| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or metastasized colorectal carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Colon carcinoma - Darmkrebs |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010036 |
| E.1.2 | Term | Colorectal carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 MTD of resminostat in combination with FOLFIRI by investigating safety, tolerability and pharmacokinetics of resminostat and FOLFIRI
Phase II: Progression-free survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
Phase I:
- Progression free survival (PFS)
- Progression free survival rate (PFSR) after 8 weeks (4 cycles) and every following 8 weeks (additional 4 cycles each)
- Time to Progression (TTP)
- Number of Objective Responses (OR)
- Overall survival (OS)
- Duration of Response (DOR)
Phase II:
- Progression free survival rate (PFSR) after 8 weeks (4 cycles) and every following 8 weeks (additional 4 cycles each)
- Time to Progression (TTP)
- Number of Objective Responses (OR)
- Overall survival (OS)
- Duration of Response (DOR)
- Safety and tolerability
- Pharmacokinetics of resminostat and FOLFIRI combination
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase I:
- Signed informed consent must be obtained prior to any study specific procedure
- Male or female patients, age ≥ 18 years
- Histologically or cytologically confirmed advanced stage colorectal carcinoma
- Documented progression after precedent treatment according to RECIST criteria
- Measurable lesion(s) as defined by modified RECIST criteria (Version 1.1)
- ECOG performance status 0 – 2
- Live expectancy of 12 weeks or more
- Patients must have previously received treatment with 5-FU alone or in combination with other anti-tumor medications; the required prior treatment with 5-FU can be replaced by the previous use of the respective prodrug capecitabine (Xeloda® ).
- Patients foreseen for chemotherapy with FOLFIRI in second or further line treatment
- Patients must have adequate bone marrow reserve as evidenced by: Absolute neutrophil count (ANC) ≥ 1,500/μl; Hb ≥ 9 g/dL and platelet count ≥ 75,000/μl
- Patients must have a glomerular filtration rate according to MDRD formula of >°60 ml/min/1.73m2
- Patients must have adequate hepatic function as evidenced by a serum bilirubin < 2.0 mg/dl and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels < 3x the ULN for the reference lab (< 5x the ULN if there is hepatic metastasis)
- Patients must be recovered from the toxicities of any prior therapy, except polyneuropathy Grade ≤ 1 and Hand-Foot-syndrome Grade ≤ 1
- Safe contraception in females of childbearing potential during the entire study using an established treatment with hormonal contraceptives for ≥ 2 months prior to start of screening
- For females of child bearing potential (without using hormonal contraceptives for at least 2 months prior to start of screening) a double contraception method is requested during the entire study meeting the criteria for an effective method of birth control. That means at least two effective birth control methods such as condoms, diaphragms or intra-uterine devices must be used. For the methods used, Pearl Index has to be < 1
- Male subjects with partners of child-bearing potential are requested to use barrier contraception in addition to having their partner use another method of contraception during the trial and for three months after the last dose. Male subjects will also be advised to abstain from sexual intercourse with pregnant or lactating women, or to use condoms. For the methods used, Pearl Index has to be
< 1
- Study participants must avoid excessive UV-radiation (sun bathes and solarium)
and protect their eyes during exposure to direct sunlight
Phase II (only those listed, that are in addition to or different to Phase I criteria):
- Documented progression after first-line treatment according to RECIST criteria
- k-ras mutation (which contraindicates EGFR inhibitor therapy, results from local
pathology will be accepted for inclusion)
- Patients must have previously received treatment with 5-FU alone or in
combination with other anti-tumor medications (except irinotecan); the required
prior treatment with 5-FU can be replaced by the previous use of the respective
prodrug capecitabine (Xeloda® ).
