Dual-immunotherapy and short-course medium-dose radiotherapy, followed by surgery for tumor microenvironment modification in early-stage NSCLC: the DIRECT-trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Stichting Amsterdam UMC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

29 Oct 2024 → ongoing

Decision date (initial)

2024-10-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516580-87-00

EudraCT number

2020-004413-13

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

1. to assess the safety of neoadjuvant single fixed-dose 1500mg IV durvalumab plus an adaptive low dose radiotherapy schedule
2. to explore the pathological response of neoadjuvant single fixed-dose 1500mg IV durvalumab plus an adaptive low dose radiotherapy schedule

Secondary objectives 2

1. to explore tumor immune infiltration after neoadjuvant single fixed-dose 1500mg IV durvalumab plus an adaptive low dose radiotherapy schedule
2. to explore the radiological and metabolic response to neoadjuvant single fixed-dose 1500mg IV durvalumab plus an adaptive low dose radiotherapy schedule

Conditions and MedDRA coding

early stage NSCLC

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Histologically confirmed NSCLC
2. T1c-3N0-2, here T3 tumors are based on size, but not based in invasion into the thoracic wall, mediastinum, vertebra or diaphragm or ipsilateral lung nodules
3. Willing and able to provide written informed consent for the trial
4. Above 18 years of age on day of signing informed consent
5. Have measurable disease based on RECIST 1.1
6. Have a ECOG performance status of 0-1, and are considered operable based on pulmonary function test and/or exercise testing
7. Demonstrate adequate organ function, as deemed acceptable by the treating physician in the context of immunotherapy: a. Leukocytes ≥ 3,000/mm3 b. Absolute neutrophil count (ANC) ≥ 1000/mm3 c. Platelet count ≥ 75,000/mm3 d. Hemoglobin ≥ 6 mmol/L (9.7 g/dL) e. Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥40 mL/min (if using the Cockcroft-Gault formula below): i. Female CrCl = [(140 - age) x weight x 0.85]/(0.85 x creat in mmol/L) ii. Male CrCl = [(140 - age) x weight x 1.00]/(0.81 x creat in mmol/L) f. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome) g. AST and ALT ≤ 2.5 times the upper limit of normal h. Subjects must have adequate lung function to permit surgical resection determined by preenrollment pulmonary function tests to include DLCO
8. Body weight >30 kg
9. Must have a life expectancy of at least 12 weeks

Exclusion criteria 12

1. Prior surgery and/or radiotherapy on the ipsilateral thorax
2. Patients deemed inoperable
3. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of day 0. Inhaled or topical steroids, and adrenal replacement steroid >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
4. Additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
5. 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], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:  Patients with vitiligo or alopecia  Patients with hypothyroidism (e.g., following Hashimoto syndrome) 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  Patients with celiac disease controlled by diet alone
6. Uncontrolled intercurrent illness, including but not limited to symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic 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
7. Active infection requiring systemic therapy.
8. A history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
9. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, 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.
10. Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
11. Has received prior therapy with an anti-PD-1, anti-PD-L1 including durvalumab, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
12. Patient is pregnant or breastfeeding or expecting to conceive within the projected duration of the trial, starting with the pre-screening or screening visit through 23 weeks after the last dose of trial treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety defined as the percentage of patients with adverse events.
2. Major pathological response (MPR) and pathological complete response (pCR) rates in resected tumor-specimens.

Secondary endpoints 2

1. Tumor immune infiltration after durvalumab and RT in 4 categories.
2. Radiological response to durvalumab and RT using RECIST v1.1 criteria, and metabolic response based on 18F-FDG PET.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Stichting Amsterdam UMC

Sponsor organisation

Stichting Amsterdam UMC

Address

De Boelelaan 1117

City

Amsterdam

Postcode

1081 HV

Country

Netherlands

Scientific contact point

Organisation

Stichting Amsterdam UMC

Contact name

Idris Bahce

Public contact point

Organisation

Stichting Amsterdam UMC

Contact name

Idris Bahce

Locations

1 EU/EEA country · 3 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 4 files

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

Application history

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