| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically confirmed adenocarcinoma of the colon or rectum that is metastatic. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the colon or rectum. |
|
| 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 | 27.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| 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 |
| To compare the overall survival (OS) of patients with metastatic pretreated CRC treated with Napabucasin plus standard bi-weekly FOLFIRI and BSC versus Napabucasin plus BSC (or BSC alone). |
|
| E.2.2 | Secondary objectives of the trial |
To compare:
• Progression free survival (PFS) of patients with metastatic pretreated CRC treated with Napabucasin plus standard bi-weekly FOLFIRI and BSC versus Napabucasin plus BSC (or BSC alone).
• Objective response rate (ORR) of patients with metastatic pretreated CRC treated with Napabucasin plus standard bi-weekly FOLFIRI and BSC versus Napabucasin plus BSC (or BSC alone).
• Disease control rate (DCR) of patients with metastatic pretreated CRC treated with Napabucasin plus standard bi-weekly FOLFIRI and BSC versus Napabucasin plus BSC (or BSC alone).
• OS, PFS, ORR and DCR of predefined biomarker positive patients with metastatic pretreated CRC treated with Napabucasin plus standard bi-weekly FOLFIRI and BSC versus Napabucasin plus BSC (or BSC alone).
• Safety Profile
• Quality of Life (QoL) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Written, signed informed consent for trial participation must be obtained from the patient appropriately in accordance with applicable ICH guidelines and local and regulatory requirements prior to the performance of any study-specific test or procedure.
• Must have histologically confirmed adenocarcinoma of the colon or rectum that is metastatic (Stage IV). Patients with more than a single primary CRC adenocarcinoma will be excluded.
• Must have failed standard chemotherapy-based regimens containing a fluoropyrimidine, irinotecan and oxaliplatin.
• Patients who are candidates for and have access to anti-VEGF therapy (i.e. bevacizumab and regorafenib) and anti-EGFR therapy (i.e. cetuximab or panitumumab) and TAS-102 must have received appropriate therapy.
• Imaging investigations, including CT/MRI of chest/abdomen/pelvis or other scans as necessary to document all sites of disease, performed within 21 days prior to randomization. Patients with either measurable disease or non-measurable evaluable disease are eligible.
• Must have ECOG Performance Status of 0 or 1, assessed within 14 days prior to randomization. For patients whose ECOG Performance Status is assessed > 7 days prior to randomization, the ECOG PS must not increase within 7 days prior to randomization. Two observers qualified to perform assessment of the performance status will be required to perform this assessment. If discrepant, the one with the most deteriorated performance status will be considered true.
• Must be ≥ 18 years of age.
• Must have life-expectancy of > 12 weeks.
• For male or female patients of child producing potential: Must agree to use contraception or take measures to avoid pregnancy during the study and for 30 days for female and 90 days for male patients, of the final napabucasin dose. Arm 1 patients must agree to use contraception or take measures to avoid pregnancy during the study and for 180 days for female and for male patients, of the final FOLFIRI dose.
• Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test within 5 days prior to randomization. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG.
• Must have alanine transaminase (ALT) ≤ 3 × institutional upper limit of normal (ULN), or ≤ 5 × ULN in presence of liver metastases within 14 days prior to randomization.
• Must have hemoglobin (Hgb) ≥ 9.0 g/dL within 14 days prior to randomization. Must not have required transfusion of red blood cells within 1 week of baseline Hgb assessment.
• Must have total bilirubin ≤ 1.5 × institutional ULN, or ≤ 2.0 × ULN in presence of liver metastases within 14 days prior to randomization.
• Must have creatinine ≤ 1.5 × institutional ULN and Creatinine Clearance > 50 mL/min (as calculated by the Cockroft-Gault equation) within 14 days prior to randomization. Actual body weight should be used for calculating creatinine clearance. For patients with a Body Mass Index (BMI) > 30 kg/m2, lean body weight should be used instead.
• Must have absolute neutrophil count ≥ 1.5 × 109/L within 14 days prior to randomization.
• Must have platelet count ≥ 100 × 109/L within 14 days prior to randomization. Must not have required transfusion of platelets within 1 week of baseline platelet assessment.
• Patients must have adequate nutritional status with Body Mass Index (BMI) > 18 kg/m2 and body weight of > 40 kg with serum albumin ≥ 3.0 g/dL. Patients must not be candidates for enteral or parenteral nutrition.
• Other baseline laboratory evaluations, listed in Section 6.0, must be done within 14 days prior to randomization.
• Patients must consent to provision of, and investigator(s) must confirm access to and agree to submit a representative formalin fixed paraffin block of tumor tissue in order that the specific correlative marker assays may be conducted. |
|
| E.4 | Principal exclusion criteria |
• Anti-cancer chemotherapy, biologic therapy or any other systemic therapy if administered prior to the first planned dose of study medication within period of time equivalent to the usual cycle length of the regimen. An exception is made for oral fluoropyrimidines (e.g. capecitabine, S-1), where a minimum of 10 days since last dose must be observed prior to the first planned dose of protocol treatment. Radiotherapy, immunotherapy (including immunotherapy administered for non-neoplastic treatment purposes), or investigational agents within four weeks of first planned dose of study medication, with the exception of limited field radiation up to 14 days before randomization.
• Major surgery within 4 weeks prior to randomization. Major surgery is defined as any invasive operative procedure in which a more extensive resection is performed, e.g. a body cavity is entered, organs are removed, or normal anatomy is altered. If a mesenchymal barrier is opened (pleural cavity, peritoneum, meninges), the surgery is considered major.
• Patients with any known brain or leptomeningeal metastases are excluded, even if treated.
• Women who are pregnant or breastfeeding.
• Gastrointestinal disorder(s) which would significantly impede the absorption of an oral agent (e.g. intestinal occlusion, Crohn’s disease, ulcerative colitis, extensive gastric and small intestine resection).
• Unable or unwilling to swallow napabucasin capsules daily.
• Prior treatment with napabucasin or participation on a napabucasin clinical trial or possible hypersensitivity to napabucasin or one of the excipients which include azo dyes sunset yellow and allura red.
• Uncontrolled intercurrent illness
• Known history of human immunodeficiency virus (HIV) infection. Known chronic hepatitis B or C active infection.
• Patients with clinically significant ascites or pleural effusions (e.g., requiring fluid removal within 2 months before randomization, and/or frequent or large volume removal, or requiring an indwelling drainage catheter).
• Patients with hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) or familial adenomatous polyposis syndrome (FAP).
• The MSI/MSS status of the tumor must be known prior to randomization. Patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) status will be excluded.
• Known hypersensitivity to fluoropyrimidine or patients who as a result of toxicity had to reduce or stop 5-FU infusion at the dose of 900 mg/m2/day (total 1800 mg/m2/day).
• Known dihydropyrimidine dehydrogenase (DPD) deficiency.
• Known hypersensitivity to irinotecan or patients who as a result of toxicity had to reduce or stop irinotecan infusion at the dose of <120 mg/m2.
• Patients receiving treatment with St. John’s wort or Phenytoin.
• Patients who plan to receive yellow fever vaccine during the course of the study treatment.
• Abnormal glucuronidation of bilirubin, known Gilbert’s syndrome.
• Patients with QTc interval > 470 millisecond.
• Patients who consumed cigarettes/tobacco within 28 days prior to randomization or plan to use these products while on study treatment.
• Patients with a history of other malignancies including concurrent colorectal co-primary tumor and except for: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with surgery or surgery with radiotherapy and/or chemotherapy with no evidence of disease for ≥ 5 years after completion of treatment.
• Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy.
• Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Survival in the general study population, defined as the time from randomization to death from any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The 623rd event will trigger the final analysis. It is estimated that 623 events will be required to detect a 23% reduction in the continuous risk of death which would be observed by randomizing 705 patients over 17 months with a follow-up period of 26 months. |
|
| E.5.2 | Secondary end point(s) |
• Progression free survival (PFS) in the general study population
• Objective response rate (ORR) in the general study population
• Disease control rate (DCR) in the general study population
• OS, PFS, ORR and DCR in the predefined biomarker positive population*
• Safety
• Quality of Life
*This biomarker-positive sub-population is defined as those patients with nuclear β-catenin and/or phospho-STAT3 positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) archival tissue |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to protocol for further information. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Napabucasin with Best Supportive Care, or Best Supportive Care alone. |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Australia |
| China |
| Russian Federation |
| Belgium |
| France |
| Italy |
| Spain |
|
| 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
|
| The primary endpoint is Overall Survival (OS) in the general population. Patients who are still alive at the time of the final analysis, or who have become lost to follow-up will become censored on the date the patient was known to be alive. |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 7 |
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