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Trial Title:
Galunisertib Combined With Capecitabine in Advanced CRC With PM
NCT ID:
NCT05700656
Condition:
Colorectal Cancer Metastatic
Peritoneal Carcinomatosis
Conditions: Official terms:
Colorectal Neoplasms
Carcinoma
Peritoneal Neoplasms
Capecitabine
Conditions: Keywords:
colorectal cancer
metastatic colorectal cancer
peritonitis carcinomatosa
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Galunisertib plus capecitabine
Description:
Combination therapy with galunisertib plus capecitabine
Arm group label:
Galunisertib plus capecitabine
Summary:
This is a two-center open-label non-randomized proof of principle study consisting of a
dose-finding part (phase I) and phase II study with Simon two-stage design investigating
the anti-tumor activity of the combination of capecitabine and galunisertib in patients
with colorectal cancer with peritoneal metastases.
Detailed description:
This is a two-center pharmacological open-label non-randomized proof of principle study
consisting of two parts: a phase I study evaluating the RP2D of galunisertib in
combination with capecitabine; and a phase II study investigating the anti-tumor activity
and safety of galunisertib in combination with capecitabine in advanced colorectal cancer
(CRC) with peritoneal metastases (PM).
In phase II of the study a Simon two-stage design will be used. 15 patients will be
treated with the galunisertib/capecitabine combination. If at least 2 out of 15 patients
respond, an additional cohort of 10 patients will be included to a total of 25 patients.
With 6 or more responses, the treatment will be declared to be of sufficient activity and
with 5 or less it will be declared of insufficient activity.
The galunisertib dose will be 150 mg twice daily (BID) for the first 14 days of every
4-week cycle, which is the maximum tolerated dose when given as single agent (except of
day 1 of cycle 1: single dose of galunisertib 150 mg for PK analysis, from day 2: 150 mg
BID).
Capecitabine will be dosed during every 14-day on time of galunisertib at 1000 mg/m2 BID,
which is the labelled dose as monotherapy and will in case of toxicities be reduced
according to standard care.
Clinical assessments will be performed routinely to monitor safety. Anti-tumor activity
will be measured by CT scan according to RECIST 1.1 criteria. Tumor biopsies will be
obtained for exploratory objectives.
Criteria for eligibility:
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
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);
11. Negative pregnancy test (urine or serum) for female patients with childbearing
potential.
12. Able and willing to swallow tablets.
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
radiation (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>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 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
first dose of study medication, 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. Treatment with CYP3A4 inducers or inhibitors and/or concomitant treatment with
CYP2C9 substrates with narrow therapeutic window, including but not limited to
vitamin K antagonizing anticoagulants (e.g. acenocoumarol, phenprocoumon and
warfarin) 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
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;
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 <1%
per year (when used consistently and correctly) during the treatment period and for
at least 90 days after the last dose of galunisertib and/or capecitabine.
15. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or
use contraceptive measures, and agreement to refrain from donating sperm.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Netherlands Cancer Institute
Address:
City:
Amsterdam
Zip:
1066CX
Country:
Netherlands
Status:
Recruiting
Investigator:
Last name:
Neeltje Steeghs, MD, PhD
Email:
Principal Investigator
Investigator:
Last name:
Alaa Embaby, MD
Email:
Sub-Investigator
Facility:
Name:
Amsterdam UMC
Address:
City:
Amsterdam
Zip:
1081 HV
Country:
Netherlands
Status:
Not yet recruiting
Investigator:
Last name:
Tineke Buffart, MD, PhD
Email:
Principal Investigator
Investigator:
Last name:
Louis Vermeulen, MD, PhD
Email:
Principal Investigator
Start date:
July 28, 2023
Completion date:
April 2025
Lead sponsor:
Agency:
The Netherlands Cancer Institute
Agency class:
Other
Collaborator:
Agency:
Amsterdam UMC
Agency class:
Other
Source:
The Netherlands Cancer Institute
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05700656