Colorectal Cancer
Conditions
Keywords
Colorectal Cancer, Axitinib, FOLFOX/Bevacizumab
Brief summary
This is a non-randomized, open-label, Phase II trial investigating axitinib as a single-agent maintenance therapy following standard first-line FOLFOX/bevacizumab therapy for patients with mCRC.
Detailed description
All patients will receive FOLFOX/bevacizumab for four 28-day cycles (a total of 16 weeks). After 4 cycles, maintenance axitinib will be started. With approval of the Medical Monitor,patients who are having significant benefit from FOLFOX/bevacizumab may continue chemotherapy to a maximum of six 28-day cycles. During trial treatment, all patients will be assessed for response every 8 weeks (2 cycles).
Interventions
DRUGAxitinib
5-mg tablets PO BID
DRUGBevacizumab
5 mg/kg Days 1 and 15; IV
DRUG5-Fluorouracil
400 mg/m2 Days 1 and 15; IV
DRUGLeucovorin
400 mg/m2 Days 1 and 15; IV
DRUGOxaliplatin
85 mg/m2 Days 1 and 15; IV
Sponsors
Pfizer
SCRI Development Innovations, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum. * Patients must have measurable disease per RECIST Version 1.1. * No previous systemic therapy for metastatic colorectal cancer. Previous radiosensitizing chemotherapy is allowed, if completed at least 4 weeks prior to Cycle 1 Day 1 of study treatment, and previous neoadjuvant and/or adjuvant chemotherapy is allowed, if completed at least 6 months prior to diagnosis of metastatic disease. * Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1. * Life expectancy \>=12 weeks. * Adequate hematologic, renal and hepatic function * Patients who are on coumadin should have an INR value within the therapeutic range (i.e., 2 to 3 x ULN). Patients who are on stable, chronic doses of coumadin are eligible. * Male patients willing to use adequate contraceptive measures. Female patients who are not of child-bearing potential, and female patients of child-bearing potential who agree to use adequate contraceptive measures, who are not breastfeeding, and who have a negative serum or urine pregnancy test performed within 72 hours prior to start of treatment. * Willingness and ability to comply with the trial and follow-up procedures. * Ability to understand the investigative nature of this trial and give written informed consent.
Exclusion criteria
* History or known presence of central nervous system (CNS) metastases. * Patients who have had a major surgical procedure (not including mediastinoscopy), or significant traumatic injury \<=4 weeks prior to beginning treatment. * Women who are pregnant or lactating. All females of child-bearing potential must have negative serum or urine pregnancy tests within 72 hours prior to study treatment (see Appendix D) * History of hypersensitivity to active or inactive excipients of any component of treatment (5 fluorouracil, bevacizumab, oxaliplatin, or axitinib), or known dipyrimidine dehydrogenase deficiency. * Patients with proteinuria at screening as demonstrated by: * Urine dipstick for proteinuria \>=2+ (patients discovered to have \>=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection, and must demonstrate \<=1 g of protein/24 hours to be eligible) * Patients with a serious non healing wound, active ulcer, or untreated bone fracture. * Patients with evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). * Patients with history of hematemesis or hemoptysis (defined as having bright red blood of ½ teaspoon or more per episode) \<=1 month prior to study enrollment. * Patients requiring concomitant treatment with potent CYP3A4 or CYP1A2 inducers and CYP3A4 inhibitors. * History of myocardial infarction or unstable angina \<=6 months prior to beginning treatment. * Inadequately controlled hypertension (defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 mmHg while on antihypertensive medications). Initiation of antihypertensive agents is permitted provided adequate control is documented at least 1 week prior to Day 1 of study treatment. * New York Heart Association Grade II or greater congestive heart failure. * Serious cardiac arrhythmia requiring medication. Patients with chronic, rate-controlled atrial fibrillation are eligible. * Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) \<=6 months prior to Day 1 of treatment. * History of stroke or transient ischemic attack \<=6 months prior to beginning treatment. * Any prior history of hypertensive crisis or hypertensive encephalopathy. * History of abdominal fistula or gastrointestinal perforation \<=6 months prior to Day 1 of beginning treatment. * Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements. * Any known positive test for human immunodeficiency virus, hepatitis C virus or acute or chronic hepatitis B infection. * Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study. * Use of any non-approved or investigational agent \<=28 days prior to administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study. * Past or current history of neoplasm other than the entry diagnosis with the exception of treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other cancers cured by local therapy alone and a disease free survival \>=5 years. * Infection requiring IV antibiotics. * Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g. active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or significant small bowel resection). * Inability to swallow whole tablets. * Patients with \> Grade 2 peripheral neuropathy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 24 months | Defined as the time from first treatment until objective tumor progression or death from any cause, assessed according to Response Evaluation Criteria for Solid Tumors (RECIST) v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | every 8 weeks until progression then every 3 months for up to 5 years. | Defined as the time from first treatment until death from any cause. |
| Objective Response Rate | every 8 weeks, assessed up to approximately 24 months | Defined as the percentage of evaluable patients showing a complete or partial response (CR or PR) per RECIST v1.1 criteria. CR = disappearance of all lesions. PR = at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease (SD) = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest (nadir) sum LD since start of treatment. |
| Time To Progression (TTP) | every 8 weeks, assessed approximately up to 24 months | Defined as the time after a disease is diagnosed (or treated) until worsening of the disease. |
| Frequency of Adverse Events as a Measure of Safety | Every 4 weeks plus 30 days during treatment and up to 5 years thereafter. | The frequency of adverse events (AEs) was analyzed in 2 groups of patients, those receiving FOLFOX/bevacizumab (N=70), and patients who received axitinib maintenance (N = 48). AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0. |
Countries
United States
Participant flow
Recruitment details
Between January 2012 and January 2014, 70 patients with histologically or cytologically confirmed metastatic carcinoma of colon or rectum were enrolled and treated. The trial was conducted at 12 sites in the United States.
