E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
colorectal carcinoma |
colon carcinoom |
|
E.1.1.1 | Medical condition in easily understood language |
intestinal cancer |
darmkanker |
|
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. |
Fase I: Bepalen van de aanbevolen fase 2 dosering van galunisertib in combinatie met capecitabine in patienten met chemotherapie resistente colorectaal carcinomen met een TGF-beta signatuur.
Fase II: Bepalen van de anti-tumor activiteit, gemeten met response rate van galunisertib in combinatie met capecitabine in patienten met chemotherapie resistente colorectaal carcinomen met een TGF-beta signatuur. |
|
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 |
- Veiligheid van galunisertib in combinatie met capecitabine in deze patientpopulatie
- Anti-tumor activiteit van galunisertib in combinaite met capecitabine, gemeten door responsduur, tijd tot respons, progressie vrije overleving en totale overleving
- Bepalen van farmacokinetisch profiel van galunisertib/capecitabine combinatie
- Onderzoeken van genetische determinanten van respons en resistentie tegen galunisertib/capecitabine combinatie. |
|
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 at least one line of treatment 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. |
1. histologisch of cytologisch bewezen CRC;
2. progressieve ziekte of recidief na tenminste 1 lijn chemotherapie met fluorpyrimidine bevattende regimen als monotherapie of in combinatie.
3. gedocumenteerde geactiveerde TGF-beta signatuur, vastgesteld met de gevalideerde assay van Agendia.
4. leeftijd ≥ 18 jaar
5. In de mogelijkheid en het willen geven van informed consent.
6. WHO performance status van ≤ 1;
7. LVEF ≥ 55%;
8. In de mogelijkheid en bereid tot bloed afnames voor PK en PD analyses.
9. in de mogelijkheid en bereid tot tumorbiopten voor, tijdens en aan het eind van behandeling
10. levensverwachting van minstens 3 maanden
11. evalueerbare ziekte volgens RECIST 1.1 (meetbare ziekte voor fase II, evalueerbare ziekte is voldoende voor fase I)
12. minimaal acceptabele bloedwaarden
a. ANC of ≥ 1.5 x 109 /L
b. trombocyten ≥ 100 x 109 /L
c. leverfunctie met serum bilirubine ≤ 1.5 x ULN, ALAT en ASAT ≤ 3.0 x ULN, of ALAT en ASAT ≤ 5 x ULN in patienten met levermetastasen
d. nierfunctie met serum kreatinine ≤1.5 x ULN
e. kreatinine klaring ≥ 50 ml/min
13. negatieve zwangerschapstest (urine of serum) voor vrouwelijke patienten in vruchtbare periode. |
|
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. Radio- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed;
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. More information is available in section 5.2.4.
15. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined in section 5.2.4.
|
1. elke behandeling met studie medicatie binnen 30 dagen voor start met de eerste dosis van studiemedicatie
2. Bekende of verwachte dihydropirimidine dehydrogenase tekort (Mutant voor DPD*2A genotype, 1236 GA genotype, 1679TG genotype en 2846A>T genotype);
3. symptomatische of onbehandelde leptomeningeale metastasen
4. symptomatische hersenmetastasen. Patienten die eerder behandelde of onbehandelde hersenmetastasen hebben die asymptomatisch zijn in de afwezigheid van corticosteroid behandeling mogen deelnemen. Hersenmetastasen moeten stabiel zijn op beeldvorming. Patientn mogen geen enzym-inducerende anti-epileptica of corticosteroiden gebruiken.
5. Hartaandoeningen in de voorgeschiedenis, inclusief myocardinfart binnen 6 maanden voor start van de studie, onstabiele angina pectoris, NYHA classificatie III/IV congestief hartfalen, of ongecontrolleerde hypertensie, grote cardiale afwijkingen, predispositie voor ontwikkelen van aneurysma, inclusief familiale belasting, Marfan syndroom, bicuspide aorta klep, of bewezen beschadiging aan de grote carciale vaten.
6. Verminderde gastro-intestinale functie of gastro-intestinale ziekte, waardoor de absorptie van medicatie significant wordt verminderd
7. Zwangere vrouwen of vrouwen die borstvoeding geven.
8. onbetrouwbare contraceptie methoden. Zowel mannen als vrouwen in deze studie moeten instemmen met het gebruik van een betrouwbare anticonceptie methode.
9. Radio- of chemotherapie in de laatste 2 weken voorafgaand aan de eerste studie medicatie inname. Palliatieve radiotherapie ( 1x 8 Gy) is toegestaan.
10. patienten die een operatie hebben ondergaan binnen 2 weken voor start met de studiemedicatie of die nog herstellende zijn van een eerdere operatie.
11. actieve infectie waarvoor systemische antibiotica noodzakkelijk zijn of ongecontrolleerde infectieziekten.
12. patienten bekend met hepatitis B of C of HIV1/HIV2
13. Andere ernstige acute of chronische medische of psychiatrische codities of afwijkende laboratorium waarden die het risico van meedoen in deze studie verhogen of interfereren met de interpretatie van de studie resultaten, naar mening van de onderzoeken, maken patient niet geschikt voor deze studie
14. Bekende hypersensitiviteit voor de studie medicatie of hulpstoffen. |
|
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. |
Fase I: Bepalen van de aanbevolen fase 2 dosering van galunisertib in combinatie met capecitabine in patienten met chemotherapie resistente colorectaal carcinomen met een TGF-beta signatuur.
Fase II: Bepalen van de anti-tumor activiteit, gemeten met response rate van galunisertib in combinatie met capecitabine in patienten met chemotherapie resistente colorectaal carcinomen met een TGF-beta signatuur. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the end of the trial |
Aan het einde van de studie. |
|
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 |
- Veiligheid van galunisertib in combinatie met capecitabine in deze patientpopulatie
- Anti-tumor activiteit van galunisertib in combinaite met capecitabine, gemeten door responsduur, tijd tot respons, progressie vrije overleving en totale overleving
- Bepalen van farmacokinetisch profiel van galunisertib/capecitabine combinatie
- Onderzoeken van genetische determinanten van respons en resistentie tegen galunisertib/capecitabine combinatie. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
at the end of the trial |
aan het einde van de studie |
|
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 |
pharmacokinetic study |
pharmacokinetiek studie |
|
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
|
|
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 | 18 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 18 |