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 (Stage IV). |
|
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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 overall survival (OS) in the General Population patients
treated with BBI-608 plus biweekly FOLFIRI (Arm 1) versus biweekly
FOLFIRI (Arm 2)
• To compare OS in the pSTAT3-positive (pSTAT3(+)) Subpopulation
patients treated with BBI-608 plus biweekly FOLFIRI (Arm 1) versus
biweekly FOLFIRI (Arm 2) |
|
E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives:
• To compare progression free survival (PFS) in the General Population
patients treated with BBI-608 plus biweekly FOLFIRI versus biweekly
FOLFIRI
• To compare PFS in the pSTAT3(+) Subpopulation patients treated with
BBI 608 plus biweekly FOLFIRI versus biweekly FOLFIRI
• To compare disease control rate (DCR) in the General Population
patients treated with BBI-608 plus biweekly FOLFIRI versus biweekly
FOLFIRI
• To compare DCR in the pSTAT3(+) Subpopulation patients treated with
BBI-608 plus biweekly FOLFIRI versus biweekly FOLFIRI
• To compare overall response rate (ORR) in the General Population
patients treated with BBI-608 plus biweekly FOLFIRI versus biweekly
FOLFIRI
• To compare ORR in the pSTAT3(+) Subpopulation patients treated with
BBI-608 plus biweekly FOLFIRI versus biweekly FOLFIRI
Please refer to the protocol for other Secondary Objectives. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.1 Written, signed 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 procedure.
1.2 Must have histologically confirmed advanced CRC that is metastatic.
1.3 Must have failed treatment with one regimen containing only a fluoropyrimidine and oxaliplatin with or without bevacizumab for metastatic disease. All patients must have received a minimum of 6 weeks of the first-line regimen that included bevacizumab, oxaliplatin and a fluoropyrimidine with or without bevacizumab in the same cycle. Treatment failure is defined as radiologic progression during or < 6 months after the last dose of first-line therapy.
1.4 FOLFIRI therapy is appropriate for the patient and is recommended by the Investigator.
1.5 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.
1.6 Must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
1.7 Must be ≥ 18 years of age.
1.8 For male or female patient of child bearing potential: 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. Patients who receive single agent BBI-608 without FOLFIRI must agree to use contraception or take measures to avoid pregnancy during the study and for 30 days for female patients and 90 days for male patients, of the final BBI-608 dose.
Female patients of child bearing potential reated with bevacizumab, per investigator choice, must agree to use contraception or take measures to avoid pregnancy during the study and for 6 months, of the final bevacizumab dose.
1.9 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.
1.10 Must have alanine transaminase (ALT) ≤ 3 × institutional upper limit of normal (ULN) [≤ 5 × ULN in presence of liver metastases] within 14 days prior to randomization.
1.11 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.
1.12 Must have total bilirubin ≤ 1.5 × institutional ULN [≤ 2.0 x ULN in presence of liver metastases] within 14 days prior to randomization.
1.13 Must have creatinine ≤ 1.5 × institutional ULN or Creatinine Clearance > 50 ml/min as calculated by the Cockcroft-Gault equation (CKD-EPI equation may also be used) within 14 days prior to randomization.
1.14 Must have absolute neutrophil count ≥ 1.5 x 109/L within 14 days prior to randomization.
1.15 Must have platelet count ≥ 100 x 109/L within 14 days prior to randomization. Must not have required transfusion of platelets within 1 week of baseline platelet assessment.
1.16 Patient must have adequate nutritional status with Body Mass Index (BMI) > 18 kg/m2 and body weight of > 40 kg with serum albumin > 3 g/dL.
1.17 Other baseline laboratory evaluations must be done within 14 days prior to randomization.
1.18 Patient 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 biomarker marker assays may be conducted ( section 12.2.1 and section 13.2)
1.19 Patient must consent to provision of a sample of blood in order that the specific correlative marker assays may be conducted ( section 12.2.1).
1.20 Patients must be accessible for treatment and follow-up.
1.21 Protocol treatment is to begin within 2 calendar days of patient randomization for patients randomized to Arm 1. Patients randomized to Arm 2 must begin protocol treatment within 7 calendar days of randomization.
(Please refer to protocol for further information) |
|
E.4 | Principal exclusion criteria |
2.1 Anti-cancer chemotherapy or biologic therapy if administered prior to the first planned dose of study medication (BBI-608 or FOLFIRI) 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 study medication.
2.2 More than one prior chemotherapy regimen administered in the metastatic setting.
2.3 Major surgery within 4 weeks prior to randomization.
2.4 Patients with any known brain or leptomeningeal metastases are excluded, even if treated.
2.5 Women who are pregnant or breastfeeding. Women should not breastfeed while taking study treatment and for 4 weeks after the last dose of BBI-608 or while undergoing treatment with FOLFIRI and for 180 days after the last dose of FOLFIRI.
2.6 Gastrointestinal disorder(s) which, in the opinion of the Qualified/Principal Investigator, would significantly impede the absorption of an oral agent (e.g. intestinal occlusion, active Crohn’s disease, ulcerative colitis, extensive gastric and small intestine resection).
2.7 Unable or unwilling to swallow BBI-608 capsules daily.
2.8 Prior treatment with BBI-608 or possible hypersensitivity to BBI-608 or one of the excipients which include azo dyes sunset yellow and allura red.
2.9 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements.
a. Known infection with Human Immunodeficiency Virus (HIV), and/or active infection with hepatitis B (patients who have had an HBV immunization are eligible), or hepatitis C.
b. Patients with clinically significant ascites or pleural effusions.
2.10 Known hypersensitivity to 5-fluorouracil/leucovorin
2.11 Known dihydropyrimidine dehydrogenase (DPD) deficiency
2.12 Known hypersensitivity to irinotecan
2.13 Chronic inflammatory bowel disease(Crohn's disease or ulcerative colitis)
2.14 Patients receiving treatment with St. John's wort or Phenytoin.
2.15 Patients who plan to receive yellow fever vaccine during the course of the study treatment.
2.13 Abnormal glucuronidation of bilirubin, known Gilbert’s syndrome
2.14 Patients with QTc interval > 470 milliseconds
2.15 For patients to be treated with a regimen containing bevacizumab: please refer to protocol
2.16 Patients with a history of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for > 3 years.
2.17 Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy.
2.18 Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol.
Please refer to protocol for further information. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary study endpoints are Overall Survival for the General
Population and the pSTAT3(+) Subpopulation. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Without adjusting for multiplicity, it is estimated that 850 events in the
General Population and 310 (approximately 36% of 850) events in the
pSTAT3(+) Subpopulation will be required to detect the reduction in the
risk of death, which would be observed by randomizing 1250 patients
(General Population) over 26 months with patient follow up for an
additional 14 months, for a total study duration of 40 months. It is
anticipated that up to 5% dropout rate will occur over the entire study.
|
|
E.5.2 | Secondary end point(s) |
• Progression Free Survival in the general study population and the
pSTAT3(+) Subpopulation
• Objective Response Rate (ORR) in the general study population
and the pSTAT3(+) Subpopulation
• Disease Control Rate (DCR) in the general study population and the
pSTAT3(+) Subpopulation
• Safety Profile in the general study population and the pSTAT3(+)
Subpopulation
• Quality of Life (QoL) in the general study population and the
pSTAT3(+) Subpopulation |
|
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 | Yes |
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 |
Standard background therapy per protocol without addition of IMP |
|
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 71 |
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 |
Belgium |
Canada |
China |
Czech Republic |
France |
Germany |
Hong Kong |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Singapore |
Spain |
Sweden |
United States |
|
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
and the pSTAT3(+) Subpopulation. Patients who are alive at the time of
the interim or the final analysis or who have become lost to follow-up
will become censored on the date the patient was last 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 | 4 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 18 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 14 |