1st Line Durvalumab in PS 2 NSCLC Patients

NSCLC Stage IV Clinical Trial

Official title:

First Line Durvalumab in Patients With PD-L1 Positive, Advanced NSCLC With Performance Status 2 Unsuitable for Combination Chemotherapy. A Multicenter, Single-arm Phase II Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03620669
• Other study ID #: SAKK 19/17
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 4, 2018
• Est. completion date: September 30, 2027

Study information

• Verified date: January 2024
• Source: Swiss Group for Clinical Cancer Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of the trial is to assess efficacy and safety of the treatment with durvalumab in PS 2 patients with treatment-naïve, locally advanced or metastatic, PD-L1 positive NSCLC who are considered unsuitable for combination platinum-containing therapy.

Description:

Lung cancer is the leading cause of cancer deaths. An estimated 30 to 40% of patients diagnosed with NSCLC have a poor Performance status (PS) defined as a score of 2 or higher on the ECOG scale. PS 2 patients are often underrepresented in clinical trials despite representing a very frequent and important subgroup.

Platinum-based (preferably carboplatin) doublets should be considered as standard of care in eligible PS 2 patients. However the toxicity profile of platinum-based doublets remains a concern. Single-agent chemotherapy represents an alternative treatment option for the PS 2 patients considered unsuitable for platinum doublet chemotherapy but its efficacy is limited and the outcome poor.

Given the superiority of the anti-PD-1 antibody pembrolizumab versus standard chemotherapy as first line therapy in a PD-L1 positive NSCLC population, it now became the standard treatment. The PS of patients enrolled in these trials were PS 0 or 1, making the benefit of PD-L1 antibodies in PS 2 patients unclear. A retrospective real-life data analysis of nivolumab in metastatic NSCLC revealed similar treatment-related AE between patients with a PS of 0 or 1 with those having a PS of 2, confirming good treatment tolerability in poor PS patients.

The overall favorable toxicity profile of durvalumab and the absence of robust efficacy data of checkpoint inhibitors in first line treatment of patients with PD-L1 positive NSCLC with a PS of 2, encourage to investigate its activity in this cohort of patients when considered unsuitable for platinum doublet chemotherapy.

Finally, this trial aims to prolong overall survival by treating this cohort of frail patients with durvalumab, compared to historical controls, treated with single agent chemotherapy.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 48
• Est. completion date: September 30, 2027
• Est. primary completion date: January 19, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Written informed consent according to Swiss law and ICH/GCP regulations before registration and prior to any trial specific procedures

• Histologically confirmed NSCLC, advanced or recurrent disease (stage IIIB to IV). Cytology could be accepted if histology is not possible

• PD-L1 expression of = 25% of the tumor cells by local testing (Ventana SP142 excluded)

• No sensitizing EGFR mutation (L858R or exon 19 deletions), ALK fusion oncogene or rearrangements of the ROS1 gene detected in patients with a non-squamous cell NSCLC

• Patient unsuitable for platinum-containing combination chemotherapy according to investigator or due to patient preference

• WHO PS of 2. Confirmation of PS2 by a second medical doctor is mandatory.

• Age = 18 years

• Baseline QoL forms and GA questionnaires have been completed

• Bone marrow function: hemoglobin = 90 g/L, neutrophil count = 1.5 x 109/L, platelet count = 100 x 109/L

• Hepatic function: bilirubin = 1.5 x ULN (except for patients with Gilbert's disease = 3.0 x ULN); patients without liver metastases: AST and ALT = 2.5 x ULN, patients with documented liver metastases: AST and ALT = 5 x ULN

• Renal function: estimated glomerular filtration rate (eGFR)> 30 mL/min/1.73m² (according to CKD-EPI formula)

• Measurable or evaluable disease (by RECIST v1.1)

• Patients with asymptomatic untreated CNS metastases are eligible, provided they meet the following:

• = 5 CNS lesions with a maximum diameter of one lesion of 10 mm

• Only supratentorial metastases allowed (i.e., no metastases to midbrain, pons, cerebellum, medulla, or spinal cord)

• No evidence of progression at registration compared to the latest brain imaging

• No ongoing requirement for corticosteroids as therapy for CNS disease

• Patients with symptomatic treated CNS metastases are eligible, provided they meet the following:

• No ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants at a stable dose allowed

• No stereotactic radiation or whole-brain radiation within 7 days prior to registration

• No evidence of progression at registration, after completion of CNS-directed therapy

• Tumor tissue available for central PD-L1 assessment and translational research (preferably histology but cytology could be allowed if histology is not possible). In case of scarce tumor material, a rebiopsy, if clinically possible, is encouraged

• Women with child-bearing potential are using effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and during the 3 months thereafter. A negative pregnancy test before inclusion into the trial is required for all women with child-bearing potential

• Men agree not to father a child during trial treatment and during 3 months thereafter

• Body weight > 30kg.

• Life expectancy > 3 months.

Exclusion criteria:

Any potential patient who meets any of the following criteria has to be excluded from entering the trial.

• History of hematologic or primary solid tumor malignancy, unless in remission for at least 3 years before registration with the exception of pT1-2 prostate cancer Gleason score <6, adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer

• Prior adjuvant systemic anti-cancer treatment within 6 months before registration

• Prior systemic treatment for metastatic NSCLC

• Prior treatment with a PD-1 or PD-L1 inhibitor

• Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses (i.e. which must not exceed 10 mg/day of prednisone or an equivalent corticosteroid)

• Concomitant drugs contraindicated for use with durvalumab such as corticosteroids, methotrexate, azathioprine and tumor necrosis factor (TNF)-a blockers

• Concurrent treatment with other experimental drugs or other anticancer therapy, treatment in a clinical trial within 28 days prior to registration

• Major surgical procedure within 14 days prior to registration

• 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:

• Patients with vitiligo or alopecia

• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years may be included but only after consultation with the coordinating investigator

• Patients with celiac disease controlled by diet alone

• Uncontrolled diabetes mellitus

• Known history of human immunodeficiency virus (HIV) or active chronic Hepatitis C or Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (iv) antimicrobial treatment

• Known history of tuberculosis

• Known history of primary immunodeficiency

• Known history of allogeneic organ transplant

• Receipt of live attenuated vaccine within 28 days prior to registration

• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV; unstable angina pectoris, history of myocardial infarction within the last six months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia), significant QT-prolongation, uncontrolled hypertension

• Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.

• Patients with dyspnea grade = 3 according to the modified Medical Research Council (mMRC) dyspnea scale.

• Patients with symptomatic pneumonitis (grade = 2) or active lung infection. Patients having fully recovered from active lung infection can be included assumed they have completed antibiotics and/or corticosteroids

• Patients with disseminated intravascular coagulopathy

• Patient with a baseline CT scan older than 21 days prior to registration.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• NSCLC Stage IIIB
• NSCLC Stage IV

Intervention

Drug:
• Durvalumab
Durvalumab 1500mg q4W until progression or unacceptable toxicity

Locations

Country	Name	City	State
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Kantonsspital Baden	Baden
Switzerland	Universitaetsspital Basel	Basel
Switzerland	IOSI Ospedale Regionale di Bellinzona e Valli	Bellinzona
Switzerland	Inselspital	Bern
Switzerland	Kantonsspital Graubuenden	Chur
Switzerland	Hopital Fribourgeois HFR	Fribourg
Switzerland	Hôpitaux Universitaires de Genève	Genève
Switzerland	Kantonsspital - St. Gallen	St. Gallen
Switzerland	Spital STS AG	Thun
Switzerland	Kantonsspital Winterthur	Winterthur

Sponsors (1)

Lead Sponsor	Collaborator
Swiss Group for Clinical Cancer Research

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS) at 6 months	OS at 6 months is defined as being alive at 6 months after registration.	At 6 months after registration
Secondary	Objective response (OR) according to RECIST 1.1	OR is defined as any complete response (CR) or partial response (PR) according to RECIST 1.1 criteria achieved during trial treatment.	At trial treatment discontinuation or the latest 5 years after last patient discontinued trial treatment
Secondary	Objective response according to iRECIST (iOR)	iOR is defined as any complete response (CR/iCR) or partial response (PR/iPR) according to RECIST1.1 or iRECIST criteria achieved during trial treatment.	At trial treatment discontinuation or the latest 5 years after last patient discontinued trial treatment
Secondary	Duration of response (DoR) according to RECIST 1.1	DoR is defined as the time from the first documentation of OR until disease progression according to RECIST 1.1 criteria or death due to disease progression, whichever occurs first.	At disease progression according to RECIST 1.1 criteria or death due to disease progression or the latest 5 years after last patient discontinued trial treatment
Secondary	Duration of response according to iRECIST (iDoR)	iDoR is defined as the time from the first documentation of iOR until disease progression according to iRECIST criteria (iPD) or death due to disease progression.	At disease progression according to iRECIST criteria (iPD) or death due to disease progression or the latest 5 years after last patient discontinued trial treatment
Secondary	Progression-free survival (PFS) according to RECIST 1.1	PFS is defined as the time from registration until disease progression according to RECIST v1.1 criteria or death due to any cause, whichever occurs first.	At disease progression according to RECIST v1.1 criteria or death due to any cause or the latest 5 years after last patient discontinued trial treatment
Secondary	Progression-free survival according to iRECIST (iPFS)	iPFS is defined as the time from registration until disease progression according to iRECIST criteria (iPD) or death due to any reason, whichever occurs first.; iPD is defined as the time point of first iUPD without subsequent iSD, iPR or iCR before trial treatment discontinuation.; Patients not experiencing an event at the time of the analysis, as well as patients starting a subsequent anticancer treatment in the absence of an event, will be censored at the date of their last available tumor assessment showing no evidence of iPD before starting a subsequent anticancer treatment, if any.	At disease progression according to iRECIST criteria (iPD) or death due to any reason or the latest 5 years after last patient discontinued trial treatment
Secondary	Overall survival (OS)	OS is defined as the time from registration until death due to any cause	At death of the patient or the latest 5 years after last patient discontinued trial treatment
Secondary	Adverse events (AEs)	All AEs will be assessed according to NCI CTCAE v5.0	From registration until 28 days after last trial treatment dose
Secondary	Quality of life (QoL): Core 30 (QLQ-C30)	QoL is measured by the Questionnaire Core 30 (QLQ-C30) including the complementary Lung Cancer Module (QLQ-LC13)	From registration until trial treatment discontinuation or the latest 1 year after registration
Secondary	Geriatric assessment (GA) - Screening instrument (G8)	Screening instrument (G8)	At baseline
Secondary	Geriatric assessment (GA) - Assessment with IADL	Assessment with IADL	At baseline
Secondary	Geriatric assessment (GA)	Comorbidities assessment with CCI	At baseline