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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04597671
Recruitment Status : Recruiting
First Posted : October 22, 2020
Last Update Posted : February 2, 2022
Information provided by (Responsible Party):
Dutch Society of Physicians for Pulmonology and Tuberculosis ( Association NVALT Studies )

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.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Drug: Durvalumab Radiation: low-dose PCI Phase 3

Detailed Description:

The brain is frequently a site of disease relapse in Non-Small Cell Lung Cancer (NSCLC) patients. For radically treated patients, stage III has the highest risk for brain metastases with a cumulative incidence of brain metastases after radical treatment of approximately 30% for which there is no cure at the moment, decreasing the long-term survival and Quality of Life. Strategies to reduce incidence of brain metastases are necessary.

Prophylactic Cranial Irradiation (PCI) has been shown to reduce the incidence of brain metastases in patients with NSCLC. However, PCI leads to a neurocognitive impairment in about 25% of patients without altering the QoL.

The addition of durvalumab after chemo-radiotherapy in stage III NSCLC could reduce the incidence of brain metastases. In pre-clinical models, immunotherapy potentiates the effects of radiotherapy by a factor two to five. This makes the combination of PCI and immunotherapy interesting to evaluate whether it can further decrease the percentage of brain metastases as well as preserve organ function as a lower radiation dose can probably be used when combined with an antiprogrammed death (ligand)1 (PD(L)-1).

The hypothesis of the NVALT28 trial is that the combination of PCI with durvalumab will decrease the incidence of brain metastases 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 170 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: NVALT 28/ PRL01 Durvalumab and Low-dose Prophylactic Cranial Irradiation (PCI) Versus Durvalumab and Observation in Radically Treated Patients With Stage III Non-small Cell Lung Cancer: A Phase III Randomized Study
Actual Study Start Date : December 6, 2021
Estimated Primary Completion Date : December 2028
Estimated Study Completion Date : December 2032

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Arm A
Durvalumab with low-dose PCI
Drug: Durvalumab
Durvalumab is used as standard of care

Radiation: low-dose PCI
PCI will be given concurrently with durvalumab. PCI will be given to a dose of 15 Gy in 10 fractions
Other Name: Prophylactic Cranial Irradiation (PCI)

Active Comparator: Arm B
Durvalumab with observation
Drug: Durvalumab
Durvalumab is used as standard of care

Primary Outcome Measures :
  1. Reduction of incidence of brain metastases [ Time Frame: From randomisation until moment of discovery of brain metastases or latest at 24 months after randomization ]
    To evaluate whether the addition of PCI to durvalumab after concurrent chemo-radiotherapy for stage III NSCLC reduces the cumulative incidence of brain metastases.

Secondary Outcome Measures :
  1. Effect on neurocognitive functioning [ Time Frame: From randomization until 24 months after randomization ]
    To evaluate what the effect is on neurocognitive functioning to be meassured with HVLT-R carried out by hospital staff.

  2. Time to develop neurological symptoms [ Time Frame: From randomization until time to develop neurological symptoms with a maximum of 24 months after randomization ]
    To evaluate time to develop neurological symptoms (CTCAE version 5.0)

  3. Toxicity assessment [ Time Frame: From randomization until end of study treatment ]
    To evaluate adverse events (CTCAE v 5.0 and PRO-CTCAE) that is the result of study treatment

  4. Patient reported neurocognitive decline [ Time Frame: From randomization until 5 years after randomization ]
    To evaluate patient reported neurocognitive decline using PRO-CTCAE (patient reported outcome)

  5. Cost-efficiency [ Time Frame: From randomization until end of study treatment ]
    To evaluate cost-efficiency of the addition of PCI to durvalumab with a state-transition model, calculated with Dutch tariff

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion criteria:

  1. Patients must sign a study-specific informed consent
  2. TNM8 stage IIIA, IIIB or IIIC non-small cell lung cancer (preferentially histology; cytology is allowed)
  3. Whole body FDG-PET-scan and brain imaging (MRI or CT with iv contrast) before the start of chemoradiotherapy: No distant metastases.
  4. Additional brain MRI (MRI mandatory) before randomization: no brain metastases.
  5. 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).
  6. Treatment completed with concurrent chemoradiation. The last day of thoracic radiotherapy should be within 52 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 cycle of chemotherapy 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.
  7. 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:

    1. Mean lung dose must be <20 Gy and/or V20Gy must be <35%
    2. Mean oesophagus dose must be <34 Gy
    3. Heart V45Gy <35% or V30Gy <30%.
  8. Proton therapy to the chest is allowed.
  9. ECOG performance status 0-1 at the time of randomization.
  10. Evidence of postmenopausal status, or negative urinary or serum pregnancy test for female premenopausal patients.

