Study of Nintedanib and Chemotherapy for Advanced Pancreatic Cancer

The study will perform a clinical study evaluating the safety and tolerability of nintedanib when combined with standard chemotherapy (Gemcitabine + nab-Paclitaxel) for metastatic pancreatic cancer. It will utilize advanced imaging correlates including dynamic contrast enhanced Magnetic Resonance Imaging (DCE-MRI) which correlates with tumor grade and microvessel density.

Preclinical data suggest nintedanib inhibits primary tumor growth in in vivo xenograft models of pancreatic cancer, as well as inhibiting metastasis in pancreatic cancer models. This effect appears primarily due to nintedanib anti-angiogenic properties. The study will perform a clinical study evaluating the safety and tolerability of nintedanib when combined with standard chemotherapy (Gemcitabine + nab-Paclitaxel) for metastatic pancreatic cancer. It will utilize advanced imaging correlates including dynamic contrast enhanced Magnetic Resonance Imaging (DCE-MRI) which correlates with tumor grade and microvessel density.

For each patient, treatment will have two phases: nintedanib monotherapy for a two week period (Days 1-14) followed by combination phase of nintedanib plus chemotherapy (Cycle 2+).

Eligibility Criteria:
Inclusion Criteria:

1. Signed and dated written informed consent prior to admission to the study;
2. Histologically or cytologically confirmed metastatic or locally advanced adenocarcinoma of the pancreas;
3. At least one measurable disease lesion according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1);
4. Age ≥ 18 years;
5. No more than one prior line of non-gemcitabine/nab-paclitaxel containing systemic therapy for metastatic/locally advanced pancreatic cancer;
6. Eastern Cooperative Oncology Group (ECOG) Performance Score of 0-1;
7. Women of childbearing potential must have a negative pregnancy test (urine or serum) within 14 days prior to registration; (Note: contraception in patients with reproductive capacity will be considered to be of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years.)
8. Adequate biological parameters at baseline (obtained within 14 days prior to registration).
9. If elevated liver function tests develop at the time of initial presentation or develop during workup and are the result of mechanical obstruction of the biliary drainage by tumor compression or invasion, a biliary drain may be placed. If drainage allows the liver function tests to come within inclusion criteria, the patient may be enrolled.

Exclusion Criteria:

1. More than one systemic therapy regimen of any type for metastatic or locally advanced disease. Adjuvant gemcitabine that ended more than 6 months from diagnosis of recurrent disease is not considered as a regimen;
2. Prior treatment with nintedanib or any other VEGFR inhibitor;
3. Known hypersensitivity to nintedanib, gemcitabine and nab-Paclitaxal peanut or soya or any other trial drug, their excipients or to contrast media;
4. Chemo-, hormon-, radio-(except for brain and extremities) or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug;
5. Radiotherapy to the target lesion within the past 3 months prior to baseline imaging
6. Persistence of clinically relevant therapy related toxicity from previous chemo and/or radiotherapy;
7. Active brain metastases (e.g. stable for \<4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before randomization);
8. Leptomeningeal disease;
9. Radiographic evidence of cavitary or necrotic tumors;
10. Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial;
11. Therapeutic anticoagulation with drugs requiring INR monitoring (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid \< 325mg per day);
12. Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period;
13. History of clinically significant hemorrhagic or thromboembolic event in the past 6 months;
14. Known inherited predisposition to bleeding or thrombosis;
15. Significant cardiovascular diseases ( i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 12 months prior to start of study treatment, congestive heart failure \> NYHA II, serious cardiac arrhythmia, pericardial effusion);
16. Proteinuria CTCAE grade 2 or greater;
17. Creatinine \> 1.5 x ULN or GFR \< 45 mL/min;
18. Hepatic function: total bilirubin outside of normal limits; ALT or AST \> 1.5 ULN in pts without liver metastasis. For Pts with liver metastasis: total bilirubin outside of normal limits, ALT or AST \> 2.5 ULN;
19. Coagulation parameters: International Normalized Ratio (INR) \> 2, prothrombin time (PT) and partial thromboplastin time (PTT) \> 50% of deviation of institutional ULN;
20. Absolute neutrophil count (ANC) \< 1500/mL, platelets \< 100,000/mL, Hemoglobin \< 9.0 g/dl;
21. Any known active cancer other than pancreatic primary;
22. Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy;
23. Active or chronic hepatitis C and/or B infection;
24. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug;
25. Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study;
26. Pregnancy or breast feeding female;
27. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule;
28. Active alcohol or drug abuse;
29. Significant weight loss (\> 20% of BW) within past 6 months prior to inclusion into the trial or actual body weight of less than 50 kg;
30. Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectable, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomized partner for participating females, condoms for participating males) during the trial and for at least three months after end of active therapy.