- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03470350
Galunisertib and Capecitabine in Advanced Resistant TGF-beta Activated Colorectal Cancer (EORTC1615)
MoTriColor: Phase I/II Study With Galunisertib (LY2157299) Combined With Capecitabine in Patients With Advanced Chemotherapy Resistant Colorectal Cancer and an Activated TGF-beta Signature
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.
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
Noord-Holland
-
Amsterdam, Noord-Holland, Netherlands, 1066 CX
- Antoni van Leeuwenhoek (NKI-AVL)
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Histological or cytological proof of CRC;
- 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);
- Written documentation of activated TGF-β signature-like gene signature, as determined by the validated assay of Agendia;
- Age ≥ 18 years;
- Able and willing to give written informed consent;
- WHO performance status of ≤ 1;
- LVEF ≥ 55%;
- Able and willing to undergo blood sampling for PK and PD analysis;
- Able and willing to undergo tumor biopsies before start, during treatment and at the end of treatment
- Life expectancy ≥ 3 months allowing adequate follow up of toxicity evaluation and anti-tumor activity;
- Evaluable disease according to RECIST 1.1 criteria (measurable disease for the phase II part; evaluable disease is sufficient for the phase I part);
Minimal acceptable safety laboratory values
- ANC of ≥ 1.5 x 109 /L
- Platelet count of ≥ 100 x 109 /L
- 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
- Renal function as defined by serum creatinine ≤1.5 x ULN
- Creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula or MDRD);
- Negative pregnancy test (urine or serum) for female patients with childbearing potential.
Exclusion Criteria:
- Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment;
- Known or suspected dihydropirimidine dehydrogenase deficit (Mutant for DPD*2A genotype, 1236 GA genotype, 1679TG genotype and 2846A>T genotype);
- Symptomatic or untreated leptomeningeal disease;
- 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;
- 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.
- 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);
- Woman who are pregnant or breast feeding;
- 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);
- Radio- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed;
- 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;
- 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 type patients;
- 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;
- Known hypersensitivity to one of the study drugs or excipients.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: TGF-beta activated colorectal cancer
TGF-beta activated advanced colorectal cancer treated with galunisertib and capecitabine
|
treatment with capecitabine and galunisertib
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Phase I: The recommended phase 2 dose (RP2D) of galunisertib plus capecitabine in patients with chemotherapy resistant activated TGF-β signature-like CRC.
Time Frame: 6 months
|
6 months
|
Phase II: Response rate (RR) of galunisertib in combination with capecitabine in patients with chemotherapy resistant activated TGF-β signature-like CRC.
Time Frame: 15 months
|
15 months
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
The incidence and severity of adverse events
Time Frame: 15 months
|
15 months
|
duration of response
Time Frame: 15 months
|
15 months
|
time to response
Time Frame: 15 months
|
15 months
|
overall survival (phase II only)
Time Frame: 15 months
|
15 months
|
progression free survival (phase II only)
Time Frame: 15 months
|
15 months
|
Plasma concentrations of galunisertib in combination with chemotherapy
Time Frame: 15 months
|
15 months
|
Gene alterations/expression profiles (e.g. baseline, relapse) in tumor tissue upon progression
Time Frame: 15 months
|
15 months
|
Baseline molecular status of potential predictive markers of tumor response
Time Frame: 15 months
|
15 months
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: F Ciardiello, Prof, UNINA2
Study record dates
Study Major Dates
Study Start (Anticipated)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Neoplasms
- Neoplasms by Site
- Gastrointestinal Neoplasms
- Digestive System Neoplasms
- Gastrointestinal Diseases
- Colonic Diseases
- Intestinal Diseases
- Intestinal Neoplasms
- Rectal Diseases
- Colorectal Neoplasms
- Molecular Mechanisms of Pharmacological Action
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Capecitabine
Other Study ID Numbers
- M16TGA
- 2016-002349-50 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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