LCI-GI-APX-NIN-001: Nintedanib in Metastatic Appendiceal Carcinoma

The purpose of this trial is to evaluate the disease control rate of nintedanib in subjects with metastatic appendiceal cancer for whom initial fluoropyrimidine-based chemotherapy has failed. Based on previous studies, the anticancer activity of nintedanib in lung and ovarian cancer trials, along with the similarities between appendiceal and colorectal cancer and potentially ovarian cancer, warrant additional investigation for the optimal treatment of metastatic appendiceal carcinomas.

The primary study objective is to evaluate the disease control rate. The secondary study objectives are to evaluate safety and toxicity, objective response rate, overall and 6-month progression free survival, and overall survival. Exploratory study objectives include evaluation of serum and ascites VEGF, hypertension, and paracentesis frequency in subjects with ascites at study entry.

Eligibility Criteria:
Inclusion Criteria

Subjects must meet all of the following criteria:

1. Age at least 18 years old
2. Histologically confirmed appendiceal carcinoma stage IV
3. Failure of initial fluoropyrimidine -based chemotherapy. Failure is defined as progression on or within 6 months of last day of therapy or intolerance of initial fluoropyrimidine-based chemotherapy.
4. Life expectancy at least 3 months
5. ECOG performance status score 0-2
6. Presence of measurable and/or evaluable, non-measurable disease according to RECIST 1.1 criteria
7. Written informed consent signed and dated by subject or Legally Authorized Representative (LAR) prior to admission to the study in accordance with ICH-GCP guidelines and to the local legislation.

Exclusion Criteria

Subjects must not meet any of the following criteria.

1. Prior treatment with nintedanib or any other VEGFR inhibitor
2. Known hypersensitivity to peanut or soya or to contrast media. History of hypersensitivity to contrast media is allowed if the subject is able to tolerate contrast media with pre-medication.
3. Chemo-, hormone-, 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.
4. Radiotherapy to any target lesion within the past 3 months prior to baseline imaging when that target lesion is the only target lesion identified on baseline imaging, unless it has subsequently grown.
5. Persistence of clinically relevant therapy related toxicity from previous chemo and/or radiotherapy as determined by the investigator.
6. 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) or leptomeningeal disease.
7. Radiographic evidence of cavitary or necrotic tumors.
8. Tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels.
9. Anti-neoplastic treatment for appendiceal cancer, with other investigational drugs or treatment in another clinical trial within 30 days before start of study treatment.
10. 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 less than or equal to 325mg per day).
11. Major injuries and/or surgery within the past 4 weeks prior to start of study treatment, incomplete wound healing or planned surgery during the on-treatment study period.
12. History of clinically significant hemorrhagic or thromboembolic event in the past 6 months prior to consent.
13. Known inherited predisposition to bleeding or thrombosis.
14. Significant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction, congestive heart failure \> NYHA II, serious cardiac arrhythmia, pericardial effusion) within the past 12 months prior to start of study treatment.
15. Proteinuria CTCAE grade 2 or greater.
16. Creatinine \> 1.5x ULN or GFR \< 45 ml/min.
17. Hepatic function: total bilirubin above normal limits; ALT or AST \> 1.5x ULN in subjects without liver metastasis. For subjects with liver metastasis: total bilirubin above normal limits; ALT or AST \> 2.5x ULN.
18. Coagulation parameters: International normalised ratio (INR) \> 2x ULN, prothrombin time (PT) and partial thromboplastin time (PTT) \> or equal to 1.5x ULN.
19. Absolute neutrophil count (ANC) \< 1500/ml, platelets \< 100000/ml, Hemoglobin \< 9.0 g/dl.
20. Other malignancies at the time of signing the informed consent other than basal cell skin cancer or carcinoma in situ of the cervix.
21. Active serious infections if requiring systemic antibiotic or antimicrobial therapy.
22. Active or chronic hepatitis C and/or B infection.
23. Gastrointestinal disorders (like chronic diarrhea) or abnormalities that would interfere with absorption of the study drug. Subjects with this disorder may be allowed if able to tolerate anti-diarrheal medications like loperamide.
24. 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 subject inappropriate for entry into the study.
25. Sexually active women of child-bearing potential and men who are sexually active with women of child-bearing potential and unwilling to use at least 2 medically acceptable methods of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, condoms for participating males) during the trial and for at least three months after end of active therapy. Female subjects will be considered of child-bearing potential unless surgically sterilized by hysterectomy or bilateral tubal/salpingectomy, or post-menopausal for at least 2 years.
26. Pregnancy or breast feeding; female participants of child-bearing potential must have a negative pregnancy test (B-HCG test in urine or serum) before commencing study treatment.

aa. Psychological, familial, sociological, or geographical factors potentially hampering compliance with the study protocol and follow-up schedule per the investigator.

bb. Alcohol or drug abuse which in the determination of the investigator would interfere with trial participation.

cc. Significant weight loss (\> 10% of baseline weight) within past 2 months prior to consenting for the trial. Removal of ascites should not be calculated as weight loss.