Durvalumab and Chemotherapy Induction Followed by Durvalumab and Radiotherapy in Large Volume Stage III NSCLC

Phase 2

Active, not recruiting

• Conditions: Non-small Cell Lung Cancer Stage III
• Interventions: Combination Product: durvalumab plus platinum-based chemotherapy (cisplatin or carboplatin plus vinorelbine or pemetrexed); Combination Product: Durvalumab plus radiotherapy; Biological: durvalumab

• Registration Number: NCT04765709
• Lead Sponsor: Mario Negri Institute for Pharmacological Research

Brief Summary

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 the proportion of patients who did not progress and who achieved a mean lung dose \<20 Gy and/or a lung V20\<35% (response) after part 1. The primary objective of the study is to increase the proportion of patients eligible for immunotherapy plus radiotherapy after induction with durvalumab and chemotherapy, in comparison with historical controls.

This study will last approximately 60 months and will include approximately 65 eligible patients in 3 international cancer centres of excellence.

Detailed Description

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 with a sufficient tumor shrinkage to be considered eligible for part 2 and they will be treated concomitantly with durvalumab and radiotherapy.

* Part 3: patients with partial response or stable disease 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 the proportion of patients who did not progress and who achieved a mean lung dose \<20 Gy and/or a lung V20\<35% (response) after part 1. The primary objective of the study is to increase the proportion of patients eligible for immunotherapy plus radiotherapy after induction with durvalumab and chemotherapy, in comparison with historical controls.

This study will last approximately 60 months and will include approximately 65 eligible patients in 3 international cancer centres of excellence.

Study Timeline

• Study First Submitted: 2021-02-08
• Study First Submitted QC: 2021-02-19
• Study First Posted: 2021-02-21
• Study Start: 2021-09-24
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-18
• Last Update Posted: 2023-10-19
• Primary Completion: 2026-06
• Study Completion: 2026-06

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

Not provided

Exclusion Criteria

1. Stage IV NSCLC

2. Patient amenable to curative intent surgery or concurrent chemoradiation

3. Mixed small cell and non-small cell lung cancer histology

4. Patients who already received therapy for locally advanced 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. Prior exposure to any anti-PD-1 or anti-PD-L1 antibody, including durvalumab

9. Participation in another clinical study with an investigational product during the last 4 weeks, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study

10. 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.

11. Active or prior documented autoimmune disease within the past 2 years 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 (e.g. patients with psoriasis not requiring systemic treatment within the past 2 years)
    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

12. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, ongoing or active infection, including any patient known to have evidence of acute or chronic hepatitis B (positive HBV surface antigen (HBsAg) result), hepatitis C, human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent. [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.]

13. 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

14. 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

15. 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

    1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
    2. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.

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. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms

19. History of active primary immunodeficiency

20. 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

21. 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.

22. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

23. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BRIDGE single arm	durvalumab plus platinum-based chemotherapy (cisplatin or carboplatin plus vinorelbine or pemetrexed)	Treatment plan: * Part 1: induction with durvalumab plus histology-based chemotherapy regimen. * Part 2: patients with a sufficient tumor shrinkage to be considered eligible for part 2 and they will be treated concomitantly with durvalumab and radiotherapy. * Part 3: patients with partial response or stable disease after part 2 will be eligible for durvalumab maintenance, for up to 2 years or until disease progression or unacceptable toxicity.
BRIDGE single arm	Durvalumab plus radiotherapy	Treatment plan: * Part 1: induction with durvalumab plus histology-based chemotherapy regimen. * Part 2: patients with a sufficient tumor shrinkage to be considered eligible for part 2 and they will be treated concomitantly with durvalumab and radiotherapy. * Part 3: patients with partial response or stable disease after part 2 will be eligible for durvalumab maintenance, for up to 2 years or until disease progression or unacceptable toxicity.
BRIDGE single arm	durvalumab	Treatment plan: * Part 1: induction with durvalumab plus histology-based chemotherapy regimen. * Part 2: patients with a sufficient tumor shrinkage to be considered eligible for part 2 and they will be treated concomitantly with durvalumab and radiotherapy. * Part 3: patients with partial response or stable disease after part 2 will be eligible for durvalumab maintenance, for up to 2 years or until disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Proportion of patients who did not progressed and who achieved a mean lung dose <20 Gy and/or a lung V20<35% (response) after part 1	At the end of part 1 of induction chemo-immunotherapy/before part 2 (assessed up to 60 months)	The primary objective of the study is to increase the proportion of patients eligible for immunotherapy plus radiotherapy after induction with durvalumab and chemotherapy, in comparison to historical controls.

Secondary Outcome Measures

Name	Time	Method
Proportion of patients with complete response or partial response (as best response)	Assessed up to 60 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.	Assessed up to 60 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).	Assessed up to 60 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.
Progression-Free Survival (PFS) of patients receiving durvalumab and chemotherapy induction followed by immuno-radiotherapy and durvalumab consolidation.	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 60 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).

Trial Locations

Locations (3)

Gustave Roussy Institute; 🇫🇷 Paris, France

Fondazione IRCCS Istituto Nazionale dei Tumori; 🇮🇹 Milan, Italy

Vall d'Hebron Barcelona Hospital; 🇪🇸 Barcelona, Spain