Exclusion Criteria:

  1. Participation in another clinical study with an investigational product during the last 4 weeks.
  2. 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.
  3. Mixed small cell and non-small cell lung cancer histology.
  4. Patients who receive sequential chemoradiation therapy for locally advanced NSCLC.
  5. Disease progression after completion of definitive platinum based, concurrent chemoradiation therapy.
  6. 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.
  7. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment.
  8. Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
  9. Active or prior documented inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis).
  10. History of primary immunodeficiency.
  11. History of organ transplant that requires therapeutic immunosuppression.
  12. 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.
  13. Known history of tuberculosis, hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV).
  14. 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.
  15. Prior cranial irradiation is not allowed.
  16. Except for durvalumab after concurrent chemoradiotherapy, no previous treatment with PD-(L)1-inhibitors is allowed.
  17. Female patients who are pregnant, breastfeeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
  18. Any condition that, in the opinion of the investigator, would interfere with evaluation of the study drug or interpretation of patient safety or study results.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04597671

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Contact: Dirk De Ruysscher, MD PhD 0031 88 44 55 666
Contact: Lizza Hendriks, MD PhD 0031 43 387 5047

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ZGT Recruiting
Almelo, Netherlands
Contact: Jeske Staal, MD PhD         
Contact: Margo Kamp    088 7083454   
Principal Investigator: Jeske Staal, MD PhD         
Radiotherapie Groep Not yet recruiting
Arnhem, Netherlands
Contact: Marcel Stam         
Rijnstate Not yet recruiting
Arnhem, Netherlands
Contact: Niels Claessens, MD    0880056730      
Principal Investigator: Niels Claessens, MD         
Gelderse Vallei Not yet recruiting
Ede, Netherlands
Contact: Wouter de Jong, MD    0318-434343   
Principal Investigator: Wouter de Jong, MD         
Sub-Investigator: Marcel Stam, MD         
Catharina Ziekenhuis Not yet recruiting
Eindhoven, Netherlands
Contact: Katrien de Jaeger         
Contact: Helma van Berkum    040 239 7178   
Principal Investigator: Katrien de Jaeger, MD PhD MBA         
UMCG Recruiting
Groningen, Netherlands
Contact: Anthonie Van der Wekken, MD PhD         
Contact: Marjan Dubbelman    050 3616161   
Principal Investigator: Anthonie Van der Wekken, MD PhD         
Maastro Recruiting
Maastricht, Netherlands, 5912 BL
Contact: Dirk De Ruysscher, MD PhD    0031 88 44 55 600   
Contact: Chantal Overhof    088 4455863   
Principal Investigator: Dirk De Ruysscher, MD PhD         
Canisius Wilhemina Ziekenhuis Not yet recruiting
Nijmegen, Netherlands
Contact: Yvonne Berk, MD         
Contact: Britt Hulen    024 3657944   
Principal Investigator: Yvonne Berk, MD         
Radboud UMC Not yet recruiting
Nijmegen, Netherlands
Contact: Michel van den Heuvel, MD PhD         
Contact: Femke Cuppen    06 11 83 33 89    ''   
Principal Investigator: Michel van den Heuvel, MD PhD         
ZorgSaam Ziekenhuis Not yet recruiting
Terneuzen, Netherlands
Contact: Marijn Smits, MD         
Contact: Mandy Nielen    0115-688251   
Principal Investigator: Marijn Smits, MD         
Maxima Medisch Centrum Recruiting
Veldhoven, Netherlands
Contact: Maggy Youssef, MD PhD         
Contact: Marleen Bax    040 888 6154   
Principal Investigator: Maggy Youssef, MD PhD         
Zaans Medisch Centrum Not yet recruiting
Zaandam, Netherlands
Contact: Svitlana Tarasevych, MD         
Contact: Patricia Sierink    075 6507657      
Principal Investigator: Svitlana Tarasevych, MD         
Sponsors and Collaborators
Association NVALT Studies
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Principal Investigator: Dirk De Ruysscher, MD PhD Maastricht University/ Maastro clinic
Principal Investigator: Lizza Hendriks, MD PhD Maastricht UMC
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Responsible Party: Association NVALT Studies Identifier: NCT04597671    
Other Study ID Numbers: NVALT28
First Posted: October 22, 2020    Key Record Dates
Last Update Posted: February 2, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dutch Society of Physicians for Pulmonology and Tuberculosis ( Association NVALT Studies ):
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents