Study of MM-398 With or Without 5-FU/LV, Versus 5-FU/LV in Patients With Metastatic Pancreatic Cancer

Overall survival was the primary efficacy endpoint of the study and was defined as the time from the date of patient randomization to the date of death or the date the patient was last known to be alive. OS was summarized by Kaplan-Meier methodology for each treatment group. Pairwise treatment group comparisons were carried out using unstratified log rank analyses on the ITT population. Hazard ratio estimates are from Cox regression analysis. The comparison of Arm C is based only on patients who were randomized under the 3-arm version of the protocol. Consequently, the 5-FU+Leucovorin (Combo Therapy Comparison) group is a subset of all patients randomized to 5-FU+Leucovorin, which is the Mono Therapy Comparison control and contains patients randomized under both the 2-arm and 3-arm versions of the protocol.

Time frame: From randomization to death; until the data cut off 14 Feb 2014. The maximum time in follow up was 25 months.

Population: Intent to Treat population (ITT population) consisted of all randomized participants. Efficacy analyses in the ITT population consider treatment group according to randomization. Comparisons of the MM-398+5-FU/LV to 5-FU/LV were carried out only on patients who were randomized under protocol version 2 or later.

This patient recorded outcome consists of 15 subscales in 3 independent domains: global health-related quality of life (HRQoL), functional scales (cognitive, emotional, physical, role and social functioning), and symptom scales (appetite loss, constipation, diarrhea, dyspnea, fatigue, insomnia, nausea and vomiting, and pain). For each subscale, patients were classified as improved, worsened or stable. Improvement is indicated by achievement of subscale score at least 10% improved from baseline and maintained for at least 6 weeks. Worsened is indicated by subscale score at least 10% worse than baseline. Stable is indicated by neither improvement nor worsened. Achievement of improvement prior to worsening was classified as improvement.

Time frame: Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months

Population: ITT patients who had baseline and at least one-post baseline EORTC-QLQ-C30 assessment.

The objective response rate was a secondary efficacy endpoint of the study and was defined by the percentage of patients in the study population with a best overall response of Complete Response (CR) or Partial Response (PR) as assessed by the investigator. Best overall response was defined per RECIST (version 1.1) recorded from randomization until progression or end of study. RECIST (v 1.1) criteria does not require confirmation of response, but an additional, more stringent analysis was also conducted, with designation of CR (or PR) requiring confirmation of response at least 4 weeks following the initial assessment of CR (or PR). Stable disease (SD) required an assessment of SD at least 6 weeks after starting treatment. Subjects with insufficient data for response classification were classified as Not Evaluable for best overall response, and as a non-responder for objective response, in the ITT population. Treatment groups are as indicated for the primary outcome of OS.

Time frame: Assessment every 6 weeks after initial response; Day 1 to data cut off of 14 Feb 2014; maximum time on study 25 months.

Population: ITT Population

Composite measure based on patient-reported pain (per VAS), patient-reported pain medication, KPS, and weight. Clinical benefit is indicated by either: (a) improvement in pain (less pain intensity with stable or decreased pain medication; or less pain medication with stable or decreased pain intensity) with stable or improved KPS; or (b) improvement in KPS with stable or improved pain. With stable for KPS and pain, clinical benefit may be indicated with an observation of positive weight change. Clinical benefit response (CBR) was classified weekly and a patient was considered a clinical benefit responder if clinical benefit was observed and maintained over a 4 week period.

Time frame: Randomization to treatment discontinuation.The maximum time in follow up was 25 months

Population: Clinical Benefit Response Evaluable Population: Patients who received study drug and met at least one of the following criteria were defined as eligible for evaluation of CBR:~* baseline pain intensity ≥ 20 (out of 100)~* baseline morphine consumption ≥ 10 mg/day PO morphine equivalents~* baseline KPS of 70 to 90 points

Tumor marker response (TMR) was evaluated by the change in CA19-9 serum levels. Response was defined as a decrease of 50% of CA19-9 in relation to the baseline level at least once during the treatment period.

Time frame: Baseline to treatment discontinuation every 6 weeks; The maximum time in follow up was 25 months

Population: Patients with elevated baseline CA19-9 value (\> 30 U/mL) who received study drug.

Plasma concentration-time data for MM-398 will be analyzed using population pharmacokinetic methods.

Time frame: 6 weeks after first study drug administration

Population: PK population was based on Protocol, all participants who received the appropriate dose of MM-398.

Progression-free survival was defined as the time from the date of randomization to the date of disease progression, or death (any cause) on or prior to the clinical cutoff date, whichever occurred earlier. Participants who did not have disease progression or had not died were censored at the date of the last tumor assessment. Patients with two or more consecutive missing response assessments prior to a visit with documented progression (or death) were censored at the last date of tumor assessment when the patient was documented to be progression free. PFS was summarized using Kaplan-Meier methods. The comparison of Arm C is based only on patients who were randomized under the 3-arm version of the protocol. Consequently, the 5-FU+Leucovorin (Combo Therapy Comparison) group is a subset of all patients randomized to 5-FU+Leucovorin, which is the Mono Therapy Comparison control and contains patients randomized under both the 2-arm and 3-arm versions of the protocol.

Time frame: Randomization until disease progression or death from any cause; Until the data cut off of 14 Feb 2014. The maximum time in follow up was 25 months.

Population: ITT Population

Time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity or death.

Time frame: Randomization to treatment discontinuation (any cause). The maximum time in follow up was 25 months

Population: ITT Population