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Fostering Efficacy of Anti - PD-1 - Treatment: Nivolumab Plus Radiotherapy in Advanced NSCLC (FORCE)

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ClinicalTrials.gov Identifier: NCT03044626
Recruitment Status : Recruiting
First Posted : February 7, 2017
Last Update Posted : July 30, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
AIO-Studien-gGmbH

Brief Summary:
AIO-YMO/TRK-0415 (FORCE) is a Phase 2, open-label of nivolumab, patients with metastatic non-squamous NSCLC with the necessity of radiotherapy of a metastatic site (e.g. bone) in 2nd-line or 3rd-line treatment for study group A and patients with metastatic non-squamous NSCLC without the necessity of radiotherapy in 2nd-line or 3rd-line treatment for study Group B.

Condition or disease Intervention/treatment Phase
Carcinoma,Non-Small-Cell Lung Metastatic Lung Cancer Nonsmall Cell Lung Cancer Lung Adenocarcinoma Metastatic Large Cell Lung Carcinoma Metastatic Drug: Radiotherapy Drug: Nivolumab Phase 2

Detailed Description:
The primary objective is to investigate efficacy of a nivolumab-radiotherapy combination treatment in metastatic non-squamous NSCLC patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Fostering Efficacy of Anti - PD-1 - Treatment: Nivolumab Plus Radiotherapy in Advanced NSCLC
Actual Study Start Date : February 10, 2017
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: study group A

Patients with metastatic non-squamous NSCLC with the necessity of radiotherapy of a metastatic site (e.g. bone) in 2nd-line or 3rd-line treatment:

Nivolumab 240 mg fixed dose (q2w). First dose followed by radiotherapy. Radiotherapy has to start at the latest 72 hours after nivolumab administration.

Radiotherapy: A metastatic site will be treated with a radiation dose of 4 Gy for a total of 5 courses during a two week time interval (total dose 20 Gy)

Drug: Radiotherapy

Nivolumab 240 mg fixed dose (q2w). First dose followed by radiotherapy. Radiotherapy has to start at the latest 72 hours after nivolumab administration.

Radiotherapy: A metastatic site will be treated with a radiation dose of 4 Gy for a total of 5 courses during a two week time interval (total dose 20 Gy)


Drug: Nivolumab
Nivolumab 240 mg fixed dose (q2w)

study group B

Patients with metastatic non-squamous NSCLC without the necessity of radiotherapy in 2nd-line or 3rd-line treatment:

Nivolumab 240 mg fixed dose (q2w).

Drug: Nivolumab
Nivolumab 240 mg fixed dose (q2w)




Primary Outcome Measures :
  1. objective response rate (ORR) according to RECIST 1.1 criteria [ Time Frame: through study completion, an average of 18 months ]

Secondary Outcome Measures :
  1. progression free survival (PFS) [ Time Frame: approx. 6 months ]
  2. PFS using assessment according to irRECIST [ Time Frame: approx. 6 months ]
    Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST)

  3. ORR using assessment according to irRECIST [ Time Frame: approx. 6 months ]
    Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST)

  4. Overall Survival (OS) [ Time Frame: approx. 57 months ]
  5. Adverse Events [ Time Frame: approx. 36 months ]
    Adverse Events: Type, incidence, and severity according to NCI CTCAE version 4.03

  6. Assesment of Quality of life [ Time Frame: approx. 57 months ]
    as determined with FACT-L (Functional Assessment of Cancer Therapy - Lung)


Other Outcome Measures:
  1. Radiation oncology endpoint: absolute size of gross tumor (GTV) [ Time Frame: approx. 57 months ]
  2. Radiation oncology endpoint: clinical target (CTV) [ Time Frame: approx. 57 months ]
  3. Radiation oncology endpoint: planning target volume (PTV) [ Time Frame: approx. 57 months ]
  4. Radiation oncology endpoint: DVH parameters such as D2%, D50%, and D98% within the PTV [ Time Frame: approx. 57 months ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. Subject is 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.

3. Age ≥ 18 years at time of study entry. 4. ECOG performance status 0-1. 5. Patients with measurable disease (at least one uni-dimensionally measurable target lesion by CT-scan or MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) are eligible. For patients in group A, non-measurable and measurable lesions may be chosen for irradiation. However, in order to allow for evaluation of abscopal effects, patients in group A must have at least one measurable lesion beside the lesion planned to be irradiated. Lesions planned to be irradiated may not be defined as a measurable target lesion. Radiographic tumor assessment must be performed within 28 days before initiation of study treatment.

