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Table 1 Complete list of inclusion and exclusion criteria

From: Fostering efficacy of anti-PD-1-treatment: Nivolumab plus radiotherapy in advanced non-small cell lung cancer - study protocol of the FORCE trial

Inclusion criteria

 • 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.

 • Subject is willing and able to coxmply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

 • Age ≥ 18 years at time of study entry.

 • ECOG performance status 0–1.

 • Patients with measurable disease (at least one uni-dimensionally measurable target lesion by CT-scan or MRI) according to 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.

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

 • Patients with metastatic non-squamous NSCLC in 2nd-line and 3rd-line treatment and

 a) no necessity of radiotherapy or

 b) 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 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.

 • An FFPE tumor tissue block (archival or recent) or a minimum of 15 unstained slides of tumor sample must be available for biomarker (PD-L1) evaluation.

 • 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.

 • 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.

 • Adequate blood count, liver-enzymes, and renal function (obtained no later than 14 days prior to start of treatment):

 • Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception and must have a negative serum pregnancy test within 24 h prior to the start of nivolumab.

 • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year.

Exclusion criteria

 • 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.

 • Brain metastases mandating active treatment in terms of irradiation (whole brain irradiation or stereotactic brain irradiation).

 • Known activating EGFR mutation or a known ALK translocation.

 • Prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents.

 • Patients with interstitial lung disease.

 • 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.

 • All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to grade 1 (CTCAE version 4) or baseline before administration of study drug.

 • Patients should be excluded if they have an active, known or suspected autoimmune disease. 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.

 • 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.

 • 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.

 • Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

 • History of severe hypersensitivity reactions to other monoclonal antibodies or any excipient.

 • 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)

 • 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

 • 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

 • History of solid organ or tissue transplantation including allogenic hematopoietic stem cell transplantation

 • Previous enrollment in the present study

 • Involvement in the planning and/or conduct of the study (applies to both BMS staff and/or staff of sponsor and study site)

 • Patient, who might be dependent on the sponsor, site or the investigator

 • Patient, who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG