1. Lowered the starting dose of NKTR-102 from 170 mg/m^2 to 145 mg/m^2 based on safety data from the Phase 1 study with NKTR-102 (06-IN-IR001) and ongoing Phase 2 studies in colorectal and ovarian cancer. 2. A secondary objective to collect pharmacokinetic samples was removed and all procedures related to pharmacokinetic sampling were omitted.No pharmacokinetic samples had been collected prior to this amendment. 3. An exploratory objective of the study (CA27.29) was removed. 4. Eligibility was changed to clarify that subjects were to have metastatic breast cancer (subjects with locally advanced disease were excluded). 5. Eligibility criteria regarding measurable disease was clarified (RECIST version 1.0 would be used; the sponsor was no longer required to review the baseline radiological assessment for acceptability). 6. Entry criteria for total bilirubin was changed to be ≤ 2.0 mg/dL instead of below the upper limit of normal range. 7. Entry criteria for albumin ≥ 3.0 g/dL was deleted. 8. Amended exclusion criteria. 9. The washout period for prior malignancy was expanded from 3 to 5 years. 10. Screening period was expanded from 14 to 28 days. 11. Non-treatment day study visits were removed. 12. Period of birth control was changed to at least 8 months after the last dose of study drug per request from Health Canada. 13. Added that the duration of treatment will conclude at 12 months measured from the date of randomization. 14. Added the dose modifications of 25 mg/m^2 for non-hematologic and nondiarrheal toxicities of Grade 2, 3, and 4 excluding alopecia, anorexia, and asthenia. 15. Included sponsor consideration for treatment delays beyond 2 weeks. 16. Allowed the use of erythroid stimulating agents as clinically indicated rather than as a rescue setting only. 17. Defined interval for follow-up contacts as quarterly following the End-of-Treatment Visit. 18. Study personnel names and contact information were updated.

1. Changed the eligibility criteria such that subjects who receive taxanes in the adjuvant setting as well as the metastatic setting were allowed to enter the study if they had failed taxanes and required additional chemotherapy. 2. The adverse event reporting requirements and follow-up were revised to require the collection and reporting of new Suspected Unexpected Serious Adverse Reactions that were experienced by subjects in the follow-up period. In addition, it also provided clarification on data entry regarding outcome of unrelated AEs that were ongoing at the time of End-of-Treatment visit. 3. Clarified the language on the screening tests for hematology, chemistry, and coagulation such that screening laboratories should have been performed within 28 days of first dose of study treatment. 4. Increased the pretreatment interval for clinical laboratory tests form 1 day to 3 days. 5. Updated the language concerning anti-diarrheal therapy. 6. Updated the pH of the formulation of NKTR-102 and the storage duration of reconstituted NKTR-102. 7. The infusion time for NKTR-102 was updated to include a window of ± 10 minutes. 8. Added language defining adequate forms of birth control. 9. Deleted requirement for reporting AEs using synonyms in NCI-CTCAE. 10. Study personnel names and contact information were updated.

1. Clarified that study drug continued until progression of disease, unacceptable toxicity, completion of 12 months of therapy measured from the date of randomization, death, withdrawal by subject, PI decision, lost to follow-up, protocol violations, or study termination by Sponsor. 2. Provided instruction for use of antiemetic therapy. 3. Clarified censoring rules for progression-free survival and overall survival. 4. Radiographic imaging should only have occurred at the End-of-Treatment visit if these tests had not been performed within the prior 6 weeks. 5. Clarified that documented tumor measurements were required using computed tomography scans or magnetic resonance imaging, as appropriate, and were to be performed during screening, approximately every 6 weeks from Cycle 1 Day 1 until documented disease progression, start of new therapy for cancer, or end of study. 6. Progression was to be only assessed during the follow-up period if the subject did not progress during the study drug treatment period. Quarterly follow-up continued until death, withdrawal by subject, PI decision, lost to follow-up, or study termination by Sponsor. Quarterly follow-up continued until the completion of the study. 7. Section 8.4 (Dose Modification and Delays) clarified that dose medication should have only been made for “drug-related” non-hematologic toxicities. Clarified dose modification guidelines in a setting of nausea/vomiting. 8. The time frame in which information regarding collection of concomitant medications was clarified. 9. Glutamyl transpeptidase was removed for assessments for liver function tests; aspartate aminotransferase and alanine aminotransferase continue to be required for liver function test assessment. 10. Section 10 (AE Reporting) was made consistent with similar language in other Phase 2 NKTR-102 protocols. 11. Clarified that duration of response applied to partial responses as well as complete responses.