate bone marrow and renal function including the following: / - Hemoglobin ≥ 9.0 g/dL / - absolute neutrophil count ≥ 1.0 x 109 /L / - platelets ≥75x 109 /L / - Calculated creatinine clearance ≥30 mL/min as determined by the Cockcroft-Gault equation
Adequate hepatic function (with stenting for any obstruction, if required) including the following: - Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) / - AST (SGOT) / ALT (SGPT) ≤ 2.5x institutional ULN
Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: - Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). / - Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiationinduced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.

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Exclusion Criteria

Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the followup period of an interventional study.
Participation in another clinical study with an investigational product within 21 days prior to the first dose of the study treatment.
Prior immunotherapy or use of other investigational agents, including prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti- Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte associated antigen-4 (anti-CTLA-4) antibody, therapeutic cancer vaccines.
History or current radiology suggestive of interstitial lung disease.
Oxygen-dependent medical condition.
Any concurrent chemotherapy, investigational product (IMP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is acceptable.
Prior thoracic radiotherapy within the past 5 years before the first dose of study drug.
Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment into the study; patients must have recovered from effects of any major surgery. Note: Local non-major surgery for palliative intent is acceptable.
Active or prior documented autoimmune or inflammatory disorders (except inflammatory bowel disease [e.g. ulcerative colitis or Crohn's disease]; including diverticulitis [with the exception of diverticulosis], celiac disease, systemic lupus erythematosus, Sarcoidosis, or Wegener’s syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis). The following are exceptions to this criterion: - Patients with vitiligo or alopecia / - Patients with hypothyroidism (e.g., ollowing Hashimoto’s disease) stable on hormone replacement / - Any chronic skin condition that does not require systemic therapy / - Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
Active, uncontrolled inflammatory bowel disease [e.g. ulcerative colitis or Crohn's disease]. Patients in stable remission for more than 1 year may be included.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, interstitial lung disease, gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
History of another primary malignancy except for: - Malignancy treated with curative intent and with no known active disease ≥ 3 years before the first dose of IMP and of low potential risk for recurrence / - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease / - Adequately treated carcinoma in situ without evidence of disease
History of leptomeningeal carcinomatosis
History of active primary immunodeficiency
History of allogenic organ or tissue transplantation.
Clinical diagnosis of active tuberculosis.
Positive testing for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
Positive testing for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: - Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra articular injection) / - Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent / - Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab monotherapy.
Known allergy or hypersensitivity to any of the IMPs or any of the constituents of the product.
Any co-existing medical condition that in the investigator’s judgement will substantially increase the risk associated with the patient’s participation in the study.
Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].