| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic colorectal cancer (CRC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10010035 |
| E.1.2 | Term | Colorectal cancer stage IV |
| 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 progression-free survival (PFS) between tivozanib in combination with mFOLFOX6 with bevacizumab in combination with mFOLFOX6 based on investigator radiological tumor assessment.
|
|
| E.2.2 | Secondary objectives of the trial |
• Progression-Free Survival (PFS) based on Independent Radiological Review (IRR)
• Overall survival (OS)
• Objective Response Rate (ORR)
• Duration of Response (DoR)
• Time to Treatment Failure (TTF)
• Health-Related Quality of Life (HRQoL)
• Safety and tolerability
• Assess relationships that may be predictive of the level of response to tivozanib/ mFOLFOX6 vs. bevacizumab/mFOLFOX6
• LDH
• VEGF-C, VEGF-D and VEGF-A
• CD68 and myeloid-derived gene signature (MGS)
• Serum soluble cytokines
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
This protocol will include an optional, pharmacogenomic sub-study. A blood sample will be collected from subjects (who provide a separate consent) to evaluate the influence of genetic variation on drug response in subjects by correlating gene expression with tivozanib efficacy or toxicity. One blood sample will be taken from subjects at time of consent.
|
|
| E.3 | Principal inclusion criteria |
Subject is eligible for the study if all of the following apply:
1.) The subject, prior to any study-related procedures, has provided IRB/IEC approved written Informed Consent and privacy language as per national regulations (e.g., HIPAA Authorization for US sites).
2.) The subject is male or female, aged 18 years or older.
3.) The subject has histologically or cytologically confirmed mCRC for which bevacizumab/ mFOLFOX6 chemotherapy regimen would be the appropriate treatment per the investigator.
4.) The subject has at least one measurable lesion by RECIST Version 1.1. A lesion that has received prior radiotherapy may only be counted as a target lesion if it has progressed since radiotherapy as determined by PI or radiologist assessment.
5.) The subject has had no prior systemic chemotherapy for advanced colorectal cancer; no fluorouracil containing adjuvant therapy in previous 6 months.
6.) The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7.) Female subject must be either:
• post-menopausal (defined as women who are > 46 years of age and last menstrual period was more than 2 years ago) prior to Screening, or
• premanarchal prior to Screening, or
• documented surgically sterile or status post hysterectomy (at least 1 month prior to
Screening), or
• if of childbearing potential, must have a negative serum or urine pregnancy test at Screening. All females of childbearing potential who are sexually active will be required to use highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and throughout the study period and for 90 days after final study drug administration. Highly effective contraception is defined as established use of oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device (IUD) or intrauterine system (IUS), or barrier methods of contraception including a condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
8.) Male subject and their female spouses/partners who are of childbearing potential and sexually active must be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) starting at Screening and continue throughout the study period and for 90 days after final study drug administration. Highly effective contraception is defined as established use of oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device (IUD) or intrauterine system (IUS), or barrier methods of contraception including a condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
9.) Female subject must not be breastfeeding at Screening or during the study period and for 90 days after final study drug administration.
10.) Female subject must not donate ova starting at Screening and throughout the study period and for 90 days after final study drug administration.
11.) Male subject must not donate sperm starting at Screening and throughout the study period and for 90 days after final study drug administration.
12.) Subject agrees not to participate in another investigational study while on study treatment. |
|
| E.4 | Principal exclusion criteria |
The subject has;
1. had any prior VEGF-directed therapy including VEGF antibody or any other agent or investigational agent targeting the VEGF pathway.
2. primary CNS malignancies or CNS metastases; subjects with previously treated brain metastases will be allowed if the brain metastasis have been stable without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery).
3. any of the following hematologic abnormalities:
• Hemoglobin < 9.0 g/dL (90 g/L, 5.5854 mmol/L)
• ANC < 2000 per mm3
• Platelet count < 100,000 per mm3
• PT or PTT > 1.5 X ULN
4. any of the following serum chemistry abnormalities:
• Total bilirubin > 1.5 X ULN (or > 2.5 X ULN for subjects with Gilbert’s syndrome)
• AST or ALT > 2.5 X ULN (or > 5 X ULN for subjects with liver metastasis)
• Alkaline phosphatase > 2.5 X ULN (or > 5 X ULN for subjects with liver or bone metastasis)
• Serum albumin < 2.0 g/dL
• Creatinine > 1.5 X ULN (or calculated creatinine clearance < 60mL/min/1.73m2)
• Proteinuria > 2+ by urine dipstick; protein greater than 2+ must have 24-hour urine collection that is less than 2 gm/24hr
5. significant cardiovascular disease, including:
• History of clinically symptomatic left ventricular failure
• Uncontrolled hypertension: Systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg on 2 or more antihypertensive medications, documented on 2 consecutive measurements taken at least 24 hours apart
• Hypertensive crisis or hypertensive encephalopathy within 6 months prior to administration of first dose of study drug
• Myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of first dose of study drug
• History of serious ventricular arrhythmia
• Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well-controlled with anti-arrhythmic medication)
• Significant structural or congenital heart disease
6. significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug, including but not limited to:
• Deep vein thrombosis
• Pulmonary embolism
• Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
• Peripheral arterial ischemia > Grade 2
• Coronary or peripheral artery bypass graft
7. a non-healing wound, bone fracture, or skin ulcer.
8. inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug, or anticipation of major surgical procedure during the course of the study.
9. history of significant gastrointestinal (GI) toxicity, diarrhea, or stomatitis within the last 6 weeks.
10. active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation.
11. history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug.
12. a serious/active infection or infection requiring antibiotics.
13. significant bleeding disorders within 6 months prior to administration of first dose of study drug, including but not limited to:
• Hematemesis, hematochezia, melena or other gastrointestinal bleeding not directly attributable to mCRC > Grade 2. For subjects with gastrointestinal bleeds attributable to their underlying mCRC, this should be ≤ Grade 3 at the time of study entry.
• Hemoptysis or other pulmonary bleeding > Grade 2
• Hematuria or other genitourinary bleeding ≥ Grade 2
14. currently active second primary malignancy, including hematologic malignancies, other than non-melanoma skin cancers, non-metastatic prostate cancer and in situ cervical cancer and ductal or lobular carcinoma in situ of the breast. Subject is not considered to have currently active malignancy if they have completed anti-cancer therapy and have been disease free for > 5 years.
15. history of allergic reactions, or intolerance, attributed to compounds of similar chemical or biologic composition to 5-fluorouracil, history of Grade 3 hypersensitivity to oxaliplatin, history of allergic reaction to folic acid.
16. Female subject is pregnant or lactating.
The subject has;
17. a known history of genetic or acquired immune suppression disease including HIV; subjects on immune suppressive therapy for organ transplant.
18. an inability to swallow pills, malabsorption syndrome or gastrointestinal disease that would severely affect the absorption of tivozanib, major resection of the stomach or small bowel, or gastric bypass.
19.) uncontrolled neuro-psychiatric disorder or altered mental status precluding informed consent or necessary testing.
20.) peripheral neuropathy ≥ Grade 2.
21.) participated in any interventional clinical study or has been treated with any investigational drugs within 28 days or 5 half lives, whichever is longer, prior to the initiation of Screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free surival. PFS is defined as the time from the date of randomization until the date of radiological disease progression assessed by the investigator, or until death due to any cause, even in the absence of radiological progression. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 166 progression-free events have been observed in the study |
|
| E.5.2 | Secondary end point(s) |
- PFS is defined as the time from the date of randomization until the date of radiological disease progression assessed by the IRR, or until death due to any cause, even in the absence of radiological progression.
- Overall survival (OS)
- Objective Response Rate (ORR)
The ORR is defined as the proportion of subjects with a confirmed complete or partial objective response based on the RECIST criteria V1.1.
- Duration of Response (DoR)
DoR is defined as the time from the date of the first documented radiological response (complete response [CR] or Partial Response [PR]) to the date of first documented radiological progression. If a subject has not progressed, the DoR will be censored at the date of last radiological assessment. DoR is only defined for subjects with confirmed CR or PR.
Time to Treatment Failure (TTF):
TTF is defined as the time from randomization to treatment discontinuation for any reason, including disease progression, toxicity, withdrawn consent, or death. If a subject remains on study, TTF will be censored at the date of last study visit.
- Health Related Quality of Life (HRQoL)
HRQoL will be assessed with the use of the FACT-C, FCSI and EQ-5D questionnaires.
- Biomarkers
Biomarker subgroup analyses will be performed to explore the potential heterogeneous treatment effect of tivozanib + mFOLFOX6 arm compared with bevacizumab + mFOLFOX6 arm. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The biomarker assays will be batched throughout the course of the
study; analysis will be done retrospectively.
The other secondary objectives will be assessed at the time of final PFS
analysis and OS analysis will be looked at after the completion of the
trial. |
|
| 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 | No |
| 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 | 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) | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| Finland |
| Hungary |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
