| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Advanced colorectal cancer
Cáncer Colorrectal avanzado |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010030 |
| E.1.2 | Term | Colorectal cancer recurrent |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010035 |
| E.1.2 | Term | Colorectal cancer stage IV |
|
| 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 assess if the addition of oral ABT-869 to mFOLFOX6 (5-fluorouracil, folinic acid, and oxaliplatin) can prolong progression-free survival (PFS) compared to bevacizumab plus mFOLFOX6 as second-line treatment in subjects with advanced colorectal cancer. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate overall survival and additional efficacy endpoints (listed in Section 8.1.6 of the study protocol), as well as the safety and tolerability of the combination.
The tertiary objectives are to evaluate quality of life and performance status. |
|
| 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 |
| At selected clinical study sites, an optional pharmacogenetic sample collection will be performed. For subjects who have signed the appropriate Informed Consent Form, DNA samples from this protocol may be used to assess the influence of genetic variants on pharmacokinetics, safety or efficacy. For example, polymorphisms in genes encode drug metabolizing enzymes (such as cytochrome P450s or uridine glucuronosyltransferases) or drug transport proteins (such as ATP-binding cassette or solute-linked carrier proteins) may be assessed for their influence on ABT-869 pharmacokinetics. Other genes potentially related to ABT-869 response, such as genes for targets (such as VEGF or PDGF RTKs), disease progression or kinase inhibitor responsivity, may also be assessed. |
|
| E.3 | Principal inclusion criteria |
1. The subject must be ? 18 years of age.
2. The subject must be diagnosed with adenocarcinoma of the colon or rectum.
3. The subject must have metastatic disease or locally recurrent disease that is not
amenable to surgical resection with curative intent.
4. The subject must have received one prior chemotherapy regimen containing
irinotecan or a fluoropyrimidine for locally recurrent or metastatic colorectal
cancer. The subject has experienced progressive disease during or following the
prior chemotherapy treatment.
5. The subject may have received prior adjuvant treatment for colorectal cancer.
6. The subject has measurable disease, defined as at least 1 unidimensionally
measurable lesion on a CT scan as defined by RECIST version 1.1 (for subjects in
the randomized portion only).
7. The subject has an Eastern Cooperative Oncology Group (ECOG) performance
score of 0-1.
8. The subject must have adequate bone marrow, renal and hepatic function as
follows:
a. Bone Marrow: absolute neutrophil count (ANC) ? 1,500/mm3
(1.5 × 109/L); platelets ? 100,000/mm3 (100 × 109/L); hemoglobin
? 9.0 g/dL (1.4 mmol/L);
b. Renal function: serum creatinine ? 2.0 mg/dL (0.177 mmol/L);
c. Hepatic function: AST and ALT ? 1.5 × ULN unless liver metastases are present, then AST and ALT ? 5.0 × ULN; bilirubin ? 1.5 mg/dL (0.026 mmol/L).
9. The subject must have PTT ? 1.5 × ULN and INR ? 1.5.
10. Female subjects of childbearing potential must have a negative urine pregnancy
test within 7 days prior to initiation of treatment, must be surgically sterile and/or
post menopausal women must be amenorrheic for at least 12 months to be
considered of non-childbearing potential. Female subjects of childbearing
potential and male subjects must agree to use adequate contraception (one of the following listed below) prior to study entry, for the duration of study participation
and up to two months following completion of therapy.
? Total abstinence from sexual intercourse (minimum one complete menstrual
cycle);
? A vasectomized partner;
? Hormonal contraceptives (oral, parenteral or transdermal) for at least
3 months prior to study drug administration;
? Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal
ring with spermicidal jellies or cream).
11. The subject is capable of understanding and complying with parameters as
outlined in the protocol and able to sign and date the informed consent, approved
by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB),
prior to the initiation of any screening or study-specific procedures. |
|
| E.4 | Principal exclusion criteria |
1. The subject has received more than one prior therapy in the metastatic setting.
Lead-in Cohort only: The subject may have received more than one prior therapy
in the metastatic setting.
2. The subject has received cytotoxic chemotherapy (i.e. alkylating agents,
microtubule inhibitors, anti-metabolites) within 21 days prior to Study Day 1.
