M402 in Combination With Nab-Paclitaxel and Gemcitabine in Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
People with primary metastatic pancreatic cancer will be treated with nab-paclitaxel and gemcitabine in combination with an investigational agent called necuparanib (M402). It is made from heparin, which is a well known blood thinner. Blood thinners have been shown in prior animal and human studies to have anti-cancer effects. Necuparanib has been re-engineered from heparin to have much lower blood thinning activity while keeping the anti-tumor activity. The investigators are testing whether necuparanib administered in combination with nab-paclitaxel and gemcitabine may be more effective than nab-paclitaxel and gemcitabine.

Detailed Description
-----------------
Part A was an open-label, multiple ascending dose patient study of necuparanib given first as a single dose and then daily in combination with the nab-paclitaxel and gemcitabine regimen. It was conducted to evaluate the safety and tolerability of necuparanib alone and in combination with nab-paclitaxel and gemcitabine and to recommend a necuparanib dose regimen for subsequent evaluation in Part B. Part B is a randomized, double-blind study investigating the antitumor activity of necuparanib in combination with nab-paclitaxel and gemcitabine compared with nab-paclitaxel, gemcitabine, and placebo. In both Parts A and B, a treatment period consists of one 28-day cycle. The Study Patient and Investigator can decide to continue with additional 28-day cycles according to the patient's status at the end of each 28-day cycle. Part A has completed enrollment and Part B is currently open. Part A - Primary Objectives: To evaluate the safety and tolerability of necuparanib in combination with nab-paclitaxel and gemcitabine. To determine the dose of necuparanib to be carried forward into Part B. Part B - Primary Objective: To evaluate overall survival in patients treated with necuparanib + nab-paclitaxel + gemcitabine compared with placebo + nab-paclitaxel + gemcitabine.

Official Title
-----------------
A Phase I/II, Two-Part, Multicenter Study to Evaluate the Safety and Efficacy of M402 in Combination With Nab-Paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer

Conditions
-----------------
Metastatic Pancreatic Cancer

Intervention / Treatment
-----------------
* Drug: nab-paclitaxel
* Drug: gemcitabine
* Drug: placebo
* Drug: Necuparanib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age of 18 years or older Confirmed pancreatic ductal adenocarcinoma Metastatic disease as documented by CT scan or MRI (locally advanced disease only NOT eligible) At least 1 site of disease measurable by RECIST ver1.1 ECOG performance status of 0 to 1 Adequate bone marrow, renal capacity and hepatic function Willing to administer daily subcutaneous injections at home Exclusion Criteria: Any prior radiotherapy, chemotherapy, surgery, or investigational therapy for adjuvant or metastatic pancreatic cancer History of suspected history, or presence of heparin induced toxicity (w/ or w/o thrombosis) History of unexplained bleeding episodes within 3 months of M402 dosing Received thrombolytic agents w/in the previous month Had full-dose anticoagulation with heparin, enoxaparin, dalteparin, other LMWH, a/or other anticoagulants w/in 90 days before first dose of M402 High cardiovascular risk, including but not limited to, recent coronary stenting or myocardial infarction in the past year Major trauma or surgery w/in prior 4 weeks

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: nab-paclitaxel, gemcitabine, placebo<br>Part A: Not applicable. Part B: nab-paclitaxel, gemcitabine, and placebo. Placebo administered daily along with nab-paclitaxel and gemcitabine administration on Day 1, Day 8, and Day 15 of each 28-day cycle. | Drug: nab-paclitaxel<br>* nab-paclitaxel dosed on Day 1, Day 8, Day 15 of each 28-day cycle<br>* Other names: Abraxane (nab-paclitaxel);Drug: gemcitabine<br>* gemcitabine will be dosed on Day 1, Day 8, Day 15 of each 28-day cycle<br>* Other names: Gemzar (gemcitabine);Drug: placebo<br>* Placebo will be dosed daily<br>|
| Experimental: nab-paclitaxel, gemcitabine, necuparanib<br>Part A: Following a single-dose of necuparanib and a 7-day follow-up period, necuparanib was administered daily along with nab-paclitaxel and gemcitabine administration on Day 1, Day 8, and Day 15 of each 28-day cycle. Dose escalation of necuparanib proceeded by cohort in a 3+3 design. Part B: A fixed dose of necuparanib will be administered daily along with nab-paclitaxel and gemcitabine administration on Day 1, Day 8, and Day 15 of each 28-day cycle. | Drug: nab-paclitaxel<br>* nab-paclitaxel dosed on Day 1, Day 8, Day 15 of each 28-day cycle<br>* Other names: Abraxane (nab-paclitaxel);Drug: gemcitabine<br>* gemcitabine will be dosed on Day 1, Day 8, Day 15 of each 28-day cycle<br>* Other names: Gemzar (gemcitabine);Drug: Necuparanib<br>* Necuparanib will be dosed daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Safety | At baseline and then each of 6 visits after the start of dosing in a 28-day treatment cycle, adverse event surveillance, liver function enzyme levels, WBC with differential, ANC, aPTT, and PT are measured. This is repeated for each 28 day treatment cycle until disease progression or end of treatment. A final assessment is performed 30 days post-final necuparanib dose. | Part A: Baseline to 28 days after first-dose and end of study | 
| Part B: Overall Survival | Time in months from first dose of study medication until death | Time in months from first dose of study medication until death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Maximum concentration of necuparanib | One before and seven blood samples after the first dose followed by 5 additional lab draws, once at each of the 5 remaining visits in the first 28-day cycle. | Baseline to 28 days after first dose. | 
| Part B: Duration of progression-free survival | Time in months from first dose of study drug until disease progression | Time from first dose of study drug until disease progression | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
necuparanib, gemcitabine, heparin, low molecular weight heparin, nab-Paclitaxel