ODSH has demonstrated in vitro and in vivo inhibitory activity on mechanisms that are believed to play important roles in pancreatic cancer invasion, metastasis, and resistance to chemotherapy and radiation. Pancreatic cancer appears to have a dependence on autophagy, a regulated catabolic pathway to degrade and recycle cellular organelles and macromolecules. Autophagy appears to be largely driven by the binding of high mobility group box-1 protein (HMGB1) to the receptor for advanced glycation end-products (RAGE), which is strongly inhibited by ODSH. Autophagy appears to not only assist pancreatic cancer cells to survive in a hypoxic, relatively avascular environment, but also appears to play an important role in chemotherapy resistance. Other important biological activities promoting pancreatic cancer invasion and metastasis affected by ODSH include the inhibition of heparanase and the binding of tumor cells to endothelium and platelets mediated by the selectins. It is believed that these biological activities such as the inhibition of RAGE, heparanase, and selectin-mediated metastasis, can be inhibited by ODSH at dose levels that can safely be administered without clinically significant anticoagulation.
The standard of care of pancreatic cancer is evolving. It appears that two combination regimens, the "FOLFIRINOX" regimen (a combination of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin) and the combination of gemcitabine + nab-paclitaxel, could have more activity than the previous standard treatment of gemcitabine alone.
Subjects with advanced metastatic pancreatic cancer that have not received chemotherapy, surgical or radiation treatments and have a good performance status will be eligible to participate in this study. 10 patients will be enrolled in a Run-in Period to receive gemcitabine + nab-paclitaxel +ODSH. PK sampling and safety assessments will be conducted to decide on the continuation to the Controlled Period of the study where 50 patients will be randomized at a 1:1 ratio to either of the two study arms: Arm A will receive gemcitabine + nab-paclitaxel + ODSH and Arm B will receive gemcitabine + nab-paclitaxel.
The primary endpoint of the study is mean progression free survival. The secondary endpoints consist of tumor response by RECIST criteria, overall survival at the end of the study and changes from baseline for CA19-9 marker, weight and plasma albumin.
Inclusion Criteria:
1. Patients must have histologically confirmed adenocarcinoma of the pancreas that is metastatic and for which potential curative measures, such as resection of an isolated metastasis, are not available. Patients with islet cell neoplasms are excluded.
2. Patient has one or more metastatic tumors measurable by CT scan AND a serum CA19-9 measurement > 2 times the upper limit of normal. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan.
3. Male or non-pregnant and non-lactating female and ≥ 18 to ≤ 75 years of age. If a female patient is of child-bearing potential, she must have a negative serum pregnancy test documented within 72 hours prior to the first administration of study drug and on Day 1 of each cycle thereafter. If sexually active, the patient must agree to use contraception prior to study entry and for the duration of study participation.
4. Patients must have received no prior radiotherapy or chemotherapy for metastatic disease. Patients who have received radiotherapy or chemotherapy as adjuvant o neo-adjuvant therapy for locally advanced disease six months or more prior to enrollment into this study are eligible.
5. Patient has adequate biological parameters as demonstrated by the following blood counts at Screening (obtained ≤ 14 days prior to randomization) and at Baseline-Day 0: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L; Platelet count ≥ 100,000/mm3 (100 × 109/L); Hemoglobin (Hgb) ≥ 9 g/dL.
6. Patient has the following blood chemistry levels at Screening (obtained ≤ 14 days prior to randomization) and at Baseline-Day 0:
- AST (SGOT), ALT (SGPT) ≤ 2.5 × upper limit of normal range (ULN), unless liver metastases are present, then ≤ 5 × ULN is allowed. Total bilirubin ≤ 1.5 × ULN.
- Serum creatinine (Cr) within normal limits or calculated clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine (Cr) levels above or below the institutional normal value. If using Cr clearance, actual body weight should be used for calculating Cr clearance (e.g., using the Cockcroft-Gault formula).
7. Patient has acceptable coagulation studies at Screening (obtained ≤14 days prior to randomization) as demonstrated by prothrombin time (PT) and partial thromboplastin time (PTT) within normal limits (± 15%).
8. Patient has ECOG performance status ≤ 1.
Exclusion Criteria:
1. Patient has brain metastases.
2. Patient has only locally advanced disease.
3. Patient has experienced an increase of ECOG to > 1 between Screening and Randomization.
4. Patient requires continuous treatment with coumadin or other oral or parenteral anticoagulation (heparin, LMWH, heparinoids) to prevent or treat thromboembolic disease. The use of prophylactic antiplatelet drugs such as clopidogrel and aspirin are allowed before and during the study.
5. Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
6. Patient has undergone major surgery, other than diagnostic surgery (i.e.--surgery done to obtain a biopsy for diagnosis without removal of an organ), within 4 weeks prior to Randomization in this study.
7. Patient has a history of allergy or hypersensitivity to any of the study drugs, their pharmaceutical class or any of their excipients.
8. Patient has a concomitant serious medical or psychiatric illness that, in the opinion of the investigator, could compromise the patient's safety or the study data integrity.
9. Patient is enrolled in any other clinical protocol or investigational trial involving administration of antineoplastic compounds for the treatment of metastatic pancreatic cancer.
10. Patient is unwilling or unable to comply with study procedures.
11. Nab-paclitaxel is metabolized by CYP2C8 and CYP3A4. Co-administration of substrates, inhibitors of CYP2C8 and/or CYP3A4 with nab-paclitaxel is not allowed. The following medications and substances are not allowed during the study: ritonavir, saquinavir, indinavir, nelfinavir, rifampicin, carbamazepine, phenytoin, efavirenz, or nevirapine, grapefruit (juice or seeds) or some herbals like St. John's wort.
12. Subjects with risk factors for or a history of Torsades des Pointes (TdP), or a significant QT prolongation that in the opinion of the investigator may place the study subject at risk.
Last updated: 11/09/2012
NCT ID: NCT01461915
IRB Number:12-001013
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