3. The subject has received non-cytotoxic, anti-cancer therapy within 21 days or
within a period defined by 5 half lives whichever is shorter, prior to study drug
administration. Anti-cancer therapies include, but are not limited to:
investigational agents (any agent not approved for use in humans),
immunotherapy, anti-cancer traditional Chinese medicine/herbal remedies,
hormonal, "targeted" agents (i.e., erlotinib, imatinib, sorafenib) or biologic
therapy.
4. The subject has not recovered to less than or equal to Grade 1 clinically significant
adverse effects/toxicities of the previous therapy.
5. The subject has received prior treatment with a tyrosine kinase inhibitor targeting
VEGF or PDGF.
6. The subject has received prior treatment for colorectal cancer with oxaliplatin in
the metastatic setting. Lead-in cohort only: Prior treatment with oxaliplatin will
be allowed provided that any neuropathy as a result of the oxaliplatin treatment has
resolved to less than or equal to Grade 1.
7. The subject has had major surgery within 28 days of Study Day 1.
8. The subject has had radiotherapy within 14 days of Study Day 1.
9. The subject has symptomatic or untreated brain or meningeal metastases. CT
scans are not required to rule out brain or meningeal metastases unless there is a
clinical suspicion of central nervous system disease. Subjects with treated brain
metastases that are radiographically or clinically stable for at least 4 weeks after
therapy and have no evidence of cavitation or hemorrhage in the brain lesion are
eligible providing that they are asymptomatic and do not require corticosteroids
(must have discontinued steroids at least 1 week prior to study drug
administration).
10. The subject has a history of hypersensitivity to recombinant murine monoclonal
antibodies, oxaliplatin or other platinum-containing compounds, 5-fluorouracil, or
folinic acid.
11. The subject has proteinuria CTC grade > 1 at baseline as measured by a urine
dipstick and confirmed by a 24-hour urine collection.
12. The subject is receiving therapeutic anticoagulation therapy. Low dose
anticoagulation (e.g., low dose warfarin) for catheter prophylaxis will be
permitted.
13. The subject has a history of, or currently exhibits, clinically significant cancer
related events of bleeding (e.g., gross hemoptysis defined as bright red blood of at
least ½ teaspoon or 2.5 mL per episode within three months prior to Study Day 1
unless definitively treated with surgery or radiation) or the subject has a recent
history of (within four weeks of Study Day 1) or currently exhibits other clinically
significant signs of bleeding.
14. The subject currently exhibits symptomatic or persistent, uncontrolled
hypertension defined as diastolic blood pressure (BP) > 90 mmHg; or systolic
blood pressure (BP) > 140 mmHg. Subjects may be re-screened if blood pressure
is shown to be controlled with or without intervention.
15. The subject has a history of myocardial infarction, stroke, or transient ischemic
attack (TIA) within six months of Study Day 1.
16. The subject has a history of abdominal fistula or gastrointestinal perforation within six months prior to Study Day 1.
17. The subject has a documented left ventricular (LV) ejection fraction < 50%.
18. The subject has known autoimmune disease with renal involvement (e.g., lupus).
19. The subject is receiving combination anti-retroviral therapy for HIV.
20. Female subject is pregnant or breast-feeding.
21. The subject has clinically significant uncontrolled condition(s) including but not
limited to:
? active uncontrolled infection,
? symptomatic congestive heart failure,
? unstable angina pectoris or cardiac arrhythmia,
? history of adrenal insufficiency,
? psychiatric illness/social situation that would limit compliance with study
requirements.
22. The subject has active ulcerative colitis, Crohn's disease, celiac disease or any
other conditions that interfere with absorption.
23. The subject has had another active malignancy within the past five years except for cervical cancer in situ, in situ carcinoma of the bladder or non-melanoma
carcinoma of the skin. Questions regarding inclusion of individual subjects should
be directed to the Abbott Medical Monitor.
24. The subject has a medical condition, which in the opinion of the study investigator, places them at an unacceptably high risk for toxicities. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is progression free survival. The secondary endpoints of the study will be overall survival, 12-month survival rate, time to disease progression, objective response rate, best response rate, best percent change in tumor size, duration of response, as well as the safety and tolerability of the combination. The tertiary endpoints are quality of life and performance status. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | Information not present in EudraCT |
| 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 | 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
|
| The date of the last subject?s last scheduled visit or the actual date of follow-up contact, whichever is longer. |
|
| 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 | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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