Phase I/II study with galunisertib combined with capecitabine in patients with advanced chemotherapy resistant colorectal cancer with peritoneal metastases

1. Histological or cytological proof of CRC with at least confirmed peritoneal
metastases (presence of additional extraperitoneal metastases is allowed);
2. Disease progression or relapse upon treatment for advanced CRC with
fluoropyrimidine containing chemotherapy as single agent or in combination with
other anti-cancer drugs, with no treatment options at time of inclusion
(combinations with oxaliplatin, irinotecan, bevacizumab and
cetuximab/panitumumab are allowed);
3. Age >= 18 years;
4. Able and willing to give written informed consent and informed consent form
must have been signed before start of the trial;
5. WHO performance status of <=1;
6. Able and willing to undergo blood sampling for PK analysis;
7. Able and willing to undergo tumor biopsy before start, during treatment and
at the end of treatment;
8. Life expectancy > 3 months allowing adequate follow up of toxicity and
anti-tumor activity;
9. Evaluable disease according to RECIST 1.1 criteria (measurable disease for
the phase II part; evaluable disease is sufficient for the phase I part);
10. Minimal acceptable safety laboratory values
a. ANC of >=1.5 x 109 /L
b. Platelet count of >=100 x 109 /L
c. Hepatic function as defined by serum bilirubin <= 1.5 x ULN, ALAT and ASAT <=
3.0 x ULN, or ALAT and ASAT < 5 x ULN in patients with liver metastases
d. Renal function as defined by serum creatinine <= 1.5 x ULN
e. Creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula or MDRD);
11. Negative pregnancy test (urine or serum) for female patients with
childbearing poten-tial.
12. Able and willing to swallow tablets.

1. Any treatment with investigational drugs within 30 days prior to receiving
the first dose of investigational treatment and/or radio- or chemotherapy
within the last 2 weeks prior to receiving the first dose of investigational
treatment. Palliative radia-tion (1x 8Gy) is allowed; except radiotherapy
focused on the liver;
2. Known or suspected complete or partial dihydropyrimidine dehydrogenase
deficien-cy (Mutant for DPD*2A genotype, 1236G>A genotype, 1679T>G genotype and
2846A>T genotype);
3. Symptomatic or untreated leptomeningeal disease;
4. Symptomatic brain metastasis. Patients previously treated or untreated for
these conditions that are asymptomatic in the absence of corticosteroid therapy
are al-lowed to enrol. Brain metastasis must be stable with verification by
imaging (e.g. brain MRI or CT completed at screening demonstrating no current
evidence of pro-gressive brain metastases). Patients are not permitted to
receive enzyme inducing anti-epileptic drugs or corticosteroids;
5. History of cardiac disease, including myocardial infarction within 6 months
before first dose of study medication, unstable angina pectoris, New York Heart
Associa-tion Class III/IV congestive heart failure, or uncontrolled
hypertension, major cardiac abnormalities, a predisposition for developing
aneurysms including family history of aneurysms, Marfan syndrome, bicuspid
aortic valve, or evidence of damage to the large vessels of the heart;
6. Treatment with CYP3A4 inducers or inhibitors and/or concomitant treatment
with CYP2C9 substrates with narrow therapeutic window, including but not
limited to vit-amin K antagonizing anticoagulants (e.g. acenocoumarol,
phenprocoumon and war-farin) and phenytoin is not allowed;
7. Impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral galunisertib (e.g., ulcerative
diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome,
major small bowel surgery);
8. Woman who are pregnant or breast feeding;
9. Patients who have undergone any major surgery within the last 2 weeks prior
to starting study drug or who would not have fully recovered from previous
surgery;
10. Active infection requiring systemic antibiotics or uncontrolled infectious
disease;
11. Patients with a known history of hepatitis B or C or known Human
Immunodeficiency Virus HIV-1 or HIV-2 type patients;
12. Other severe, acute, or chronic medical or psychiatric condition or
laboratory abnor-mality that may increase the risk associated with study
participation or study drug administration or that may interfere with the
interpretation of study results and, in the judgment of the investigator, would
make the patient inappropriate for the study;
13. Known hypersensitivity to one of the study drugs or excipients.
14. For women of childbearing potential: agreement to remain abstinent (refrain
from heterosexual intercourse) or use contraceptive methods with a failure rate
of <1% per year (when used consistently and correctly) during the treatment
period and for at least 90 days after the last dose of galunisertib and/or
capecitabine.
15. For men: agreement to remain abstinent (refrain from heterosexual
intercourse) or use contraceptive measures, and agreement to refrain from
donating sperm.