Standard treatment for stage III Non-Small Cells Lung Cancer (NSCLC) not eligibile for surgery is concomitant chemoradiotherapy. However median progression free survival and overall survival is still poor with only 15% of patients alive at 5 years. The addition of maintenance therapy with durvalumab after chemoradiation showed a significant benefit in PFS and OS, with good tolerability and no concerns in terms of safety. However, about 30% of patients with stage III are not eligible to concurrent chemoradiotherapy because of large volumes of the tumor. To date, these patients are initially treated with chemotherapy with the aim of reducing tumor volumes and allowing sequential radiotherapy. Response rate ranges between 25-30% and majority of patients will not become suitable for radiotherapy. The combination of immunotherapy plus standard chemotherapy in advanced stages doubles response rates and provides major tumor shrinkage compared to standard chemotherapy alone. For these reasons, the investigators want to exploit the synergistic effect of immunotherapy combined with chemotherapy in the induction phase, in order to render suitable for radiotherapy a larger number of patients, and in a second phase the synergistic effect with radiotherapy. Based on these premises the investigators designed a single arm, phase 2 trial to determine the efficacy and safety of combining immunotherapy with the drug durvalumab in association with standard chemotherapy and subsequently with standard radiotherapy, followed by a treatment of maintenance with only durvalumab. The study population includes patients with NSCLC not eligible for surgery or concurrent chemoradiation at diagnosis because of large tumor volumes. BRIDGE trial aims to evaluate and increase the proportion of patients eligible for immunotherapy plus radiotherapy (response) after induction with durvalumab and chemotherapy and to increase this proportion in comparison to historical controls. This study will last approximately 48 months and will include approximately 65 eligible patients in 3 international cancer centres of excellence.
Full Title of Study: “BRIDGE Trial: Phase II Trial of durvalumaB and chemotheRapy Induction Followed by Durvalumab and Radiotherapy in larGe volumE Stage III NSCLC”
- Study Type: Interventional
- Study Design
- Allocation: N/A
- Intervention Model: Single Group Assignment
- Primary Purpose: Treatment
- Masking: None (Open Label)
- Study Primary Completion Date: April 2025
Standard treatment for stage III Non-Small Cells Lung Cancer (NSCLC) not eligibile for surgery is concomitant chemoradiotherapy. However median progression free survival and overall survival is still poor with only 15% of patients alive at 5 years. The addition of maintenance therapy with durvalumab after chemoradiation showed a significant benefit in PFS and OS, with good tolerability and no concerns in terms of safety. However, about 30% of patients with stage III are not eligible to concurrent chemoradiotherapy because of large volumes of the tumor. To date, these patients are initially treated with chemotherapy with the aim of reducing tumor volumes and allowing sequential radiotherapy. Response rate ranges between 25-30% and majority of patients will not become suitable for radiotherapy. The combination of immunotherapy plus standard chemotherapy in advanced stages doubles response rates and provides major tumor shrinkage compared to standard chemotherapy alone. For these reasons, the investigators want to exploit the synergistic effect of immunotherapy combined with chemotherapy in the induction phase, in order to render suitable for radiotherapy a larger number of patients, and in a second phase the synergistic effect with radiotherapy. Based on these premises the investigators designed a single arm, phase 2 trial to determine the efficacy and safety of combining immunotherapy with the drug durvalumab in association with standard chemotherapy and subsequently with standard radiotherapy, followed by a treatment of maintenance with only durvalumab. The study population includes patients with NSCLC not eligible for surgery or concurrent chemoradiation at diagnosis because of large tumor volumes. The study consists of 3 parts: – Part 1: induction with durvalumab plus chemotherapy. – Part 2: patients responding or stable and eligible for radiotherapy after induction will be treated concomitantly with durvalumab and radiotherapy. – Part 3: patients responding or stable after part 2 will be eligible for durvalumab maintenance, for up to 2 years or until disease progression or unacceptable toxicity. BRIDGE trial aims to evaluate and increase the proportion of patients eligible for immunotherapy plus radiotherapy (response) after induction with durvalumab and chemotherapy and to increase this proportion in comparison to historical controls. This study will last approximately 48 months and will include approximately 65 eligible patients in 3 international cancer centres of excellence.