- Patients foreseen for 2nd line chemotherapy with FOLFIRI |
|
| E.4 | Principal exclusion criteria |
Phase I:
- Patients who have received previous treatment with an HDAC inhibitor
- Anticipation of need for a major surgical procedure or radiation therapy (RT) during the study
- Patients who have received an investigational therapy within 4 weeks prior to first drug administration in the current study
- Any gastrointestinal disorder that could interfere with the absorption of resminostat, such as active ulcerative colitis, Crohn’s disease, diabetic gastroparesis, or other syndromes characterized by malabsorption
- Therapy with agents known to prolong the QT interval, such as certain antibiotics (i.e. erythromycin, clarithromycin), antidepressants (i.e. doxepin, amitryptilin) or neuroleptics (i.e. haloperidol, clozapin)
- Patients who are homozygous for the UGT1A1 and characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter ((TA)7TAA)
- Therapy with strong CYP3A4 inhibitors (e.g. ketoconazole) or inductors (e.g. carbamazepine, phenytoin, St. John’s Wort)
- Patients who are homozygous for the UGT1A1 and characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter ((TA)7TAA). For patients having shown good tolerability of irinotecan in a precedent treatment line according to the investigator´s judgement, the availability of the UGT1A1 result is not mandatory for study inclusion.
- Severe internal disease: insufficiently treated or uncontrolled arterial hypertension, hemoptoe, New York Heart Association (NYHA) grade II or greater congestive heart failure, symptomatic coronary heart disease, myocardial infarction (≤ 12 months prior to inclusion), serious cardiac arrhythmia requiring medication, peripheral arterial occlusive disease stage II or greater, uncontrolled severe disease
- Patients with a confirmed QTcF > 480 ms, or a history of additional risk factors for Torsades de Pointes (e.g. heart failure, hypokalemia, family history of long QT syndrome)
- Patients with a history of other malignancies unless having undergone definitive treatment more than 5 years prior to entry into the study and without evidence of recurrent malignant disease; Note: patients with basal cell carcinoma of the skin, superficial carcinoma of the bladder, carcinoma of the prostate with a current PSA < 0.1 ng/ml, or cervical intraepithelial neoplasia within the last 5 years are allowed
- Patients with any other medical, psychiatric or social condition, which in the opinion of the investigator would preclude participation in the trial, pose an undue medical hazard, interfere with the conduct of the trial or interfere with interpretation of the trial results
- Patients with a history of hypersensitivity reactions to compounds of similar chemical or biological composition to resminostat or to any component of the FOLFIRI treatment
- Women who are pregnant or lactating or who are planning on becoming pregnant during the trial or for 90 days after completion of the trial
- Patients with a history of, who were treated for, or who are suspected of having, hepatitis B, hepatitis C or HIV. Patients suspected of having any of these conditions should undergo appropriate evaluations prior to being enrolled in the study
- History or current evidence of clinically relevant allergies or idiosyncrasy to drugs or food
- History of organ transplantation
- Symptomatic brain and/or CNS metastases
- Major surgery within the last 4 weeks
- Patients who are employees at the investigational site, relatives or spouse of the investigator
- Planned donation of germ cells, blood, organs, or bone marrow during the course of the study
Phase II (only those listed, that are in addition to or different to Phase I criteria):
- First-line treatment with an irinotecan-based regimen (e.g. FOLFIRI)
- Patients who are homozygous for the UGT1A1 and characterized by the presence
of an additional TA repeat in the TATA sequence of the UGT1A1 promoter
((TA)7TAA) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Phase I: Potential MTD and optimal dosing schedule of resminostat in combination with FOLFIRI
- Phase II: Progression free survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the end of phase I and at the end of phase II |
|
| E.5.2 | Secondary end point(s) |
- Progression free survival (PFS)
- Progression free survival rate (PFSR) after 8 weeks (4 cycles) and every following 8 weeks (additional 4 cycles each)
- Time to Progression (TTP)
- Number of Objective Responses (OR)
- Overall survival (OS)
- Duration of Response (DOR)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of phase I and at the end of phase II |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 |
| Dose escalation phase for MTD definition |
|
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Randomisation not applicable during phase I, randomisation in 2 arms during phase II |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | Yes |
| 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
|
For patients being on drug after the first half of the year 2015 an option to continue therapy will be provided.
After study discontinuation patients will be followed up at staging visits or, if the patient has discontinued the study, by phone calls until 28 months after first treatment with study drug for OS data collection.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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