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

Prior treatment

• Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigationaltreatment and/or radio- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigationaltreatment. Palliative radia-tion (1x 8Gy) is allowed; except radiotherapy focused on the liver;
• 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 uncontrolledhypertension, major cardiac abnormalities, a predisposition for developing aneurysms including family history ofaneurysms, Marfan syndrome, bicuspid aortic valve, or evidence of damage to the large vessels of the heart;
• Treatment with CYP3A4 inducers or inhibitors and/or concomitant treatment with CYP2C9 substrates withnarrow therapeutic window, including but not limited to vit-amin K antagonizing anticoagulants (e.g.acenocoumarol, phenprocoumon and war-farin) and phenytoin is not allowed;
• Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or whowould not have fully recovered from previous surgery;

Other illness

• Active infection requiring systemic antibiotics or uncontrolled infectious disease;
• Patients with a known history of hepatitis B or C or known Human Immunodeficiency Virus HIV-1 or HIV-2 typepatients;
• Known hypersensitivity to one of the study drugs or excipients.
• Symptomatic or untreated leptomeningeal disease;
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oralgalunisertib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, majorsmall bowel surgery);

Lab values

• Other severe, acute, or chronic medical or psychiatric condition or laboratory abnor-mality that may increasethe risk associated with study participation or study drug administration or that may interfere with the interpretationof study results and, in the judgment of the investigator, would make the patient inappropriate for the study;

Other

• Known or suspected complete or partial dihydropyrimidine dehydrogenase deficien-cy (Mutant for DPD*2Agenotype, 1236G>A genotype, 1679T>G genotype and 2846A>T genotype);
• Symptomatic brain metastasis.
• Woman who are pregnant or breast feeding;

• Histological or cytological proof of CRC with at least confirmed peritoneal metastases (presence of additionalextraperitoneal metastases is allowed);
• 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 < 5x 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);
• Negative pregnancy test (urine or serum) for female patients with childbearing poten-tial.
• Able and willing to swallow tablets.
• Disease progression or relapse upon treatment for advanced CRC with fluoropyrimidine containingchemotherapy as single agent or in combination with other anti-cancer drugs, with no treatment options at time ofinclusion
• Age ≥ 18 years;
• Able and willing to give written informed consent and informed consent form must have been signed before startof the trial;
• WHO performance status of ≤1;
• Able and willing to undergo blood sampling for PK analysis;
• Able and willing to undergo tumor biopsy before start, during treatment and at the end of treatment;
• Life expectancy > 3 months allowing adequate follow up of toxicity and anti-tumor activity;
• Evaluable disease according to RECIST 1.1 criteria