Durvalumab and Low-dose PCI vs Durvalumab and Observation in Radically Treated Patients With Stage III NSCLC (NVALT28)

NCT04597671 | Active Not Recruiting Phase 3 DMC

• 1 other identifier: NVALT28
• Study Type: interventional
• Target: 170
• Locations: 1 country
• Sites: 14

Brief Summary

This trial studies the combination of low-dose PCI with or without durvalumab in patients with radically treated stage III NSCLC. The hypothesis is that the incidence of brain metastases will be reduced from 30% to 15 % with durvalumab and to a maximum of 5% with the addition of low-dose PCI. This strategy would make brain metastases in stage III NSCLC history and this would improve QoL.

Conditions

Carcinoma, Non-Small-Cell Lung

Keywords

PCI; immunotherapy; NSCLC; QoL

Outcome Measures

Primary Outcomes (1)

• Reduction of incidence of brain metastases

  To evaluate whether the addition of PCI to durvalumab after concurrent chemo-radiotherapy for stage III NSCLC reduces the cumulative incidence of brain metastases.

  From randomisation until moment of discovery of brain metastases or latest at 24 months after randomization

Secondary Outcomes (5)

• Effect on neurocognitive functioning

  From randomization until 24 months after randomization

• Time to develop neurological symptoms

  From randomization until time to develop neurological symptoms with a maximum of 24 months after randomization

• Toxicity assessment

  From randomization until end of study treatment

• Patient reported neurocognitive decline

  From randomization until 5 years after randomization

• Cost-efficiency

  From randomization until end of study treatment

Study Arms (2)

Arm A

EXPERIMENTAL

Durvalumab with low-dose PCI

Drug: Durvalumab; Radiation: low-dose PCI

Arm B

ACTIVE COMPARATOR

Durvalumab with observation

Drug: Durvalumab

Interventions

Durvalumab DRUG

Durvalumab is used as standard of care

Also known as: Imfinzi

Arm A; Arm B

low-dose PCI RADIATION

PCI will be given concurrently with durvalumab. PCI will be given to a dose of 15 Gy in 10 fractions

Also known as: Prophylactic Cranial Irradiation (PCI)

Arm A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must sign a study-specific informed consent
• TNM8 stage IIIA, IIIB or IIIC non-small cell lung cancer before start of concurrent chemoradiotherapy (preferentially histology; cytology is allowed)
• Whole body FDG-PET-scan and brain imaging (MRI or CT with iv contrast) before the start of chemoradiotherapy: No distant metastases.
• Additional brain MRI (MRI mandatory) dated within 28 days before randomization: no brain metastases.
• Eligible for durvalumab treatment according to registration label of durvalumab in the Netherlands. Durvalumab has to be given in standard of care. (durvalumab has to be started already before randomization and PCI (i.e. at least one administration of durvalumab has to be given before randomization).
• Treatment completed with concurrent chemoradiation. The last day of chemoradiotherapy should be within 80 days of randomization and randomization should be after start of durvalumab. Any platinum doublet or daily cisplatin regimen that is standard of care in The Netherlands is allowed. No disease progression after chemoradiotherapy (evaluated with CT-thorax and upper abdomen during/after the last dose of chemoradiotherapy and comparison with CT before start of chemoradiotherapy). Consolidation chemotherapy cycles after radiotherapy is not permitted but administration of 1 cycle of chemotherapy prior to concurrent chemo-radiotherapy is acceptable. Where possible, chemotherapy regimens should be given according to National Comprehensive Cancer Network (NCCN) Guidelines or European Society for Medical Oncology (ESMO) Guidelines.
• To be eligible for randomization, patients must have received a total dose of thoracic radiotherapy of 60-66 Gy in 2 - 2.75 Gy per day, oncedaily fractions, or in case of daily cisplatin regimen 60.5-66 Gy in 22-24 fractions. Other radiotherapy schedules are not allowed. Sites are encouraged to adhere to the organ at risk constraints as used in the PACIFIC study as well as the EORTC recommendations for high-dose radiotherapy for lung cancer:
• Mean lung dose must be \<20 Gy and/or V20Gy must be \<35%
• Mean oesophagus dose must be \<34 Gy
• Heart V45Gy \<35% or V30Gy \<30%.
• Proton therapy to the chest is allowed.
• ECOG performance status 0-1 at the time of randomization.
• Evidence of postmenopausal status, or negative urinary or serum pregnancy test for female premenopausal patients.

You may not qualify if:

• Participation in another clinical study with an investigational product during the last 4 weeks.
• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or a study that will not influence the primary and secondary endpoint parameters (e.g. bioimpedance measurements, E-Nose) or the follow-up period of an interventional study. Note: participation in the NVALT31 study (follow up with CT thorax or PET-CT) is allowed
• Mixed small cell and non-small cell lung cancer histology.
• Patients who receive sequential chemoradiation therapy for locally advanced NSCLC.
• Disease progression after completion of definitive platinum based, concurrent chemoradiation therapy, as proven by a CT scan after end of chemoradiation.
• Any unresolved toxicity CTCAE (v. 5.0) more than grade 2 (i.e. grade 3 or higher) from the prior chemoradiation therapy. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by PCI may be included (e.g. hearing loss) after consultation with the principal investigator.
• Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment.
• Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients with vitiligo, Grave's disease, diabetes type I or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
• Active or prior documented inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis).
• History of primary immunodeficiency.
• History of organ transplant that requires therapeutic immunosuppression.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses or psychiatric illness/ social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent.
• Known history of tuberculosis, hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV).
• History of another primary malignancy within 2 years prior to starting study drug, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ and the disease under study.
• Prior cranial irradiation is not allowed.

Sponsors & Collaborators

• Association NVALT Studies: lead

Study Sites (14)

ZGT

Almelo, Netherlands

Location

AmsterdamUMC - location VUmc

Amsterdam, Netherlands

Location

Radiotherapie Groep

Arnhem, Netherlands

Location

Rijnstate

Arnhem, Netherlands

Location

Gelderse Vallei

Ede, Netherlands

Location

Catharina Ziekenhuis

Eindhoven, Netherlands

Location

ZRTI

Flushing, Netherlands

Location

UMCG

Groningen, Netherlands

Location

Maastro

Maastricht, 5912 BL, Netherlands

Location

Canisius Wilhemina Ziekenhuis

Nijmegen, Netherlands

Location

Radboud UMC

Nijmegen, Netherlands

Location

ZorgSaam Ziekenhuis

Terneuzen, Netherlands

Location

Maxima Medisch Centrum

Veldhoven, Netherlands

Location

Zaans Medisch Centrum

Zaandam, Netherlands

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

durvalumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Dirk De Ruysscher, MD PhD

  Maastricht University/ Maastro clinic

  PRINCIPAL INVESTIGATOR

• Lizza Hendriks, MD PhD

  Maastricht UMC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 24, 2020
• First Posted: October 22, 2020
• Study Start: December 6, 2021
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2032
• Last Updated: January 29, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

NL (14)