6. Target Lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site.

7. Patients with metastatic non-squamous non-small cell lung cancer in 2nd-line and 3rd-line treatment and

  1. no necessity of radiotherapy or
  2. the necessity of radiotherapy of a metastatic bone lesion or soft tissue lesion.

    • Patients with intrathoracic metastases or intrathoracic progressive disease will be included if radiotherapy of the lung parenchyma is NOT required
    • Subjects with symptomatic brain metastases are eligible if metastases have been treated and treatment has been completed at least 12 weeks before inclusion in this study for group B and 2 weeks for group A. Moreover, there must be no magnetic resonance imaging (MRI) evidence of progression within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. Patients with stable/asymptomatic brain metastases that do not require local therapy with irradiation (whole brain irradiation or stereotactic brain irradiation) can be included. In ambiguous cases, consultation with the LKP or his/her delegate is advised.

      8. Patients who will receive study therapy after acceptable prior therapy as specified below are eligible: i. Patients who will receive study therapy as 2nd-line or 3rd-line of treatment:

      1. Patients must have experienced disease recurrence or progression during or after one prior platinum doublet-based chemotherapy regimen for advanced or metastatic disease.

        First line therapy is defined as therapy used to treat advanced disease. Each subsequent line of therapy is preceded by disease progression. A switch of an agent within a regimen in order to manage toxicity does not define the start of a new line of therapy. Subjects must have received at least 2 cycles of platinum doublet based chemotherapy before discontinuation for toxicity.

        Experimental therapies when given as separate regimen are considered as separate line of therapy.

        Maintenance therapy following platinum doublet-based chemotherapy is not considered as a separate regimen of therapy and could comprise continuation of one or more of the agents used in the first-line therapy regimen or switch to another non cross-resistant agent. The initiation of maintenance therapy requires the lack of progressive disease with front-line therapy.

        Treatment given for locally advanced disease is not considered as a line of therapy for advanced disease. Subjects with recurrent disease > 6 months after platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, who also subsequently progressed during or after a platinum doublet-based regimen given to treat the recurrence, are eligible.

      2. Patients who received platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, and developed recurrent (local or metastatic) disease within 6 months of completing therapy are eligible.

        Adjuvant or neoadjuvant platinum-doublet chemotherapy (after surgery and/or radiation therapy) followed by recurrent or metastatic disease within 6 months of completing therapy is considered as first line therapy for advanced disease.

      9. A formalin fixed, paraffin-embedded (FFPE) tumor tissue block (archival or recent) or a minimum of 15 unstained slides of tumor sample (2-3 µm sections, slices must be recent and collected on 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 insufficient.

      10. Prior therapies and surgeries are allowed if completed 2 weeks for minor surgery (group A and B) or 12 weeks for any previous radiotherapy for group B, respectively prior to start of treatment and patient recovered from toxic effects. For group A, any prior radiotherapy not involving the lungs must be completed 2 weeks prior to start of treatment. A prior radiotherapy involving the lungs must be completed 12 weeks prior to start of treatment.

      11. Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment.

      12. Adequate blood count, liver-enzymes, and renal function (obtained no later than 14 days prior to start of treatment): WBC ≥ 2000/μL Neutrophils ≥ 1500/μL Platelets ≥ 100 x103/μL Hemoglobin ≥ 9.0 g/dL

    Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

    Female CrCl = ((140 - age in years) x weight in kg x 0.85) / (72 x serum creatinine in mg/dL)

    Male CrCl = ((140 - age in years) x weight in kg x 1.00) / (72 x serum creatinine in mg/dL)

    AST/ALT ≤ 3 x ULN Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

    13. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of nivolumab.

    14. Women of childbearing potential must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab.

    15. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception).

    Exclusion criteria

    1. Previous malignancy (other than NSCLC), which either progresses or requires active treatment.

      Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, endometrial, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required or anticipated to be required during the study period.

