Ensayos clínicos

Inclusion Criteria:

• 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.
• Must have histologically confirmed advanced CRC that is metastatic.
• 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 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.
• No additional prior lines of therapy in the metastatic setting will be allowed. Patients who discontinued first-line therapy due to toxicity may be enrolled for as long as progression occurred < 6 months after the last dose of first-line therapy.
• Patients who show tumor progression while on maintenance therapy with a fluoropyrimidine with or without bevacizumab after prior fluoropyrimidine-oxaliplatin with or without bevacizumab induction therapy are eligible.
• Prior neoadjuvant or adjuvant systemic treatment is allowed as long as no more than 2 prior systemic chemotherapy regimens were administered with no more than one prior regimen permitted in the metastatic setting. Patients who received oxaliplatin/fluoropyrimidine-based neoadjuvant or adjuvant therapy and have disease recurrence or progression > 6 months from their last dose of neoadjuvant or adjuvant treatment (or > 6 months from surgery if no adjuvant therapy was administered) will be required to receive fluoropyrimidine/oxaliplatin-based therapy with or without bevacizumab for metastatic disease.
• For participants with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen.
• Rechallenge with oxaliplatin is permitted and will be considered part of the first-line regimen for metastatic disease, with both initial oxaliplatin treatment and subsequent rechallenge being considered as 1 regimen.
• Patients receiving any other systemic therapy in the metastatic setting will be excluded.
• FOLFIRI therapy is appropriate for the patient and is recommended by the Investigator.
• 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 an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Must be ≥ 18 years of age.
• For male or female patient of child producing 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 producing potential treated 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.
• Adequate contraception is defined as follows:
  • Complete true abstinence: when this is in line with the preferred and usual lifestyle of the subject.
  • Consistent and correct use of one of the following methods of birth control:
    • male partner who is sterile prior to the female subjects entry into the study and is the sole sexual partner for that female subject; or
    • implants of levonorgesterol; or
    • injectable progestagen; or
    • any intrauterine device (IUD) with a documented failure rate of less than 1% per year; or
    • oral contraceptive pill (either combined or progesterone only); or
    • one barrier method for example diaphragm with spermicide or condom with spermicide in combination with either implants of levonorgesterol or injectable progestagen, any intrauterine device (IUD) with a  documented failure rate of less than 1% per year, or oral contraceptive pill (either combined or progesterone only).
• 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.
• WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhoea > 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL). Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g. vasectomy), should be considered to be of child bearing potential.
• 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.
• 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 [≤ 2.0 x ULN in presence of liver metastases] within 14 days prior to randomization.
• 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.
• Must have absolute neutrophil count ≥ 1.5 x 109/L within 14 days prior to randomization.
• 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.
• 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.
• Other baseline laboratory evaluations, listed in Section 5.0, must be done within 14 days prior to randomization.
• 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 correlative marker assays proscribed in Section 13.6 (Correlative Studies) of this protocol may be conducted.
• Submission of the tissue does not have to occur prior to randomization. Where local center regulations prohibit submission of blocks of tumor tissue, two 2 mm cores of tumor from the block and 10-30 unstained slides of whole sections of representative tumor tissue are preferred. Where two 2 mm cores of tumor from the block are unavailable, 10-30 unstained slides of whole sections of representative tumor tissue alone are acceptable. Where no previously resected or biopsied tumor tissue exists or is available, on the approval of the Sponsor/designated CRO, the patient may still be considered eligible for the study.
• Patient must consent to provision of a sample of blood in order that the specific correlative marker assays proscribed in Sections 13.6 (Correlative Studies) and 13.7 (Exploratory Analyses)_may be conducted.
• Patients must be accessible for treatment and follow-up. Patients registered on this trial must receive protocol treatment and be followed at the participating center. This implies there must be reasonable geographical limits placed on patients being considered for this trial. Investigators must ensure that the patients randomized on this trial will be available for complete documentation of the treatment, response assessment, adverse events, and follow-up.
• 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.
• Must have histologically confirmed advanced CRC that is metastatic.
• 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 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.
• No additional prior lines of therapy in the metastatic setting will be allowed. Patients who discontinued first-line therapy due to toxicity may be enrolled for as long as progression occurred < 6 months after the last dose of first-line therapy.
• Patients who show tumor progression while on maintenance therapy with a fluoropyrimidine with or without bevacizumab after prior fluoropyrimidine-oxaliplatin with or without bevacizumab induction therapy are eligible.
• Prior neoadjuvant or adjuvant systemic treatment is allowed as long as no more than 2 prior systemic chemotherapy regimens were administered with no more than one prior regimen permitted in the metastatic setting. Patients who received oxaliplatin/fluoropyrimidine-based neoadjuvant or adjuvant therapy and have disease recurrence or progression > 6 months from their last dose of neoadjuvant or adjuvant treatment (or > 6 months from surgery if no adjuvant therapy was administered) will be required to receive fluoropyrimidine/oxaliplatin-based therapy with or without bevacizumab for metastatic disease.
• For participants with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen.
• Rechallenge with oxaliplatin is permitted and will be considered part of the first-line regimen for metastatic disease, with both initial oxaliplatin treatment and subsequent rechallenge being considered as 1 regimen.
• Patients receiving any other systemic therapy in the metastatic setting will be excluded.
• FOLFIRI therapy is appropriate for the patient and is recommended by the Investigator.
• 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 an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Must be ≥ 18 years of age.
• For male or female patient of child producing 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 producing potential treated 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.
• Adequate contraception is defined as follows:
  • Complete true abstinence: when this is in line with the preferred and usual lifestyle of the subject.
  • Consistent and correct use of one of the following methods of birth control:
    • male partner who is sterile prior to the female subjects entry into the study and is the sole sexual partner for that female subject; or
    • implants of levonorgesterol; or
    • injectable progestagen; or
    • any intrauterine device (IUD) with a documented failure rate of less than 1% per year; or
    • oral contraceptive pill (either combined or progesterone only); or
    • one barrier method for example diaphragm with spermicide or condom with spermicide in combination with either implants of levonorgesterol or injectable progestagen, any intrauterine device (IUD) with a  documented failure rate of less than 1% per year, or oral contraceptive pill (either combined or progesterone only).
• 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.
• WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhoea > 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL). Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g. vasectomy), should be considered to be of child bearing potential.
• 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.
• 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 [≤ 2.0 x ULN in presence of liver metastases] within 14 days prior to randomization.
• 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.
• Must have absolute neutrophil count ≥ 1.5 x 109/L within 14 days prior to randomization.
• 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.
• 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.
• Other baseline laboratory evaluations, listed in Section 5.0, must be done within 14 days prior to randomization.
• 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 correlative marker assays proscribed in Section 13.6 (Correlative Studies) of this protocol may be conducted.
• Submission of the tissue does not have to occur prior to randomization. Where local center regulations prohibit submission of blocks of tumor tissue, two 2 mm cores of tumor from the block and 10-30 unstained slides of whole sections of representative tumor tissue are preferred. Where two 2 mm cores of tumor from the block are unavailable, 10-30 unstained slides of whole sections of representative tumor tissue alone are acceptable. Where no previously resected or biopsied tumor tissue exists or is available, on the approval of the Sponsor/designated CRO, the patient may still be considered eligible for the study.
• Patient must consent to provision of a sample of blood in order that the specific correlative marker assays proscribed in Sections 13.6 (Correlative Studies) and 13.7 (Exploratory Analyses)_may be conducted.
• Patients must be accessible for treatment and follow-up. Patients registered on this trial must receive protocol treatment and be followed at the participating center. This implies there must be reasonable geographical limits placed on patients being considered for this trial. Investigators must ensure that the patients randomized on this trial will be available for complete documentation of the treatment, response assessment, adverse events, and follow-up.
• 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.
• The patient is not receiving therapy in a concurrent clinical study and the patient agrees not to participate in other interventional clinical studies during their participation in this trial while on study treatment. Patients participating in surveys or observational studies are eligible to participate in this study.

Exclusion Criteria:

• 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.
• Standard dose of bevacizumab (5 mg/kg) may be administered prior to FOLFIRI infusion, per Investigator decision, for as long as permanent decision to include or exclude bevacizumab is made prior to patient randomization.
• 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 a single dose of radiation up to 8 Gray (equal to 800 RAD) with palliative intent for pain control up to 14 days before randomization.
• More than one prior chemotherapy regimen administered in the metastatic setting.
• Major surgery within 4 weeks prior to randomization.
• Patients with any known brain or leptomeningeal metastases are excluded, even if treated.
• 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.
• 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).
• Unable or unwilling to swallow BBI-608 capsules daily.
• 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.
• 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.
• Known hypersensitivity to 5-fluorouracil/leucovorin.
• Known dihydropyrimidine dehydrogenase (DPD) deficiency.
• Known hypersensitivity to irinotecan.
• Chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis).
• 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 milliseconds.
• For patients to be treated with a regimen containing bevacizumab:
  • History of cardiac disease: congestive heart failure (CHF) > NYHA Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
  • Current uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management) as well as prior history of  hypertensive crisis or hypertensive encephalopathy.
  • History of arterial thrombotic or embolic events (within 6 months prior to study entry).
  • Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic peripheral vascular disease).
  • Evidence of bleeding diathesis or clinically significant coagulopathy.
  • Major surgical procedure (including open biopsy, significant traumatic injury, etc.) within 28 days, or anticipation of the need for major surgical procedure during the course of the study as well as minor surgical procedure (excluding placement of a vascular access device or bone marrow biopsy) within 7 days prior to study enrollment.
  • Proteinuria at screening as demonstrated by urinalysis with proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
  • History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within 6 months.