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

• Part A: Safety [ Time Frame: Part A: Baseline to 28 days after first-dose and end of study ] [ Designated as safety issue: Yes ]
  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 M402 dose.
• Part B: Overall Survival [ Time Frame: Time in months from first dose of study medication until death ] [ Designated as safety issue: Yes ]
  Time in months from first dose of study medication until death

• Part A: Maximum concentration of M402 [ Time Frame: Baseline to 28 days after first dose. ] [ Designated as safety issue: Yes ]
  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.
• Part B: Duration of progression-free survival [ Time Frame: Time from first dose of study drug until disease progression ] [ Designated as safety issue: Yes ]
  Time in months from first dose of study drug until disease progression

• Maximum concentration of M402 [ Time Frame: Baseline to 28 days after first dose. ] [ Designated as safety issue: Yes ]
  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.
• Time to maximum concentration of anti-Factor Xa [ Time Frame: Baseline to 28 days after first dose. ] [ Designated as safety issue: Yes ]
  One sample will be taken before the first dose, once before dosing on Days 1, 2, 15, 16, and at the end of the first 28-day treatment cycle.

People with primary metastatic pancreatic cancer will be treated with nab-paclitaxel and gemcitabine in combination with an investigational agent called 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. M402 has been re-engineered from heparin to have much lower blood thinning activity while keeping the anti-tumor activity. The investigators are testing whether M402 administered in combination with nab-paclitaxel and gemcitabine may be more effective than nab-paclitaxel and gemcitabine.

Part A is an open-label, multiple ascending dose patient study of M402 given first as a single dose and then daily in combination with the nab-paclitaxel and gemcitabine regimen. It will be conducted to evaluate the safety and tolerability of M402 alone and in combination with nab-paclitaxel and gemcitabine and to recommend an M402 dose regimen for subsequent evaluation in Part B. Part B is a randomized, double-blind study investigating the antitumor activity of M402 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. Only Part A is currently open.

Part A - Primary Objectives:

• To evaluate the safety and tolerability of M402 in combination with nab-paclitaxel and gemcitabine.
• To determine the dose of M402 to be carried forward into Part B.

Part B - Primary Objective:

To evaluate overall survival in patients treated with M402 + nab-paclitaxel + gemcitabine compared with placebo + nab-paclitaxel + gemcitabine.

• Drug: nab-paclitaxel
  nab-paclitaxel dosed on Day 1, Day 8, Day 15 of each 28-day cycle
  Other Name: Abraxane (nab-paclitaxel)
• Drug: gemcitabine
  gemcitabine will be dosed on Day 1, Day 8, Day 15 of each 28-day cycle
  Other Name: Gemzar (gemcitabine)
• Drug: placebo
  Placebo will be dosed daily
• Drug: M402
  M402 will be dosed daily

• Placebo Comparator: nab-paclitaxel, gemcitabine, placebo

  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.

  Interventions:

  • Drug: nab-paclitaxel
  • Drug: gemcitabine
  • Drug: placebo
• Experimental: nab-paclitaxel, gemcitabine, M402

  Part A: Following a single-dose of M402 and a 7-day follow-up period, M402 will be 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 M402 only will proceed by cohort in a 3+3 design.

  Part B: A fixed dose of M402 will be administered daily along with nab-paclitaxel and gemcitabine administration on Day 1, Day 8, and Day 15 of each 28-day cycle.

  Interventions:

  • Drug: nab-paclitaxel
  • Drug: gemcitabine
  • Drug: M402

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
• Brain metastasis or active second malignancy
• 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
• Used NSAIDs, ASA (except ≤ 81 mg) for at least 10 days of the preceding 14 days before screening
• 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