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MM-398 120 mg/m2 Q3W IV. Note: The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 120 mg/m2 dose of irinotecan hydrochloride trihydrate is equivalent to 100 mg/ m2 of irinotecan free base.

MM-398 80 mg/m2, 5-FU and Leucovorin Q2W IV. Note: The published dose of ONIVYDE was expressed as the irinotecan hydrochloride trihydrate until October 2015. It is now expressed as the irinotecan free base. Converting a dose based on irinotecan hydrochloride trihydrate to a dose based on irinotecan free base is accomplished by substituting the Molecular Weight of irinotecan hydrochloride trihydrate (677.19 g/mole) with the Molecular Weight of irinotecan free base (586.68 g/mole), which results in a conversion factor of 0.866. 80 mg/m2 dose of irinotecan hydrochloride trihydrate is equivalent to 70 mg/ m2 of irinotecan free base.

Arm A: MM-398 120 mg/m2 IV Q3W

Arm C: MM-398 80mg/m2 IV Q2W

MM-398

Arm B: 5 Fluorouracil 2000 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks

Arm C: 5 Fluorouracil 2400 mg/m2 IV every 2 weeks

5 Fluorouracil

Arm B: Leucovorin 200 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks

Arm C: Leucovorin 400 mg/m2 IV every 2 weeks

Eliel Bayever, MD

The study is an open label, randomized phase 3 study of MM-398 with or without 5-Fluorouracil (5-FU) and Leucovorin (also known as folinic acid), versus 5-FU and leucovorin in metastatic pancreatic cancer patients who have progressed on prior gemcitabine based therapy.

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

A Randomized, Open Label Phase 3 Study of MM-398, With or Without 5-Fluorouracil and Leucovorin, Versus 5 Fluorouracil and Leucovorin in Patients With Metastatic Pancreatic Cancer Who Have Failed Prior Gemcitabine-based Therapy

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.

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.

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

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.

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.

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.

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

Merrimack Pharmaceuticals

5-FU= 5-fluorouracil; LV=leucovorin Events were collected by systematic assessment Term from vocabulary, MedDRA version 14.1

MM-398 Q3W IV

MM-398: Arm A: MM-398 120 mg/m2 IV Q3W

Arm C: MM-398 80mg/m2 IV Q2W

5 Fluorouracil and Leucovorin IV

5 Fluorouracil: Arm B: 5 Fluorouracil 2000 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks

Arm C: 5 Fluorouracil 2400 mg/m2 IV every 2 weeks

Leucovorin: Arm B: Leucovorin 200 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks

Arm C: Leucovorin 400 mg/m2 IV every 2 weeks

5 Fluorouracil and Leucovorin IV

MM-398, 5-FU and Leucovorin Q2W IV

MM-398: Arm A: MM-398 120 mg/m2 IV Q3W

Arm C: MM-398 80mg/m2 IV Q2W

5 Fluorouracil: Arm B: 5 Fluorouracil 2000 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks

Arm C: 5 Fluorouracil 2400 mg/m2 IV every 2 weeks

Leucovorin: Arm B: Leucovorin 200 mg/m2 IV for 4 weeks followed by 2 weeks of rest every 6 weeks

Arm C: Leucovorin 400 mg/m2 IV every 2 weeks

MM-398, 5-FU and Leucovorin

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

American Indian or Alaska Native

Asian

Black or African American

White

other race

RACE (NIH/OMB)

100% = normal, no complaints, no signs of disease

90% = normal activity, few symptoms of disease

80% = normal activity, some symptoms of disease

70% = caring for self, unable to work

60% [2] = needs help, can manage most tasks

50%[2]= needs help often and medical care

Not recorded

1. One patient in the 5-FU/LV arm did not have a recorded Baseline KPS value.
2. Designation of the KPS level for the randomization strata is made during the screening period prior to knowledge of the treatment assignment. Baseline KPS is the last observed KPS value prior to treatment in treated patients and the last observed value in patients who were randomized and did not receive study drug. The observed baseline KPS value may be recorded post-randomization.

