An open-label, multi-center, phase 2 study of chemo-immunotherapy followed by reduced-dose hypofractionated RT and maintenance immunotherapy for stage III unresectable NSCLC

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione IRCCS Policlinico San Matteo

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

3 Dec 2024 → ongoing

Decision date (initial)

2024-12-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518408-32-00

EudraCT number

2021-001203-32

ClinicalTrials.gov

NCT05128630

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

To assess the safety and tolerability, as defined by Grade 3 and Grade 4 possibly related adverse events (PRAEs) within 6 months from the initiation of treatment.

Secondary objectives 1

1. To assess the efficacy in terms of PFS and OS

Conditions and MedDRA coding

Non Small Cell Lung Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
2. Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses
3. 18 years or older at the time of signing the ICF
4. Histologically- or cytologically-documented NSCLC with locally-advanced, unresectable Stage III disease (according to the IASLC Staging Manual Version 8 [IASLC 2016]). Positron emission tomography (PET)/CT, MRI of the brain, and endobronchial ultrasound with biopsy are highly encouraged at diagnosis
5. Patients with measurable disease assessed at baseline by CT/MRI will be entered in this study
6. Must have a life expectancy of at least 12 weeks at enrolment
7. WHO/ECOG PS 0-1
8. Patient not eligible for concurrent chemo radiation according to investigator assessment
9. Adequate organ and marrow function at enrolment as defined below. These parameters should be achieved without augmentation by growth factors, transfusions, or infusions within 28 days of screening unless required for SoC: (a) Haemoglobin ≥9.0 g/dL; (b) Absolute neutrophil count >1.0 × 10^9/L; (c) Platelet count >75 × 10^9/L; (d) Serum bilirubin ≤1.5 × upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician. (e) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN. (f) Measured creatinine clearance >40 mL/min or calculated creatinine clearance >40 mL/min as determined by Cockcroft-Gault (using actual body weight) (Cockcroft and Gault 1976). Males: Creatinine clearance (mL/min) = [Weight (kg) × (140 - Age)] / 72 × serum creatinine (mg/dL) Females: Creatinine clearance (mL/min) = [Weight (kg) × (140 - Age) × 0.85] / 72 × serum creatinine (mg/dL)
10. Body weight >30 kg at enrollment
11. Male or female
12. Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female premenopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. Women sexually active in a way that could result in pregnancy, subjects of childbearing potential must agree to use 2 contraception methods (including 1 highly effective) during the study (Appendix 4) and for 3 months (12 weeks) after the last dose of Durvalumab. Subjects who can father children and have partners of childbearing potential must agree to use 2 contraception methods during the study (Appendix 4).. Subjects born male who are sexually active with a pregnant or breastfeeding person must use contraceptives outlined in Appendix 4 to prevent secondary exposure to seminal fluid. The following age-specific requirements apply: (a) 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). (b) 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 radiation-induced 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)

Exclusion criteria 22

1. Patients who have disease considered for surgical treatment as part of their care plan, such as Pancoast or superior sulcus tumors
2. Mixed small-cell lung cancer and NSCLC histology
3. History of allogeneic organ transplantation
4. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, 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: (a) Patients with vitiligo or alopecia. (b) Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement. (c) Any chronic skin condition that does not require systemic therapy. (d) Patients without active disease in the last 5 years at enrolment may be included but only after consultation with the Study Physician. (e) Patients with celiac disease controlled by diet alone
5. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, serious chronic GI conditions associated with diarrhoea, 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.
6. History of another primary malignancy except for: (a) Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence. (b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. (c) Adequately treated carcinoma in situ without evidence of disease
7. History of leptomeningeal carcinomatosis
8. History of active primary immunodeficiency
9. Active infection including hepatitis B (known positive hepatitis B surface antigen [HbsAg] result), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies). Patients with a past or resolved hepatitis B virus (HBV) infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HbsAg) are eligible. Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
10. Any unresolved toxicity of NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. (a) Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. (b) Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician
11. Known allergy or hypersensitivity to durvalumab or any of the IP excipients
12. Prior chemo-radiotherapy for lung cancer. Prior surgical resection (ie, Stage I or II) is permitted
13. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP
14. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP
15. Prior exposure to immune-mediated therapy, including but not limited to, other anti-CTLA-4, antiPD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccine
16. Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. The following are exceptions to this criterion: (a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection); (b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent; (c) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
17. Previous IP assignment in the present study
18. Concurrent enrollment in another clinical study, unless it is an observational (non interventional) clinical study or the follow-up period of an interventional study
19. Participation in another clinical study with an IP during the 4 weeks prior to the first IP dose administration
20. Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.
21. 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 90 days after the last dose of IP (Appendix 4)
22. Judgment by the Investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions, and requirements

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Grade 3 and Grade 4 PRAEs

Secondary endpoints 1

1.  Median PFS according to RECIST 1.1 as assessed by the Investigator  PFS6 and PFS12 (12 months) according to RECIST 1.1 as assessed by the Investigator  Median OS and OS12 (12 months)

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione IRCCS Policlinico San Matteo

Sponsor organisation

Fondazione IRCCS Policlinico San Matteo

Address

Viale Camillo Golgi 19

City

Pavia

Postcode

27100

Country

Italy

Scientific contact point

Organisation

Fondazione IRCCS Policlinico San Matteo

Contact name

Agustoni Francesco

Public contact point

Organisation

Fondazione IRCCS Policlinico San Matteo

Contact name

Agustoni Francesco

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 7 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