- Combination Product: durvalumab plus platinum-based chemotherapy (cisplatin or carboplatin plus vinorelbine or pemetrexed)
- Induction therapy: durvalumab plus histology-based chemotherapy regimen (cisplatin or carboplatin plus vinorelbine for squamous histology and pemetrexed for non-squamous histology).
- Combination Product: Durvalumab plus radiotherapy
- Concomitant durvalumab and radiotherapy
- Biological: durvalumab
- Consolidation treatment with durvalumab
Arms, Groups and Cohorts
- Experimental: BRIDGE single arm
- Treatment plan: Part 1: induction with durvalumab plus histology-based chemotherapy regimen. Part 2: patients responding or stable after part a and eligible for radiotherapy after induction will be treated concomitantly with durvalumab and radiotherapy. Part 3: patients responding or stable after part 2 will be eligible for durvalumab maintenance
Clinical Trial Outcome Measures
- Proportion of patients eligible for immunotherapy plus radiotherapy after induction with durvalumab and chemotherapy.
- Time Frame: At the end of part 1 of induction chemo-immunotherapy/before part 2 (assessed up to 48 months)
- To increase the proportion of patients eligible for immunotherapy plus radiotherapy after induction with durvalumab and chemotherapy, in comparison to historical controls.
- Progression-Free Survival (PFS) of patients receiving durvalumab and chemotherapy induction followed by immuno-radiotherapy and durvalumab consolidation.
- Time Frame: From the date of start of induction chemo-immunotherapy until the date of first documented progression or death from any cause, whichever came first (assessed up to 48 months)
- PFS is defined as the time from the date of start of induction treatment until the date of objective disease progression or death to any cause whichever comes first. PFS will be evaluated using RECIST 1.1 criteria according to investigators and blinded central review (BCR).
- Proportion of patients with complete response or partial response (as best response)
- Time Frame: Assessed up to 48 months
- To evaluate Objective Response Rate (ORR) of each phase of treatment and the overall response rate. ORR is defined as the proportion of patients with complete or partial response (as best response) according to RECIST 1.1 as assessed by Investigators and BCR.
- Overall Survival (OS) of patients receiving durvalumab and chemotherapy induction followed by immuno-radiotherapy and durvalumab consolidation.
- Time Frame: Assessed up to 48 months
- OS is defined as the time from the date of start of induction treatment until death due to any cause. Patients alive at the time of statistical analysis will be censored at their last information on vital status.
- Frequency and nature of adverse reactions (ARs) and Serious Adverse Events (SAEs) (toxicity and safety).
- Time Frame: Assessed up to 48 months
- The assessment of safety will be mainly based on adverse reactions (ARs) and the frequency and nature of SAEs. Toxicity and safety will be evaluated during each part of the program, throughout study duration.
Participating in This Clinical Trial
Inclusion Criteria FOR PART 1 (INDUCTION CHEMOTHERAPY IN ASSOCIATION WITH DURVALUMAB): 1. Capable of giving signed informed consentwhich includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (eg, 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 at time of study entry 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 4. Life expectancy of > 12 weeks 5. Histologically- or cytologically-documented NSCLC, in locally advanced (Stage III-v.8 IASLC) 6. Eligible for platinum-based chemotherapy (platinum – pemetrexed for non-squamous and platinum-vinorelbine for squamous histology) 7. Patients not eligible for surgery and chemoradiation (each patient will be discussed in a web multidisciplinary team among all the three involved Cancer Core Europe [CCE] centers). Main criteria for avoiding concurrent chemoradiation from the beginning are:
- Bilateral supraclavicular involvement – Contralateral mediastinal and/or hilar involvement – Primary tumor > 7 cm or several nodules in different lobes of the same lung 8. Tumor sample requirements: availability of an archived tumour tissue block (or unstained slides to perform local PDL1 assessment following protocol procedure) 9. Patient's willingness to undergo blood draws to provide plasma and blood samples for analysis according to study objectives 10. Body weight > 30 Kg 11. Adequate normal organ and marrow function as defined below: – Haemoglobin ≥9.0 g/dL – Absolute neutrophil count (ANC) 1.5 x 109/L (> 1500/mm3) – Platelet count ≥100 x 109/L – Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. – AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal – Adequate renal function defined as normal serum creatinine levels or calculated creatinine clearance (according to Cockroft-Gault or by 24 hour-urine collection): ≥60 ml/min for patient receiving cisplatin ≥45 ml/min for patient receiving carboplatin. Cockcroft-Gault formula (Cockcroft and Gault 1976): Males: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 – Age) x 0.85 72 x serum creatinine (mg/dL) 12. 