Galunisertib Combined With Capecitabine in Advanced CRC With PM

Inclusion Criteria:

1. Histological or cytological proof of CRC with at least confirmed peritonealmetastases (presence of additional extraperitoneal metastases is allowed);

2. Disease progression or relapse upon treatment for advanced CRC with fluoropyrimidinecontaining chemotherapy as single agent or in combination with other anti-cancerdrugs, with no treatment options at time of inclusion (combinations withoxaliplatin, irinotecan, bevacizumab and cetuximab/panitumumab are allowed);

3. Age ≥ 18 years;

4. Able and willing to give written informed consent and informed consent form musthave 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 theend of treatment;

8. Life expectancy > 3 months allowing adequate follow up of toxicity and anti-tumoractivity;

9. Evaluable disease according to RECIST 1.1 criteria (measurable disease for the phaseII part; evaluable disease is sufficient for the phase I part);

10. Minimal acceptable safety laboratory values

11. ANC of ≥1.5 x 109/L

12. Platelet count of ≥100 x 109/L

13. Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ALAT and ASAT ≤ 3.0x ULN, or ALAT and ASAT < 5 x ULN in patients with liver metastases

14. Renal function as defined by serum creatinine ≤ 1.5 x ULN

15. Creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula or MDRD);

16. Negative pregnancy test (urine or serum) for female patients with childbearingpotential.

17. Able and willing to swallow tablets.

Exclusion Criteria:

1. Any treatment with investigational drugs within 30 days prior to receiving the firstdose of investigational treatment and/or radio- or chemotherapy within the last 2weeks prior to receiving the first dose of investigational treatment. Palliativeradiation (1x 8Gy) is allowed; except radiotherapy focused on the liver;

2. Known or suspected complete or partial dihydropyrimidine dehydrogenase deficiency (Mutant for DPD*2A genotype, 1236G>A genotype, 1679T>G genotype and 2846A>Tgenotype);

3. Symptomatic or untreated leptomeningeal disease;

4. Symptomatic brain metastasis. Patients previously treated or untreated for theseconditions that are asymptomatic in the absence of corticosteroid therapy areallowed to enrol. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening demonstrating no current evidence ofprogressive brain metastases). Patients are not permitted to receive enzyme inducinganti-epileptic drugs or corticosteroids;

5. History of cardiac disease, including myocardial infarction within 6 months beforefirst dose of study medication, unstable angina pectoris, New York Heart AssociationClass III/IV congestive heart failure, or uncontrolled hypertension, major cardiacabnormalities, a predisposition for developing aneurysms including family history ofaneurysms, Marfan syndrome, bicuspid aortic valve, or evidence of damage to thelarge vessels of the heart;

6. Treatment with CYP3A4 inducers or inhibitors and/or concomitant treatment withCYP2C9 substrates with narrow therapeutic window, including but not limited tovitamin K antagonizing anticoagulants (e.g. acenocoumarol, phenprocoumon andwarfarin) and phenytoin is not allowed;

7. Impairment of gastrointestinal (GI) function or GI disease that may significantlyalter the absorption of oral galunisertib (e.g., ulcerative diseases, uncontrollednausea, 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 tostarting 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 ImmunodeficiencyVirus HIV-1 or HIV-2 type patients;

12. Other severe, acute, or chronic medical or psychiatric condition or laboratoryabnormality that may increase the risk associated with study participation or studydrug administration or that may interfere with the interpretation of study resultsand, in the judgment of the investigator, would make the patient inappropriate forthe study;

13. Known hypersensitivity to one of the study drugs or excipients.

14. For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods with a failure rate of <1%per year (when used consistently and correctly) during the treatment period and forat least 90 days after the last dose of galunisertib and/or capecitabine.

15. For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse contraceptive measures, and agreement to refrain from donating sperm.