Thoracic Radiotherapy plus Durvalumab in Elderly and/or frail NSCLC stage III patients unfit for chemotherapy - Employing optimized (hypofractionated) radiotherapy to foster durvalumab efficacy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

8 May 2020 → 21 Jan 2026

Decision date (initial)

2024-08-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca

External identifiers

EU CT number

2024-513948-28-00

EudraCT number

2019-002192-33

ClinicalTrials.gov

NCT04351256

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

Primary objective
To evaluate the safety and tolerability of either conventionally fractionated (CON-group) or hypofractionated (HYPO-group) thoracic radiotherapy in combination with durvalumab.

Primary efficacy objective
To investigate the efficacies of either mode of fractionation of radiotherapy in combination with durvalumab with respect to the response rates in patients with unresectable stage III NSCLC, who are not suitable for chemotherapy.

Secondary objectives 1

1. To determine further parameters for efficacy, safety, and quality of life in both treatment arms.

Conditions and MedDRA coding

unresectable stage III NSCLC (Non–small-cell lung cancer)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. 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.
2. Age ≥ 18 years.
3. Histologically documented diagnosis of unresectable stage III NSCLC
4. 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.
5. Fulfills at least one of the following criteria: - Performance status (PS) 2 (ECOG scale) / - ECOG 1 and CCI ≥ 1 / - Age ≥ 70 years
6. Must have a life expectancy of at least 12 weeks.
7. FEV1 ≥ 40% (Best/Soll)
8. DLCO or DLCO/VA (Hb-corrected, if available) ≥ 40% (Best/Soll)
9. FVC or VC ≥ 70% (Best/Soll)
10. At least one measurable site of disease as defined by RECIST 1.1 criteria.
11. 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
12. 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
13. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
14. 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).
15. 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.

Exclusion criteria 24

1. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the followup period of an interventional study.
2. Participation in another clinical study with an investigational product within 21 days prior to the first dose of the study treatment.
3. 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.
4. History or current radiology suggestive of interstitial lung disease.
5. Oxygen-dependent medical condition.
6. 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.
7. Prior thoracic radiotherapy within the past 5 years before the first dose of study drug.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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
13. History of leptomeningeal carcinomatosis
14. History of active primary immunodeficiency
15. History of allogenic organ or tissue transplantation.
16. Clinical diagnosis of active tuberculosis.
17. 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.
18. Positive testing for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
19. 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)
20. 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.
21. Known allergy or hypersensitivity to any of the IMPs or any of the constituents of the product.
22. 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.
23. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
24. 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].

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Primary Endpoint: Toxicity, defined by the occurence of treatment-related pneumonitis grade ≥ 3
2. Primary Efficacy Endpoint: Objective response according to RECIST 1.1 criteria

Secondary endpoints 8

1. Occurence of treatment-related AEs and SAEs according to CTCAE V5.0
2. Abnormal values of laboratory parameters
3. PFS according to RECIST 1.1
4. Duration of Clinical Benefit (Duration of CR, PR, SD) according to RECIST 1.1
5. MFS
6. OS
7. QoL (FACT-L)
8. Descriptive sub-group analyses of efficacy in relation to PD-L1 expression levels (<°1% vs ≥°1%)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Sponsor organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Address

Steinbacher Hohl 2-26, Praunheim Praunheim

City

Frankfurt Am Main

Postcode

60488

Country

Germany

Scientific contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial project manager

Public contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial project manager

Third parties 1

Locations

1 EU/EEA country · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications