Phase II Study of Neoadjuvant Durvalumab and Platinum-Based Chemotherapy in Resectable Stage IIB-IIIB Non-Small Cell Lung Cancer
- Trial ID
- 2023-503357-35-00
- Protocol
- D9106C00002
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the efficacy of **neoadjuvant durvalumab** combined with platinum-based chemotherapy in terms of resection rate in participants with resectable and borderline resectable stage IIB-IIIB **Non-Small Cell Lung Cancer (NSCLC)**. This is clinically relevant as it aims to improve surgical outcomes and potentially increase the number of patients eligible for complete tumor resection, which is a critical factor in improving long-term survival rates in NSCLC.
Secondary objectives include:
- Further assessment of the efficacy of neoadjuvant durvalumab plus chemotherapy in terms of resection rate in participants deemed resectable or borderline resectable at baseline.
- Investigation of surgical outcomes.
- Evaluation of the efficacy of neoadjuvant durvalumab plus chemotherapy in terms of pathological complete response (pCR) in participants deemed resectable after multidisciplinary team (MDT) re-assessment.
- Assessment of the efficacy of neoadjuvant durvalumab plus chemotherapy followed by surgery and then adjuvant durvalumab or definitive chemoradiotherapy (CRT) and then consolidation durvalumab in terms of overall survival (OS) and event-free survival (EFS).
- Evaluation of the efficacy of neoadjuvant durvalumab plus chemotherapy followed by definitive CRT and then consolidation durvalumab in terms of progression-free survival (PFS).
- Assessment of the efficacy of neoadjuvant durvalumab plus chemotherapy in terms of objective response rate (ORR) and circulating tumor DNA (ctDNA) clearance.
- Evaluation of the safety and tolerability of neoadjuvant durvalumab plus chemotherapy followed by surgery and then adjuvant durvalumab or definitive CRT and then consolidation durvalumab in participants with resectable and borderline resectable stage IIB to IIIB NSCLC.
- Assessment of the safety of neoadjuvant durvalumab plus chemotherapy as it pertains to surgical delays and complications.
Participants
The clinical trial involves a total of **16 participants** diagnosed with **Non-small Cell Lung Cancer (NSCLC)**, specifically targeting those with resectable and borderline resectable stage IIB-IIIB disease. The study population includes both male and female subjects aged 18 years and older, with no restrictions on race or ethnic groups. Participants are required to have adequate cardiac and lung function, as well as a minimum body weight of 30 kg. The trial does not include a vulnerable population. Participants were selected based on their histologically or cytologically documented NSCLC, confirmed resectability status, and a WHO or ECOG performance status of 0 or 1. Lifestyle considerations such as diet and physical activity are not specified. The trial ensures that participants have not received prior treatment for their condition and possess adequate organ and bone marrow function. The selection process also mandates a negative pregnancy test for females of childbearing potential and adherence to effective contraceptive measures for both genders. The sponsor has not provided additional information regarding specific lifestyle factors or habits of the participants.
Plans and Procedures
The clinical trial is a multicentre, Phase II, single-arm, interventional study designed to evaluate the efficacy of **durvalumab** in combination with platinum-based chemotherapy in patients with resectable or borderline resectable stage IIB-IIIB **Non-small Cell Lung Cancer (NSCLC)**. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The overall duration of the trial is estimated to extend until November 2027, with recruitment starting in December 2023. Participants will be involved in the study for a maximum treatment period of 60 weeks, depending on their response and progression.
The sequence of study visits begins with an inclusion (screening) visit, where participants are assessed for eligibility based on criteria such as age, cardiac and lung function, and histological confirmation of NSCLC. Following the screening, eligible participants will undergo a series of follow-up visits to monitor their response to the treatment regimen, which includes neoadjuvant durvalumab and chemotherapy, followed by either surgery and adjuvant durvalumab or chemoradiotherapy and consolidation durvalumab. The end-of-study visit will occur after the completion of the treatment regimen, where final assessments will be conducted to evaluate the primary and secondary endpoints, including resection rates and overall survival.
Participants are expected to remain in the study for the entire duration unless specific conditions necessitate early termination. These conditions include significant adverse events, disease progression that precludes surgery, or withdrawal of consent. The trial's primary endpoint is the resection rate, defined as the proportion of participants who undergo definitive surgery. Secondary endpoints include progression-free survival, overall response rate, and safety and tolerability assessments. The study aims to provide valuable insights into the potential benefits of durvalumab in combination with chemotherapy for patients with NSCLC, contributing to the advancement of treatment options for this condition.
Treatment
The clinical trial involves the administration of several **antineoplastic agents** and **immunomodulating agents**. **Paclitaxel** is administered as an intravenous infusion with a pharmaceutical form coded as PHF00016MIG. The maximum daily dose is 200 mg/m², with a total maximum dose of 800 mg/m² over a treatment period of 12 weeks. **Gemcitabine** is also administered intravenously, with a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 1250 mg/m², and the total maximum dose is 10,000 mg/m² over 12 weeks.
**Carboplatin** is administered intravenously with a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 750 mg, with a total maximum dose of 3000 mg over 12 weeks. **Durvalumab**, marketed as Imfinzi, is administered as a concentrate for solution for infusion. The maximum daily dose is 1500 mg, with a total maximum dose of 24,000 mg over a 60-week period. **Vinorelbine** is administered intravenously with a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 30 mg/m², with a total maximum dose of 240 mg/m² over 12 weeks.
**Anhydrous Docetaxel** is administered intravenously with a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 75 mg/m², with a total maximum dose of 300 mg/m² over 12 weeks. **Infliximab**, marketed as Inflectra, is administered as a powder for concentrate for solution for infusion. The maximum daily dose is 350 mg/kg, with a total maximum dose of 1050 mg/kg over a 6-week period. **Mycophenolate Mofetil** is administered orally in capsule form. The maximum daily dose is 2 g, with a total maximum dose of 168 g over 12 weeks.
**Cisplatin** is administered intravenously with a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 75 mg/m², with a total maximum dose of 300 mg/m² over 12 weeks. **Pemetrexed** is administered as an intravenous infusion with a pharmaceutical form coded as PHF00016MIG. The maximum daily dose is 500 mg/m², with a total maximum dose of 2000 mg/m² over 12 weeks. Participant compliance is monitored through regular assessments and adherence checks throughout the trial duration.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the **resection rate**, defined as the proportion of participants who undergo definitive surgery. This analysis will be conducted on all participants who have received at least one dose of the study intervention. Secondary endpoints include the resection rate in subsets of participants assessed as resectable or borderline resectable at baseline, as well as the R0, R1, and R2 resection rates in subgroups who underwent definitive surgery. Additionally, **pathological complete response (pCR)** will be evaluated, defined as the proportion of participants with 0% residual viable tumor cells in resected lung and lymph nodes, analyzed in the Resectable Participants Cohort.
Other secondary endpoints include overall survival (OS), event-free survival (EFS), progression-free survival (PFS), and objective response rate (ORR), assessed using RECIST 1.1 criteria. The trial will also evaluate circulating tumor DNA (ctDNA) clearance, defined as the change from detectable to undetectable ctDNA. Safety and tolerability will be assessed through adverse events (AEs), including serious adverse events (SAEs) and surgery-related AEs, as well as vital signs, clinical laboratory assessments, and ECGs. The analysis will be performed in the full analysis set (FAS), which includes all participants who received at least one dose of the study intervention.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be ≥ 18 years, at the time of screening.
- Histologically or cytologically documented NSCLC
- Deemed resectable or borderline resectable at baseline, confirmed by MDT evaluation at diagnosis
- Previously untreated and pathologically confirmed stage IIB to select (ie, N2) stage IIIB disease (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology 2016).(a) Nodal status should be investigated with whole body FDG-PET, plus contrast-enhanced computed tomography, and it is required that nodal status be proven by biopsy via endobronchial ultrasound, mediastinoscopy, or thoracoscopy. (b) Mandatory brain MRI with IV contrast or brain computed tomography with IV contrast at the time of staging
- WHO or ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dose
- Participants must have been confirmed as EGFR/ALK wild type via an appropriately validated local test Participants with known sensitising EGFR mutations or ALK rearrangements are excluded from the study.
- At least one lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with computed tomography or MRI and is suitable for accurate repeated measurements
- Adequate organ and bone marrow function as follows: − Haemoglobin ≥ 9.0 g/dL. − Absolute neutrophil count ≥ 1.5 × 109 /. − Platelet count ≥ 100×109 /L. − Serum bilirubin ≤ 1.5×the ULN or ≤ 3×ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinaemia). − Alanine aminotransferase and AST ≤ 2.5×ULN. − Calculated CrCL > 40 mL/min as determined by Cockcroft Gault (using actual body weight).
- Minimum life expectancy of 12 weeks
- The participant should be deemed to have adequate cardiac and lung function, according to a multidisciplinary assessment. A pre- or postbronchodilator FEV1 of 1.0 L and >40% postoperative predicted value. Use of these cut-off values to assess candidacy for resection should be guided by the results of cardiopulmonary exercise testing as outlined in the ESMO guidelines on pre-treatment risk assessment. Both an FEV1 and a DLCO test are required for assessing lung function prior to resection
- Minimum body weight of 30 kg.
- Male and/or female. Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
- Negative pregnancy test (serum) for FOCBP
- Female participants must be for 1 year or more postmenopausal, surgically sterile, or using at least one highly effective method of contraception (a highly effective method of contraception isdefined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly.) (a) Females < 50 years old are considered postmenopausal if they have been amenorrhoeic for 12 months or more prior to enrolment following cessation of exogenous hormonal treatment and folliclestimulating hormone (FSH) levels in the postmenopausal range. (b) Females ≥ 50 years old are considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment, or had radiation-induced menopause with last menses > 1 year ago, or had chemotherapy-induced menopause with last menses > 1 year ago. (c) Female participants of child-bearing potential must agree to use at least one highly effective method of birth control. They should have been stable on their chosen method of birth control for a minimum of 3 months prior to enrolment (screening), while receiving study intervention, SoC CT or CRT, and for 90 days after the last dose of durvalumab and for periods specified in the local prescribing information/SmPC relating to contraception and the time limit for such precautions for SoC agents. Cessation of birth controlafter this point should be discussed with a responsible physician. (d) Non-sterilised male partners of a female participant of child-bearing potential must use a male condom plus spermicide (condom alone in countries where spermicides are not approved) from the time of screening their female partner, while their female partner is receiving study intervention, SoC CT or CRT, and for 90 days after the last dose of durvalumab and for periods specified in the local prescribing information/SmPC relating to contraception and the time limit for such precautions for SoC agents. (e) Periodic abstinence, as well as the rhythm and withdrawal methods are not acceptable methods of birth control.
- Male participants who intend to be sexually active with a female partner of child-bearing potential must be surgically sterile or using an acceptable method of contraception (see Appendix G) from the time of screening , while receiving study intervention, SoC CT or CRT and for 90 days after the last dose of durvalumab and for periods specified in the local prescribing information/SmPC relating to contraception and the time limit for such precautions for SoC agents to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the CSP
- Provision of signed and dated written informed consent prior to collection of samples. Participation is voluntary and if a participant declines to consent, they will not be excluded from the main study.
- All races, gender and ethnic groups are eligible for this study.
Exclusion Criteria
- As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diseases, active infection, active ILD/pneumonitis, serious chronic gastrointestinal conditions associated with diarrhoea, psychiatric illness/social situations), chronic diverticulitis or previous complicated diverticulosis, or history of allogenic organ transplant, which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol
- Unresectable NSCLC confirmed by MDT evaluation at diagnosis: − Deemed unresectable NSCLC by multidisciplinary evaluation -Any stage IIIC
- Participants whose planned surgery at enrolment includes wedge resections
- Participants contraindicated for surgical intervention due to comorbid conditions
- Existence of more than one primary tumour, such as: mixed small cell and NSCLC histology; synchronous or metachronous tumours that could represent distinct primary tumours
- History of another primary malignancy except for malignancy treated with curative-intent with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence, basal cell carcinoma of the skin, squamous cell carcinoma of the skin or lentigo maligna that has undergone potentially curative therapy or adequately treated carcinoma in situ without evidence of disease.
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis, and autoimmune myocarditis). The following are exceptions to this criterion: − Participants with vitiligo or alopecia. − Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement. − Any chronic skin condition that does not require systemic therapy. − Participants without active disease in the last 5 years may be included but only after consultation with the Study Clinical Lead. − Participants with coeliac disease controlled by diet alone
- Known active hepatitis infection, positive HCV antibody, hBsAg or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of hBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- Known to have tested positive for HIV (positive HIV 1 or 2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice)
- History of active primary immunodeficiency
- Investigator judgement of one or more of the following: − Mean resting corrected QT interval > 470 ms, obtained from triplicate ECGs performed at screening. − History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause TdP. − Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden cardiac death under 40 years of age in first-degree relatives
- 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 vaccines.
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion: − Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection). − Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent. − Steroids as premedication for hypersensitivity reactions or as an anti-emetic (eg, computed tomography scan premedication)
- Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention
- Major surgical procedure or significant traumatic injury within 4 weeks of the first dose of study intervention
- Any medical contraindication to treatment with platinumbased doublet CT, as listed in the local labellin
- Previous treatment in the present study or a previous durvalumab clinical study regardless of treatment arm assignment
- Participation in another clinical study with a study intervention administered in the last 4 weeks prior to first dose of durvalumab or 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
- Participants with a known hypersensitivity to durvalumab or any excipients of the product(s).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 29 Dec 2023 | 6 |
 Czechia | Not Recruiting | 29 Dec 2023 | 9 |
 France | Not Recruiting | 29 Dec 2023 | 20 |
 Germany | Not Recruiting | 29 Dec 2023 | 28 |
 Hungary | Not Recruiting | 29 Dec 2023 | 7 |
 Italy | Not Recruiting | 29 Dec 2023 | 19 |
 Portugal | Not Recruiting | 29 Dec 2023 | 6 |
 Spain | Not Recruiting | 29 Dec 2023 | 23 |
 Sweden | Not Recruiting | 29 Dec 2023 | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PEMETREXED | Other | PHF00016MIG | INTRAVENOUS INFUSION | 500 | 12 | SCP60141047 |
GEMCITABINE | Other | PHF00230MIG | INTRAVENOUS USE | 1250 | 12 | SCP1686259 |
VINORELBINE | Other | PHF00230MIG | INTRAVENOUS | 30 | 12 | SCP209246 |
CARBOPLATIN | Other | PHF00230MIG | INTRAVENOUS | 750 | 12 | SCP28192792 |
Inflectra 100 mg powder for concentrate for solution for infusion | Other | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 350 | 6 | PRD6483369 |
Micofenolato de mofetil Generis 250 mg Cápsulas | Other | CÁPSULAS | ORAL | 2 | 12 | PRD1816611 |
PACLITAXEL | Other | PHF00016MIG | INTRAVENOUS USE | 200 | 12 | SCP247399 |
CISPLATIN | Other | PHF00230MIG | INTRAVENOUS USE | 75 | 12 | SCP26873719 |
DOCETAXEL | Other | PHF00230MIG | INTRAVENOUS USE | 75 | 12 | SCP725130 |
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1500 | 60 | PRD6651398 |