Advanced colorectal cancer with peritoneal metastases
Conditions
Interventions
Product Name: Galunisertib
Pharmaceutical Form: Tablet
INN or Proposed INN: Galunisertib
CAS Number: 700874-72-2
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 80-
Sponsors
Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hosp
Eligibility
Sex/Gender
All
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 =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 =65 years) yes F.1.3.1 Number of subjects for this age range 10
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.
Design outcomes
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): hase 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 duration of response (DOR), time to response (TTR), progression-free survival (PFS) and overall survival (OS). - To determine pharmacokinetics of galunisertib in combination with capecitabine as measured by plasma concentrations. - To explore biomarkers for response in tissue (such as TGF-beta expression);Timepoint(s) of evaluation of this end point: DOR, TTR, PFS: Tumor evaluations by CT scan according to RECIST 1.1 criteria every 8 weeks (every 2 cycles) OS: Until study completion (incl. follow-up of patients; every 3 months) | — |
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I: To determine the safety and recommended phase 2 dose (RP2D) of galunisertib plus capecitabine in patients with advanced chemotherapy resistant CRC with PM, who progressed after standard chemotherapy. Phase II: To determine the anti-tumor activity, as measured by objective response rate (ORR) of galunisertib in combination with capecitabine in patients with advanced chemotherapy resistant CRC with PM. Secondary objectives include the safety and tolerability of the combination therapy, duration of response (DOR), time to response (TTR), progression free survival (PFS), overall survival (OS), the pharmacokinetic profile of galunisertib in combination with capecitabine and exploratory genetic determinants of response and resistance (e.g. TGF-b expression);Secondary Objective: Secondary objectives include the safety and tolerability of the combination therapy (phase II), duration of response (DOR), time to response (TTR), progression free survival (PFS), overall survival (OS), the pharmacokinetic profile of galunisertib in combination with capecitabine and exploratory genetic determinants of response and resistance (e.g. TGF-b expression);Primary end point(s): Phase I: Number of dose-limiting toxicities (DLT's) and treatment-related adverse events, RP2D of galunisertib in combination with capecitabine. N=6. Phase II: anti-tumor activity as measured by ORR of galunisertib in combination with capecitabine. With 6 or more responses out of 25, the treatment will be declared to be effective in the selected patient population;Timepoint(s) of evaluation of this end point: Tumor evaluations by CT scan according to RECIST 1.1 criteria every 8 weeks (every 2 cycles) | — |
Countries
Netherlands
Contacts
Public ContactMs Alaa Embaby
The Netherlands Cancer Institute
Outcome results
None listed