Durvalumab (MEDI4736) in Frail and Elder Patients With Metastatic NSCLC (DURATION) (DURATION)

AIO-YMO/TRK-0416 (DURATION) is a open-label, treatment stratified and randomized phase II study of Durvalumab, frail or elderly patients with metastatic non-squamous NSCLC with no targetable molecular alterations (EGFRwt; ALKtransl-) and not amenable to cisplatinum-based standard-combination chemotherapy but eligible for at-least mono-chemotherapy with gemcitabine or vinorelbine.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Non-Small-Cell Lung; Non Small Cell Lung Cancer; Metastatic Lung Cancer; Lung Adenocarcinoma Metastatic; Large Cell Lung Carcinoma Metastatic
• Intervention / Treatment: Drug: nab-Paclitaxel; Drug: Carboplatin; Drug: Durvalumab; Drug: Vinorelbine; Drug: Gemcitabine

Detailed Description

The primary objective is to assess the safety and tolerability of sequential therapy consisting of standard of care mono- or combination chemotherapy followed by durvalumab in comparison to standard of care mono- or combination chemotherapy in frail/elderly patients.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Amberg, Germany, 92224
    • Gesundheitszentrum St. Marien GmbH
  • Berlin, Germany, 13125
    • Ev. Lungenklinik Berlin
  • Berlin-Mitte, Germany, 13359
    • DRK-Kliniken Berlin Mitte
  • Darmstadt, Germany, 64283
    • Klinikum Darmstadt
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl-Gustav-Carus
  • Esslingen, Germany, 73730
    • Klinikum Esslingen
  • Frankfurt am Main, Germany, 60590
    • Universitatsklinikum Frankfurt
  • Gerlingen, Germany, 70839
    • Klinik Schillerhohe
  • Greifswald, Germany, 17475
    • Universitätsmedizin Greifswald
  • Gütersloh, Germany, 33332
    • Onkodoc GmbH
  • Halle (Saale), Germany, 06120
    • Krankenhaus Martha-Maria Halle Dölau
  • Heidelberg, Germany
    • Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital
  • Hemer, Germany, 58675
    • Lungenklinik Hemer
  • Karlsruhe, Germany, 76137
    • "Vincentius-Diakonissen-Kliniken gAG
  • Köln, Germany, 51109
    • Kliniken der Stadt Koln gGmbH
  • Lahr, Germany, 77933
    • Ortenau-Klinikum Lahr
  • Leipzig, Germany, 04177
    • Ev. Diakonissenkrankenhaus Leipzig
  • Ludwigsburg, Germany, 71640
    • Klinikum Ludwigsburg
  • Löwenstein, Germany, 74245
    • Klinik Löwenstein gGmbH
  • München, Germany, 81377
    • Klinikum der Universität München
  • Oldenburg, Germany, 26121
    • Pius Hospital Oldenburg
  • Regensburg, Germany, 93049
    • Krankenhaus Barmherzige Brüder
  • Rheine, Germany, 48341
    • "Klinikum Rheine
  • Stuttgart, Germany, 70199
    • Marienhospital
  • Trier, Germany, 54292
    • Krankenhaus der Barmherzigen Brüder
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
  • Villingen-Schwenningen, Germany, 78052
    • Schwarzwald-Baar Klinikum
  • Völklingen, Germany, 66333
    • SHG-Kliniken-Völklingen
  • Würselen, Germany, 52146
    • Hämatologisch-Onkologische Praxis Würselen
  • Würzburg, Germany, 97074
    • Klinikum Würzburg Mitte gGmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent and any locally-required authorization (EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
2. Age ≥ 70 years at time of study entry and/or Charlson-Comorbidity-Index (CCI) >1 and/or Performance status ECOG >1
3. Histologically confirmed diagnosis of metastatic NSCLC and no targetable molecular alterations (EGFRwt; ALKtransl-) and not amenable to cisplatinum-based standard-combination chemotherapy.
4. Patients with measurable disease (at least one uni-dimensionally measurable target lesion not previously irradiated, by CT-scan or MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) are eligible.
5. A formalin fixed, paraffin-embedded (FFPE) tumor tissue block (fresh or archival less than 3 years old or recent) or a minimum of 10 unstained slides of tumor sample (slices must be less than 90 days old and collected on SuperFrost slides provided by the sponsor) must be available for biomarker (PD-L1) evaluation. Biopsy should be excisional, incisional or core needle. Fine needle aspiration is inappropriate.
6. No prior chemotherapy or any other systemic therapy for metastatic NSCLC. Patients who have received prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation for locally advanced disease are eligible, provided that progression has occurred >6 months from last therapy.
7. Prior radiotherapy and surgery are allowed if completed 4 weeks (for minor surgery and palliative radiotherapy for bone pain: 2 weeks) prior to start of treatment and patient recovered from toxic effects or associated adverse events.