    2. Brain metastases mandating active treatment in terms of irradiation (whole brain irradiation or stereotactic brain irradiation). As stated in 3.2 point 7 b, subjects with brain metastases are eligible if metastases have been treated and treatment has been completed at least 12 weeks before inclusion in this study for group B and 2 weeks for group A. Moreover, there must be no magnetic resonance imaging (MRI) evidence of progression within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. Patients with stable/asymptomatic brain metastases that do not require local therapy with irradiation (whole brain irradiation or stereotactic brain irradiation) can be included. In ambiguous cases, consultation with the LKP or his/her delegate is advised.
    3. Known activating EGFR mutation or a known ALK translocation.
    4. Prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents.
    5. Patients with interstitial lung disease.
    6. Any previous treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T‑cell co-stimulation or immune checkpoint pathways
    7. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to grade 1 (NCI CTCAE version 4) or baseline before administration of study drug.
    8. Patients should be excluded if they have an active, known or suspected autoimmune disease. NOTE: Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
    9. Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. NOTE: Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
    10. Patients should be excluded if they are positively tested for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
    11. Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
    12. History of severe hypersensitivity reactions to other monoclonal antibodies or any excipient.
    13. Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year)
    14. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) ≤14 days prior to the first dose of study treatment.
    15. Any other serious or uncontrolled medical disorder, active infection, physical examining, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a subject's ability to comply with the study requirements, substantially increase risk to the subject, or impact the interpretability of study results.
    16. History of solid organ or tissue transplantation including allogenic hematopoietic stem cell transplantation.
    17. Previous enrollment in the present study.
    18. Involvement in the planning and/or conduct of the study (applies to both BMS staff and/or staff of sponsor and study site)
    19. Patient who might be dependent on the sponsor, site or the investigator.
    20. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03044626


Contacts
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Contact: Magda Krejczy +49 30 8145 344 40 magda.krejczy@aio-studien-ggmbh.de
Contact: Farastuk Bozorgmehr, Dr. +49 6221 3968077 farastuk.bozorgmehr@med.uni-heidelberg.de

Locations
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Germany
Evangelische Lungenklinik Berlin Recruiting
Berlin, Germany, 13125
Contact: Christian Grohé, Prof. Dr.         
DRK Kliniken Berlin Mitte Recruiting
Berlin, Germany, 13359
Contact: Vincent van Laak, Dr.         
Klinikum Chemnitz Not yet recruiting
Chemnitz, Germany, 09116
Contact: Stefan Hammerschmidt, Prof. Dr.         
Universitätsklinikum Carl-Gustav-Carus Recruiting
Dresden, Germany, 01307
Contact: Martin Wermke, Dr.         
Klinikum Esslingen GmbH Recruiting
Esslingen, Germany, 73730
Contact: Martin Faehling, PD Dr.         
Krankenhaus Nordwest Recruiting
Frankfurt / Main, Germany, 60488
Contact: Akin Atmaca, Dr.         
LungenClinic Grosshansdorf Recruiting
Großhansdorf, Germany, 22927
Contact: David Felix Heigener, Dr.         
Universitätsklinikum Heidelberg Recruiting
Heidelberg, Germany, 69126
Contact: Farastuk Bozorgmehr, Dr         
Universitätsklinikum des Saarlandes Recruiting
Homburg/Saar, Germany, 66421
Contact: Jochen Fleckenstein, Dr.         
Klinikverbund Kempten-Oberallgäu Recruiting
Immenstadt, Germany, 87509
Contact: Christian Schumann, Prof. Dr.         
Kliniken der Stadt Köln Krankenhaus Merheim Recruiting
Köln, Germany, 51109
Contact: Walburga Engel-Riedel, Dr.         
Ev. Diakonissenkrankenhaus Active, not recruiting
Leipzig, Germany, 04177
Klinik Löwenstein Recruiting
Löwenstein, Germany, 74245
Contact: Jürgen R. Fischer, PD Dr.         
Universitätsklinikum Mannheim Recruiting
Mannheim, Germany, 68167
Contact: Frederik Wenz, Prof. Dr.         
Asklepios Fachkliniken München-Gauting Recruiting
München-Gauting, Germany, 82131
Contact: Nils Reinmuth, PD Dr.         
Klinikum Nürnberg Active, not recruiting
Nürnberg, Germany, 90419
Universitätsklinikum Tübingen Not yet recruiting
Tübingen, Germany, 72076
Contact: Sebastian Haen, Dr.         
Universitätsklinikum Ulm Recruiting
Ulm, Germany, 89081
Contact: Cornelia Kropf-Sanchen, Dr.         
Sponsors and Collaborators
AIO-Studien-gGmbH
Bristol-Myers Squibb
Investigators
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Principal Investigator: Farastuk Bozorgmehr, Dr. Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital

Additional Information:
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Responsible Party: AIO-Studien-gGmbH
ClinicalTrials.gov Identifier: NCT03044626     History of Changes
Other Study ID Numbers: AIO-YMO/TRK-0415
2015-005741-31 ( EudraCT Number )
CA209-430 ( Other Identifier: Bristol-Myers Squibb GmbH & Co. KGaA )
First Posted: February 7, 2017    Key Record Dates
Last Update Posted: July 30, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AIO-Studien-gGmbH:
Nivolumab
Radiotherapy

Additional relevant MeSH terms:
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Carcinoma
Lung Neoplasms
Adenocarcinoma
Carcinoma, Non-Small-Cell Lung
Adenocarcinoma of Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents