| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Colorectal Cancer (second line) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Colorectal Cancer (second line) |
|
| 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 | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Part 1: SAFETY RUN-IN PART
To determine the Maximum Tolerated Dose (MTD) and the recommended Phase II dose (RP2D) of MSC1936369B combined with FOLFIRI as second-line treatment in subjects with K Ras mutated metastatic colorectal cancer (mCRC).
Part 2: PHASE II RANDOMIZED PART
To assess the anti-tumor activity of MSC1936369B combined with FOLFIRI as second-line treatment in subjects with K Ras mutated mCRC in terms of Progression-Free Survival (PFS).
|
|
| E.2.2 | Secondary objectives of the trial |
Part 1: SAFETY RUN-IN PART
To assess the pharmacokinetics (PK) of MSC1936369B, irinotecan and 5-Fluorouracil (5-FU) (plasma) concentration when combined in subjects with mCRC.
To explore the anti-tumor activity of MSC1936369B combined with FOLFIRI as second-line treatment for subjects with K Ras mutated mCRC.
To explore candidate markers for tumor characteristics and predictive of anti-tumor activity.
To explore circulating markers in serum.
Part 2: PHASE II RANDOMIZED PART
To determine safety and tolerability of MSC1936369B combined with FOLFIRI as second-line treatment in subjects with K Ras mutated mCRC.
To assess the anti-tumor activity in terms of response rate, clinical benefit, overall survival, and time to progression.
To explore candidate markers for tumor characteristics and predictive of anti-tumor activity.
To explore circulating markers in serum.
To assess the pharmacokinetics (PK) of MSC1936369B in subjects with mCRC. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Histologically confirmed KRAS mutated colon/rectum cancer.
Subject’s disease must have progressed during or after a first-line treatment for metastatic disease with oxaliplatin and fluoropyrimidins based chemotherapy with or without bevacizumab.
Evidence of metastatic measurable disease at trial entry as per Response Evaluation Criteria in Solid Tumors [RECIST v1.0] (at least one measurable lesion). Complete tumor assessment performed within 14 days prior to first trial drug administration.
Age of subjects at least 18 years.
Subject has read, understood and given informed consent, fully understands requirements of the trial, and is willing to comply with all trial visits and assessments.
Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For the purposes of this trial, women of childbearing potential are defined as: “All female subjects after puberty unless they are post-menopausal for at least two years, are surgically sterile or are sexually inactive.”
Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to screening, during and four weeks after the last dose of trial medication. Adequate contraception is defined as two barrier methods, or one barrier method with a spermicide, or intrauterine device. The use of
hormonal contraceptives should be avoided in female subjects
of childbearing potential due to possible drug-drug
interaction. |
|
| E.4 | Principal exclusion criteria |
Bone marrow impairment as evidenced by hemoglobin < 9.0 g/dL, neutrophil count < 1.5 x 10^9/L, and/or platelets < 100 x 10^9/L.
Renal impairment as evidenced by serum creatinine > 1.5 x ULN (upper limit of normal) and/or calculated creatinine clearance < 50 mL/min.
Liver function and liver cell integrity abnormality as defined by total bilirubin > 1.5 x ULN, or AST/ALT > 2.5 x ULN, for subjects with liver involvement AST/ALT > 5 x ULN.
History of central nervous system (CNS) metastases, unless subject has been previously treated for CNS metastases, is stable by CT scan without evidence of cerebral edema, and has no requirements for corticosteroids or anticonvulsants.
History of difficulty of swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the tested product.
Eastern Cooperative Oncology Group Performance Status (ECOG PS) greater than 1.
Known HIV positivity, active hepatitis C, or active hepatitis B.
Has received extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation. Prior radiation for local disease management is allowed if last fraction was completed at least 4 weeks prior to trial entry.
Has received chemotherapy or any investigational drug in the 4 weeks prior to trial first drug administration.
Has a history of any other significant medical disease such as major gastric or small bowel surgery, or has a psychiatric condition that might impair the subject’s well being or preclude full participation in the trial.
Past or current history (within the last 2 years prior to inclusion) of malignancies except for the indication under this study and curatively treated: basal and squamous cell carcinoma of the skin and in-situ carcinoma of the cervix.
Has significant cardiac conduction abnormalities and/or pacemaker.
Is a pregnant or nursing female.
Has retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis, or history of retinal vein occlusion and/or any medically relevant abnormal findings at the initial ophthalmologic examination.
Other significant disease that in the Investigator’s opinion would exclude the subject from the trial.
Known hypersensitivity to the trial treatment(s) or diluents (when applicable), including placebo or other comparator drug(s).
Legal incapacity or limited legal capacity. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Run-in Part
Dose-Limiting Toxicity (DLT) using the NCI Common Terminology Criteria for Adverse Events v3.0 (CTCAE), evaluated over the first cycle of treatment. The number and the incidence of DLTs by dose level will be used in the primary statistical analysis of the Safety Run-in part.
Phase II Randomized Part
Progression-Free Survival (PFS) time, defined as the time (in months) from the date of randomization to the first disease progression as reported and documented by the Investigator (i.e. radiological progression per RECIST v1.0) or death for any cause. PFS will be censored at the time of subsequent therapy before progression. The PFS Hazard Ratio (HR) of experimental arm versus control arm will be used in the primary statistical analysis of the Phase II Randomized part. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety Run-in part:
After 1st cycle of treatment.
Phase II Randomized Part:
The first disease progression as reported and documented by the Investigator or death for any cause. PFS will be censored at the time of subsequent therapy before progression. |
|
| E.5.2 | Secondary end point(s) |
Safety Run-in Part:
• Treatment-emergent adverse events (TEAEs) graded according
to the NCI-CTCAE v3.0.
• Change in laboratory parameters and/or vital signs.
• Plasma PK parameters (incl. Cmax, Tmax, AUC, t1/2) of SC1936369B, irinotecan and its active metabolite SN38. Concentration of 5-FU, if applicable.
• Overall response rate: Confirmed Complete Response (CR) plus Partial Response (PR) rate (using RECIST v1.0).
• Clinical Benefit: Confirmed CR, PR and Stable Disease (SD) rate (SD lasting at least 12 weeks) (using RECIST v1.0).
• Exploratory candidate markers for tumor characteristics and
predictive of anti-tumor activity.
• Changes in levels of circulating markers in serum (e.g. cytokines).
Phase II Randomized Part
• Grade 3 or 4 toxicity using the NCI-CTCAE v3.0 during the treatment period, judged to be related to the trial medications.
• TEAEs graded according to the NCI-CTCAE v3.0.
• Change in a laboratory parameter and/or vital signs.
• Overall response rate: Confirmed CR plus PR rate (using RECIST v1.0).
• Clinical Benefit: Confirmed CR, PR and SD rate (SD lasting at least 12 weeks) (using RECIST v1.0).
• Time to Progression (TTP), defined as the time (in months) from randomization date to date of progression, as reported and documented by the Investigator (i.e. radiological progression per RECIST v1.0).
• Overall survival (OS) time, defined as the time (in months) from randomization to death due to any cause.
• Exploratory candidate markers for tumor characteristics and predictive of anti-tumor activity.
• Changes in levels of circulating markers in serum (e.g. cytokines).
• Plasma PK parameters of MSC1936369B to be presented in the population PK report according to the SAP. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety Run-in Part:
On-going or at the time of analysis.
Phase II Randomized Part:
On-going or at the time of analysis.
|
|
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
|
Safety Run-in part: All subjects enrolled in the Safety Run-in part have completed their treatment and their end of treatment and post-treatment visits.
Randomized Phase II part of the trial: All subjects have received the last dose of trial treatment (including 28 days of safety follow up and the EOT Visit) and two-thirds of the subjects have died (128 subjects). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