8. Adequate blood count, liver-enzymes, and renal function:

   • Haemoglobin ≥ 9.0 g/dL
   • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)
   • Platelet count ≥ 100 x 109/L (>100,000 per mm3)
   • Serum bilirubin ≤ 1.5 x ULN. This will not apply to subjects 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 unless liver metastases are present, in which case it must be ≤ 5x ULN
   • Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
9. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits, examinations including follow up and appropriate contraception

Exclusion Criteria:

1. Mixed small-cell lung cancer and NSCLC histology
2. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's correction
3. History of another primary malignancy except local prostate cancer without need for systemic treatment (e.g. active surveillance, operation without need for adjuvant treatment) and malignancies treated with curative intent and with no known active disease >2 years befor the first dose of study drug and of low potential risk for recurrence, e.g. adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, adequately treated carcinoma in situ without evidence of disease (e.g. cervical cancer in situ)
4. Pre-existing peripheral neuropathy of Grade ≥ 2
5. Brain metastasis or spinal cord compression unless asymptomatic or treated and stable off steroids and anti-convulsants for at least 1 month prior to study treatement.
6. Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
7. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
8. History of primary immunodeficiency
9. History of allogeneic organ transplant
10. History of hypersensitivity to durvalumab or any excipient
11. History of hypersensitivity to any of the comparator agents
12. Medication that is known to interfere with any of the agents applied in the trial.
13. 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 subject 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 subject to give written informed consent
14. Clinical diagnosis of active tuberculosis
15. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab
16. Male patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year)
17. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
18. Participation in another clinical study with an investigational product during the last 30 days before inclusion
19. Any previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab
20. 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, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
21. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) ≤ 21 days prior to the first dose of study drug or ≤4 half-lifes of the agent administered, which ever comes first.
22. Previous enrollment or randomization in the present study.
23. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff of sponsor and study site)
24. Patient who might be dependent on the sponsor, site or the investigator
25. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
26. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control Arm A; Frail or elderly patients with metastatic NSCLC; CARG- Score ≤ 3 Carboplatin (AUC 5.0; D1) + nab-Paclitaxel (100mg/m2 D1,D8) Q3W	Drug: nab-Paclitaxel; (100 mg/m2 intravenous infusion over 30 minutes on D1, D8) cycle Q3W; Other Names: Abraxane; Drug: Carboplatin; (AUC = 5 mg•min/mL on Day 1) cycle Q3W
Experimental: Experimental Arm B; Frail or elderly patients with metastatic NSCLC; CARG- Score ≤ 3 Induction:Carboplatin (AUC 5.0; D1) + nab-Paclitaxel (100mg/m2) D1,D8; Q3W [2 cyc] followed by durvalumab (1125 mg; Q3W) [ 2 cyc] Maintenance:durvalumab (1500 mg) Q4W	Drug: nab-Paclitaxel; (100 mg/m2 intravenous infusion over 30 minutes on D1, D8) cycle Q3W; Other Names: Abraxane; Drug: Carboplatin; (AUC = 5 mg•min/mL on Day 1) cycle Q3W; Drug: Durvalumab; Induction: (1125 mg) cycle Q3W Maintenance: (1500 mg) cycle Q4W; Other Names: MEDI4736
Experimental: Experimental Arm C; Frail or elderly patients with metastatic NSCLC; CARG- Score > 3 Induction: Vinorelbine (30 mg/m2; D1+D8) Q3W [ 2 cyc] or Gemcitabine (1000 mg/m2; D1+D8) Q3W [ 2 cyc] followed by durvalumab (1125 mg) Q3W [2 cyc] Maintenance:durvalumab (1500 mg; Q4W)	Drug: Durvalumab; Induction: (1125 mg) cycle Q3W Maintenance: (1500 mg) cycle Q4W; Other Names: MEDI4736; Drug: Vinorelbine; (30 mg/m2 D1 + D8 as infusion) cycle Q3W; Drug: Gemcitabine; (1000 mg/m2 D1 + D8 as infusion) cycle Q3W
Active Comparator: Control Arm D; Frail or elderly patients with metastatic NSCLC; CARG- Score > 3 Vinorelbine (30 mg/m2; D1+D8) Q3W or Gemcitabine (1000 mg/m2; D1+D8) Q3W	Drug: Vinorelbine; (30 mg/m2 D1 + D8 as infusion) cycle Q3W; Drug: Gemcitabine; (1000 mg/m2 D1 + D8 as infusion) cycle Q3W