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 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). 13. Patient willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. 14. Absence of a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents and/or to durvalumab and/or to any of their excipients. FOR PART 2 (RADIOTHERAPY CONCURRENTLY WITH DURVALUMAB): 1. Evidence of partial response or stable disease at the evaluation conducted at the end of Part 1 (each patient will be discussed in a web multidisciplinary team among the involved CCE centers to discuss eligibility for part 2) 2. ECOG Performance Status of 0 – 1 3. Absence of dyspnea of minimal exertion or oxygen requirement after CT+D 4. Sufficient PFTs performed after the last cycle of CT+D: – FEV1 > 1L or ≥ 30% – DLCO > 30% 5. The patient's dosimetry must meet the following constraints to organs at risk (Kong 2011, Marks 2010, De Ruysscher 2017, Marks 2010, Gagliardi 2010, Wang 2017, Kirkpatrick 2010): – Spinal cord maximum dose < 50 Gy – Total mean lung dose (Right Lung+Left Lung-GTV) ≤ 23 Gy [De Ruysscher] and/or – Lung V20 defined as percentage of normal parenchyma receiving 20 Gy or more (Right Lung+Left Lung-PTV) ≤ 37% – Heart V45 <30% and Mean Heart Dose ≤26 Gy if possible, Heart V45 <30% or Mean Heart Dose ≤26 Gy FOR PART 3 (MAINTENANCE WITH DURVALUMAB): 1. Evidence of partial response or stable disease at the evaluation conducted at the end of Part 2 2. Absence of grade 2-3 pneumonitis Exclusion Criteria:
1. Patient amenable to curative intent surgery or concurrent chemoradiation 2. Mixed small cell and non-small cell lung cancer histology 3. Patients who already received therapy for locally advanced NSCLC 4. Stage IV NSCLC 5. Dyspnea of minimal exertion or oxygen requirement 6. Recent medical history of cardiac events during the last 6 months (ischemic or congestive heart failure) 7. Pancoast tumors 8. Previous radiotherapy to the thorax (prior to inclusion), including radiotherapy for breast cancer 9. Prior exposure to any anti-PD-1 or anti-PD-L1 antibody, including durvalumab 10. Participation in another clinical study with an investigational product during the last 4 weeks 11. 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. 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 including any patient known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), 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. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study 14. Any unresolved toxicity 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. 15. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable. 16. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational product. 17. History of allogenic organ transplantation. 18. 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: 1. Patients with vitiligo or alopecia 2. Patients with Grave's disease not requiring systemic treatment within the past 2 years 3. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement 4. Any chronic skin condition that does not require systemic therapy 5. Patients without active disease in the last 2 years may be included but only after consultation with the study physician 6. Patients with celiac disease controlled by diet alone 19. History of another primary malignancy except for 1. Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study drug and of low potential risk for recurrence 2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease 3. Adequately treated carcinoma in situ without evidence of disease, e.g. cervical cancer in situ 4. Superficial bladder cancer without evidence of disease 20. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms 21. History of active primary immunodeficiency 22. 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 (positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). 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. 23. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: 1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) 2. Systemic corticosteroids at physiologic doses not to exceed 10 mg daily of prednisone or its equivalent 3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) Systemic steroid administration required as prophylaxis against or to manage toxicities arising from chemotherapy and/or radiotherapy delivered as part of therapy for locally advanced NSCLC is allowed 24. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP. 25. 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 durvalumab monotherapy. 26. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 27. 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.
Gender Eligibility: All
Minimum Age: 18 Years
Maximum Age: N/A
Are Healthy Volunteers Accepted: No
- Lead Sponsor
- Mario Negri Institute for Pharmacological Research
- Provider of Information About this Clinical Study
- Overall Official(s)
- Valter Torri, Study Chair, Istituto di Ricerche Farmacologiche Mario Negri IRCCS
- Roberto Ferrara, Principal Investigator, Fondazione IRCCS Istituto Nazionale Tumori
- Overall Contact(s)
- Irene De Simone, +390239014661, email@example.com
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