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.
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.
