E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase I: To determine the recommended phase 2 dose (RP2D) of galunisertib plus capecitabine in patients with chemotherapy resistant activated TGF-β signature-like CRC.
Phase II: To determine the anti-tumor activity, as measured by response rate (RR) of galunisertib in combination with capecitabine in patients with chemotherapy resistant activated TGF-β signature-like CRC. |
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E.2.2 | Secondary objectives of the trial |
- To characterize the safety and tolerability of galunisertib in combination with chemotherapy regimens, as assessed by the incidence and severity of adverse events
- To assess anti-tumor activity of galunisertib in combination with chemotherapy, as measured by duration of response, time to response and, progression free survival (phase II only) and overall survival (phase II only)
- To determine the pharmacokinetic profile of galunisertib in combination with chemotherapy, as measured by plasma concentrations
- To explore genetic determinants of response to galunisertib in combination with chemotherapy, as measured by baseline molecular status of potential predictive markers of tumor response
- To explore the potential mechanism of resistance to galunisertib in combination with chemotherapy, as measured by gene alterations/expression profiles (e.g. baseline, relapse) in tumor tissue upon progression |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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 ≤ 5 x ULN in patients with liver metastases
d. Renal function as defined by serum creatinine ≤1.5 x ULN
e. Creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula or MDRD);
13. Negative pregnancy test (urine or serum) for female patients with childbearing potential. |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I: To determine the recommended phase 2 dose (RP2D) of galunisertib plus capecitabine in patients with chemotherapy resistant activated TGF-β signature-like CRC.
Phase II: To determine the anti-tumor activity, as measured by response rate (RR) of galunisertib in combination with capecitabine in patients with chemotherapy resistant activated TGF-β signature-like CRC. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- To characterize the safety and tolerability of galunisertib in combination with chemotherapy regimens, as assessed by the incidence and severity of adverse events
- To assess anti-tumor activity of galunisertib in combination with chemotherapy, as measured by duration of response, time to response and, progression free survival (phase II only) and overall survival (phase II only)
- To determine the pharmacokinetic profile of galunisertib in combination with chemotherapy, as measured by plasma concentrations
- To explore genetic determinants of response to galunisertib in combination with chemotherapy, as measured by baseline molecular status of potential predictive markers of tumor response
- To explore the potential mechanism of resistance to galunisertib in combination with chemotherapy, as measured by gene alterations/expression profiles (e.g. baseline, relapse) in tumor tissue upon progression |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 17 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 18 |