No study drug available. Same concept with new study drug will be explored in M19TGA study

Part I of this study is designed to identify the recommended phase 2 dose (RP2D) of the combination regimen of galunisertib/capecitabine as second line treatment in patients with 5-FU or capecitabine resistant CRC. Part II is designed to obtain proof of principle of the galunisertib plus capecitabine combination in patients with chemo-resistant CRC. The combination of galunisertib plus capecitabine will be given as second line therapy in the phase II part of this study.

Patients with chemotherapy resistant activated TGF-β signature-like tumors will have received a fluoropyrimidine (5FU or capecitabine) in the first line of chemotherapy, usually combined with oxaliplatin and, depending upon local hospital preferences or national guidelines, also bevacizumab, or cetuximab/panitumumab if the tumor is KRAS wild type. Addition of galunisertib to capecitabine should thus result in reversal of unresponsiveness, which is the first step in exploring this concept in the clinic. Capecitabine can be used as single agent in advanced CRC and is thus attractive for this study concept. If proof of principle is achieved also other tumor types can be explored with this genetic makeup, such as non-small cell lung cancer (NSCLC) in second line of treatment after platinum doublet therapy in first line, usually cisplatin/carboplatin-pemetrexed in non-squamous and cisplatin/carboplatin-gemcitabine or cisplatin/carboplatin-paclitaxel in squamous type NSCLC.

Inclusion Criteria:

1. Histological or cytological proof of CRC;

2. Disease progression or relapse upon first line of treatment (maximum lines of treatment is one for phase I and phase II of this study) for advanced CRC with fluoropyrimidine containing chemotherapy as single agent or in combination (combinations with oxaliplatin, irinotecan, bevacizumab and cetuximab/panitumumab are allowed);

3. Written documentation of activated TGF-β signature-like gene signature, as determined by the validated assay of Agendia;

4. Age ≥ 18 years;

5. Able and willing to give written informed consent;

6. WHO performance status of ≤ 1;

7. LVEF ≥ 55%;

8. Able and willing to undergo blood sampling for PK and PD analysis;

9. Able and willing to undergo tumor biopsies before start, during treatment and at the end of treatment

10. Life expectancy ≥ 3 months allowing adequate follow up of toxicity evaluation and anti-tumor activity;

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

12. Minimal acceptable safety laboratory values

    1. ANC of ≥ 1.5 x 109 /L
    2. Platelet count of ≥ 100 x 109 /L
    3. 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
    4. Renal function as defined by serum creatinine ≤1.5 x ULN
    5. Creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula or MDRD);

13. Negative pregnancy test (urine or serum) for female patients with childbearing potential.

Exclusion Criteria:

1. Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment;
2. Known or suspected dihydropirimidine dehydrogenase deficit (Mutant for DPD*2A genotype, 1236 GA genotype, 1679TG 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 allowed to enrol. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT (<21 days before start of treatment) completed at screening demonstrating no current evidence of progressive 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 study entry, unstable angina pectoris, New York Heart Association 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. 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, small bowel resection);
7. Woman who are pregnant or breast feeding;
8. Unreliable contraceptive methods. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms);
9. Radio- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed;
10. 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;
11. Active infection requiring systemic antibiotics or uncontrolled infectious disease;
12. Patients with a known history of hepatitis B or C or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;
13. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality 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;
14. Known hypersensitivity to one of the study drugs or excipients.