Added additional vital sign measurements, including orthostatic blood pressure measurements predose on Cycle 1 Day 1 and Cycle 1 Day 3, and additional AE measurement on Cycle 1 Day 3 (approximately 48 hours after administration) to allow for closer blood pressure and AE monitoring around the time of maximal hypotension (within 3 to 4 days of NKTR-214 administration). Clarified that permanent discontinuation of study treatment was required for Grade 3 drug-related thrombocytopenia > 7 days or associated with clinically significant bleeding.

Protocol Amendment 2.0 added a noncomparative, reference chemotherapy arm of gemcitabine and carboplatin (GemCarbo) to inform and confirm the treatment effect and safety in this specific patient population. Under Amendment 2.0, patients were randomized in a 2:1 ratio to receive either NKTR-214 and nivolumab or gemcitabine and carboplatin (GemCarbo). Also, added a cross-over arm to allow patients randomized to GemCarbo to receive NKTR-214 and nivolumab. Added stricter patient entry criteria due to the expected increased toxicity with GemCarbo. Clarified the treatment management guidelines that pertained to GemCarbo (eg, premedication at the first and subsequent administrations, procedures for the GemCarbo arm in case of pregnancy in a female patient or in a female partner of a male patient) and those that pertained to NKTR-214 and nivolumab (eg, hypotension guidelines, blood samples for PK and immunogenicity assessments). Added Exclusion Criterion #3 specifying the tumor must have low PD-L1 expression. Clarified reason for ending treatment: occurrence of an unacceptable, clinically significant AE or non-resolution of clinically significant AE was extended from > 6 to > 8 weeks. Expanded the population by including ECOG performance status of 2 (Inclusion Criterion 6); previously only patients with an ECOG performance status of 0 or 1 were eligible. Added 2 stratification factors to the patient randomization: the presence of liver metastases (yes vs. no) and ECOG performance status (0 or 1 vs. 2).

Amendment 3.0 removed the GemCarbo arm based on negative feedback from health authorities regarding the utility of the noncomparative GemCarbo arm, especially given that the small sample size in the reference arm was not sufficient to address whether deviation from the historical control (EORTC Study 30986; De Santis 2012) was real or anomaly.

Added a summary analysis of CVA events conducted across the NKTR-214 clinical program and added mitigation measures for CVA events. Revised treatment discontinuation criteria regarding infusion reactions, adrenal insufficiency, and hypophysitis. Removed the exploratory objective of immune-related RECIST 1.1. Removed radiation therapy from prohibited concomitant medications. Reduced the number of sites and patients to be enrolled. Clarified Inclusion #7 to indicate that a treatment-free interval of > 12 months was required following all chemotherapeutic regimens, not just platinum-based. Clarified NKTR-214 potency, handling, and reconstitution information. Added that dose delay is required if patient had signs or symptoms of systemic infection requiring antibiotic therapy. Clarified classes of antihypertensive medications in Exclusion Criterion #17. Added a new section on the effect of NKTR-214 on clearance of concomitant medication, which reflected the current understanding of drug-drug interaction risks. Revised list of AEs for which additional information would be collected; added atrial fibrillation and deleted hypotension and eosinophilic disorders. Added specification for cycles adjustments if dosing was delayed. Removed drug-induced liver injury as an AE of special interest. Updated urine protein creatinine ratio requirements throughout. Clarified that health-related quality of life to be conducted before other assessments. Added “possibly related” to the definition of causality relationship of AEs. Clarified that hospital admissions only for patient observation not reported as an SAE.

Extended primary analysis from 6 to 18 months for adequate response duration evaluation. Added guidance for reporting and management of cytokine release syndrome (CRS). Added description of planned hypothesis testing, reflecting modifications to the SAP. Add the option for a rollover study to permit the flexibility to close the study prior to completion of 5 years survival follow-up.