colorectal cancer with peritoneal metastases
Conditions
Interventions
Galunisertib will be dosed 150 mg twice daily (BID) for the first 14 days of
every 4-week cycle. If necessary, the dose of galunisertib and the dose of
capecitabine can be decreased. Capecitabine wi
Sponsors
Antoni van Leeuwenhoek Ziekenhuis
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 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 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 = 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.
Exclusion criteria
Exclusion criteria: 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The main endpoints of part 1 of this study (phase I) is the safety profile of galunisertib and capecitabine when given together and finding the optimal doses for continuation in part 2 (RP2D). The main endpoint of phase II is to evaluate the anti-tumor activity of the combination as measured by ORR according to RECIST 1.1 criteria. With 6 or more responses out of 25, the treatment will be declared to be effective in the selected patient population Phase I: To determine the RP2D of galunisertib plus capecitabine in patients with advanced chemotherapy resistant CRC with PM. Phase II: To determine the anti-tumor activity as measured by ORR of galunisertib in combination with capecitabine in patients with advanced chemotherapy resistant CRC with PM | — |
Secondary
| Measure | Time frame |
|---|---|
| Phase II: - To characterize the safety and tolerability of galunisertib in combination with capecitabine as assessed by the incidence and severity of adverse events. - To assess anti-tumor activity of galunisertib in combination with capecitabine, as measured by DOR, TTR, PFS and OS (phase II only). - To determine pharmacokinetics of galunisertib in combination with capecitabine as measured by plasma concentrations. | — |
Countries
Netherlands
Outcome results
None listed