Karnofsky Performance Status (Baseline KPS)[1]

Head

Body

Tail

Multiple locations including head

Multiple locations not including head

Unknown = not specified

Pancreatic Primary Tumor Location

Dr. Eliel Bayever

• MM-398 120 mg/m2 IV on Day 1of a 3 weekly cycle Patients who were homozygous for UGT1A1\*28 allele received the first cycle of therapy at a reduced dose of 80 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased in increments of 20 mg/m2 up to a maximum of 120 mg/m2.

MM-398 Arm A (Mono Therapy Comparison)

* 5-FU 2000 mg/m2 IV over 24-hours, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle
* Leucovorin l + d racemic form 200 mg/m2, or l form 100 mg/m2 IV over 30 minutes, every week for 4 weeks (days 1, 8, 15 and 22), followed by 2 weeks of rest, in a 6 week cycle.

5-FU + Leucovorin (Arm B) (Mono Therapy Comparison)

* MM-398 80 mg/m2 IV every 2 weeks Patients who were homozygous for UGT1A1\*28 allele and were randomized to Arm C, received the first cycle of therapy at a reduced dose of 60 mg/m2. If the patient did not experience any drug related toxicity after the first administration of MM-398, from cycle 2 onwards, the dose could be increased to 80 mg/m2.
* 5-FU 2400 mg/m2 IV over 46-hours, and
* Leucovorin l + d racemic form 400 mg/m2, or l form 200 mg/m2 IV over 30 minutes, every 2 weeks

MM-398 + 5-FU + Leucovorin(Arm C) Combo Therapy Comparison

5-FU + Leucovorin (Combo Therapy Comparison)

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.

Overall Survival

Progression Free Survival

Objective Response Rate

Time to Treatment Failure

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

Percentage of Patients With Clinical Benefit Response

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

Percentage of Patients With Tumor Marker (CA 19-9) Response

Global Health Status: Improved

Global Health Status: Stable

Global Health Status: Worsened

Physical Functioning: Improved

Physical Functioning: Stable

Physical Functioning: Worsened

Role Functioning: Improved

Role Functioning: Stable

Role Functioning: Worsened

Emotional Functioning:Improved

Emotional Functioning:Stable

Emotional Functioning:Worsened

Cognitive Functioning:Improved

Cognitive Functioning:Stable

Cognitive Functioning:Worsened

Social Functioning:Improved

Social Functioning:Stable

Social Functioning:Worsened

Fatigue:Improved

Fatigue:Stable

Fatigue:Worsened

Nausea and Vomiting:Improved

Nausea and Vomiting:Stable

Nausea and Vomiting:Worsened

Pain:Improved

Pain:Stable

Pain:Worsened

Dyspnoea:Improved

Dyspnoea:Stable

Dyspnoea:Worsoned

Insomnia:Improved

Insomnia:Stable

Insomnia:Worsened

Appetite Loss:Improved

Appetite Loss:Stable

Appetite Loss:Worsened

Constipation:Improved

Constipation:Stable

Constipation:Worsened

Diarrhoea:Improved

Diarrhoea: Stable

Diarrhoea: Worsened

Financial Difficulties: Improved

Financial Difficulties: Stable

Financial Difficulties: Worsened

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

EORTC-QLQ-C30

Total Irinotecan-Cavg

Total Irinotecan-Cmax

Total SN38-Cavg

Total SN38-Cmax

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of MM-398 With or Without 5-FU/LV, Versus 5-FU/LV in Patients With Metastatic Pancreatic Cancer	NCT01494506	Metastatic Panc...	MM-398 5 Fluorouracil Leucovorin	18 Years -	Merrimack Pharmaceuticals
Study of MM-398 With or Without 5-FU/LV, Versus 5-FU/LV in Patients With Metastatic Pancreatic Cancer	NCT01494506	Metastatic Panc...	MM-398 5 Fluorouracil Leucovorin	18 Years -	Merrimack Pharmaceuticals

Spots Global Cancer Trial Database for second line pancreatic cancer treatment