“Locally advanced” was removed throughout. Length of study period was increased. Treatment with NKTR-102 & irinotecan was concluded at 12 months from randomization. Exclusion of erythroid stimulating agents was removed. Patients discontinuing due to toxicity were followed in quarterly follow-up visits. Unnecessary duplication between the Investigator’s Brochure & protocol was removed. Quarterly follow-up visits were added. Patient eligibility criteria were modified to reflect criteria used for NKTR-102 Phase 1 study. Patients & partners with child-bearing potential must use at least 2 forms of contraception for at least 8 months after last dose of NKTR-102. Exclusion of patients receiving concomitant anti-cancer biologic therapy was added. Exclusion of patients who previously treated with a camptothecin derivative or with past intolerance to excipients of irinotecan was added. Patients should not have had any cancer within the last 5 years Exclusion of patients with past history of bowel disorders considered at increased risk to toxicity related to irinotecan therapy was added. Clarified patient withdrawal from study. Screening window was increased from 14 to 28 days Patients were required to provide a sample for UGT1A1 status. Non-treatment study day visits were removed. Repeated urinalyses were removed. Dose modifications based upon non-hematologic & non-diarrhoea toxicities were added. For study treatment delays, Sponsor/Investigator consideration was allowed for continuing therapy for delays beyond two weeks. Storage & Accountability & Reconstitution & Handling of NKTR-102 text was updated. In the anti-diarrheal therapy for toxicity management, “initiate” was changed to “recommend” anti-microbial therapy. For patients with Grade 3 neutropenia, requirements that patients “must” have daily laboratories was changed to “recommended”. Pharmacokinetic assessment & procedures were clarified. Other administrative changes were made.

Lowered the starting dose of NKTR-102 to 145 mg/m^2 from 170 mg/m^2 based on safety data from the Phase 1 study with NKTR-102. Pregnancy test was added to end of study treatment visit as the risks of the study drug on the fetus are unknown. This assessment, which was in the original protocol, was removed in Amendment 1.0 in error.

Nektar terminated the contract with PRA for services on the 08-PIR-03 study; as a result, the following changes are made to the administrative structure of study 08-PIR-03: 1. Nektar re-assigned all safety reporting responsibilities from PRA to Fulcrum Pharma Europe (Ltd). 2. Except as described in item 1, Nektar resumed primary responsibility for all remaining operational activities that had previously been delegated to PRA. To facilitate the change in scope, Nektar re-assigned medical monitoring and trial management activities. 3. The language identifying the analytical laboratory was corrected to better reflect the planned analysis of biological sample.

Updated Study Drug Treatment Discontinuation Withdrawal from Study reasons. Clarified that patients who withdrew for a reason other than disease progression, withdrawal of consent or death were followed for progression by serial radiographic imaging. Clarified censoring rules for PFS and OS. Clarified that (with adoption of RECIST version 1.1 in the protocol) confirmation of response was not required. Radiographic imaging should have occurred at the end-of-treatment visit if these tests had not been performed within the prior 6 weeks. Clarified acceptable methods of determining KRAS mutation status. Slight modifications were made to inclusion/exclusion criteria. GGT was removed for assessments for liver function tests; AST and ALT continued to be required. The time frame in which patients had screening laboratory tests performed prior to study entry (up to 3 days) and the time frame from randomization to first study drug administration (up to 24 hours) were made more flexible. Clarified dose modification guidelines in a setting of nausea / vomiting. The time frame in which information regarding concomitant medications should be captured was clarified. Added language defining adequate forms of birth control to the protocol and informed consent document. Updated the pH of the formulation of NKTR-102 and the storage duration of reconstituted NKTR-102. Provided a window of ± 10 minutes for the 90-minute infusion time for NKTR-102 and irinotecan. Section 10 (Adverse Event Reporting) was made consistent with the language in other Phase 2 NKTR-102 protocols. Updated clinical and PK data (Sections 2.1.2.1, 2.1.2.2 and 2.1.2.3) were provided. Section 12.3.4.1 (Evaluation of Target Lesions) was updated to remove any reference to “New Lesions”, as assessment of new lesions are discussed in the overall assessment of response. Updated the Sponsor Medical Monitor information to reflect current team’s roles and responsibilities.

Updated guidance on dose modifications & dose delays for dose-limiting toxicities, especially gastrointestinal & hematological toxicities, occuring following NKTR-102 or Irinotecan administration. Updated anti-diarrheal therapy text to indicate that prophylactic antidiarrheal medications should not be used to treat diarrhea AEs. Updated sponsor address and clinical contact. Updated address and fax numbers for the sponsor’s pharmacovigilance designee. Updated the date of the Camptosar® package insert to the most recent version. Specified that radiographic imaging should be performed every 6 weeks (±5 days) until progressive disease, start of new therapy for cancer, or end of study participation. Added to Inclusion Criteria that a patient was eligible if they had received prior fluoropyrimidine therapy in the neoadjuvant setting, clarifying the existing entry criterion. Updated estimated overall duration of the study to be about 42 months. Clarified that a local pathology laboratory may be used to determine KRAS mutation status, if approved by Nektar. Updated that 10 tumor tissue slides were needed by the Central Pathology Laboratory for KRAS mutation status instead of 5 to 6. Clarified that microscopic analysis of urine by the Central Laboratory was only needed if dipstick findings were abnormal. Removed the option that an alternate randomization system provided by the sponsor may be used, since only an IVRS was used in this study. Included a ± 2-day window for the duration of the 21-day treatment cycle. Removed a limit of 12 months from date of randomization for patients to receive study treatment. Corrected the acceptable methods of birth control for women to not include a male partner who has had a vasectomy. Updated text describing 2 patients who experienced kidney failure after treatment with NKTR-102 to include a third patient to be consistent with the most recent Investigator’s Brochure.