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of treatment related Grade III/IV adverse events (CTCAE V4.03)	Comparison of the outcome of sequential therapy consisting of standard of care mono- or combination chemotherapy followed by durvalumab versus standard of care mono- or combination chemotherapy in frail/elderly patients	through study completion, an average of 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	Progression Free Survival	approx. 24 months
ORR using assessment according to RECIST 1.1	Response Evaluation Criteria In Solid Tumors (RECIST)	approx. 24 months
OS	Overall Survival	approx. 60 months
Adverse Events /Serious Adverse Events	Adverse Events: Type, incidence, and severity according to NCI CTCAE version 4.03	approx. 48 months
Health related Quality of Life (HR-QoL)	as determined with FACT-L (Functional Assessment of Cancer Therapy - Lung)	approx. 60 months
Geriatric assessment	G8-questionnaire	approx. 60 months
Geriatric assessment	Timed up & go (test of basic functional mobility)	approx. 60 months
Geriatric assessment	6MWT (6 minutes walk test)	approx. 60 months

Collaborators and Investigators

• Sponsor: AIO-Studien-gGmbH
• Collaborators: AstraZeneca; Celgene
• Investigators: Principal Investigator: Jonas Kuon, Dr, Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany

Publications and helpful links

General Publications

• Kuon J, Hommertgen A, Krisam J, Lasitschka F, Stenzinger A, Blasi M, Bozorgmehr F, Maenz M, Kieser M, Schneider M, Thomas M. Durvalumab in frail and elderly patients with stage four non-small cell lung cancer: Study protocol of the randomized phase II DURATION trial. Trials. 2020 Apr 22;21(1):352. doi: 10.1186/s13063-020-04280-8.

Helpful Links

• AIO - Working Group for Medical Oncology from the German Cancer Society
• AIO-Studien-gGmbH

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2017
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: November 14, 2017
• First Submitted That Met QC Criteria: November 14, 2017
• First Posted (Actual): November 17, 2017

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: NSCLC; Non small cell lung cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma; Adenocarcinoma of Lung; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Carboplatin; Paclitaxel; Durvalumab; Vinorelbine; Gemcitabine
• Other Study ID Numbers: AIO-YMO/TRK-0416; 2016-003963-20 (EudraCT Number); ESR-15-11003 (Other Grant/Funding Number: AstraZeneca GmbH); AX-CL-NSCLC-AIO-008260 (Other Grant/Funding Number: Celgene)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No