Pre-assignment details
In this non-randomized open label trial, patients began treatment with FOLFOX/bevacizumab every 4 weeks for 16 weeks. Patients with objective response or stable disease began Axitinib maintenance therapy at week 17. Axitinib therapy continued until disease progression, unacceptable toxicity or did not meet any criteria for discontinuation.
Participants by arm
| Arm | Count |
|---|---|
| FOLFOX/Bevacizumab and Axitinib All patients receive FOLFOX/bevacizumab for four 28-day cycles (a total of 16 weeks). After 4 cycles, axitinib maintenance will be administered. FOLFOX is a combination of Leucovorin, fluorouracil and oxiloplatin.
FOLFOX/bevacizumab:
* 5-Fluorouracil: 400 mg/m2 Days 1 and 15 by IV followed by 2400 mg/m2 over 46-48 hours Days 1 and 15 by continuous infusion;
* Leucovorin: 400 mg/m2 given Days 1 and 15 by IV
* Oxaliplatin: 85 mg/m2 Days 1 and 15 by IV
* Bevacizumab: 5 mg/kg on Days 1 and 15 by;IV
Maintenance:
\- Axitinib: 5-mg tablets orally twice per day (PO BID) | 70 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Axitinib Maintenance Therapy | Adverse Event | 12 |
| Axitinib Maintenance Therapy | Disease Progression | 30 |
| Axitinib Maintenance Therapy | Intercurrent illness | 2 |
| Axitinib Maintenance Therapy | Protocol Violation | 2 |
| Axitinib Maintenance Therapy | Withdrawal by Subject | 3 |
| FOLFOX/Bevacizumab Treatment | Adverse Event | 6 |
| FOLFOX/Bevacizumab Treatment | Disease Progression | 6 |
| FOLFOX/Bevacizumab Treatment | Intercurrent illness | 1 |
| FOLFOX/Bevacizumab Treatment | Physician Decision | 2 |
| FOLFOX/Bevacizumab Treatment | Protocol Violation | 1 |
| FOLFOX/Bevacizumab Treatment | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | FOLFOX/Bevacizumab and Axitinib |
|---|---|
| Age, Continuous | 60 years |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Black/African American | 6 participants |
| Race/Ethnicity, Customized Caucasian | 62 participants |
| Race/Ethnicity, Customized Unknown | 1 participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 70 / 70 |
| serious Total, serious adverse events | 13 / 70 |
Outcome results
Primary
Progression-free Survival
Defined as the time from first treatment until objective tumor progression or death from any cause, assessed according to Response Evaluation Criteria for Solid Tumors (RECIST) v1.1.
Time frame: 24 months
Population: All patients who received at least one dose of any study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX/Bevacizumab and Axitinib | Progression-free Survival | 8.3 months |
Secondary
Frequency of Adverse Events as a Measure of Safety
The frequency of adverse events (AEs) was analyzed in 2 groups of patients, those receiving FOLFOX/bevacizumab (N=70), and patients who received axitinib maintenance (N = 48). AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0.
Time frame: Every 4 weeks plus 30 days during treatment and up to 5 years thereafter.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Thrombocytopenia | 22 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Myalgia | 8 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Fatigue | 40 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Nausea | 37 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Diarrhea | 34 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Peripheral neuropathy | 34 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Neutropenia | 25 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Dizziness | 8 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Leukopenia | 21 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Anorexia | 19 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Mucositis | 18 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Proteinuria | 16 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Anemia | 16 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Constipation | 15 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Pain | 14 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Vomiting | 14 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Hypertension | 11 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Headache | 9 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Skin changes | 7 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Arthralgia | 7 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Hand-foot skin reaction | 0 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Dyspnea | 0 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | Hoarseness | 0 participants |
| FOLFOX/Bevacizumab and Axitinib | Frequency of Adverse Events as a Measure of Safety | AST increased | 0 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Hoarseness | 7 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Anemia | 7 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Skin changes | 0 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Fatigue | 24 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Constipation | 0 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Nausea | 15 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Dyspnea | 7 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Diarrhea | 16 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Pain | 11 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Peripheral neuropathy | 16 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Arthralgia | 6 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Neutropenia | 0 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Dizziness | 0 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Myalgia | 10 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Vomiting | 0 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Thrombocytopenia | 8 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | AST increased | 5 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Leukopenia | 7 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Hypertension | 22 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Anorexia | 14 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Hand-foot skin reaction | 7 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Mucositis | 5 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Headache | 7 participants |
| Axitinib | Frequency of Adverse Events as a Measure of Safety | Proteinuria | 12 participants |
Secondary
Objective Response Rate
Defined as the percentage of evaluable patients showing a complete or partial response (CR or PR) per RECIST v1.1 criteria. CR = disappearance of all lesions. PR = at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease (SD) = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest (nadir) sum LD since start of treatment.
Time frame: every 8 weeks, assessed up to approximately 24 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFOX/Bevacizumab and Axitinib | Objective Response Rate | Objective Response | 34 percentage of participants |
| FOLFOX/Bevacizumab and Axitinib | Objective Response Rate | Stable Disease | 57 percentage of participants |
Secondary
Overall Survival (OS)
Defined as the time from first treatment until death from any cause.
Time frame: every 8 weeks until progression then every 3 months for up to 5 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX/Bevacizumab and Axitinib | Overall Survival (OS) | 24.2 months |
Secondary
Time To Progression (TTP)
Defined as the time after a disease is diagnosed (or treated) until worsening of the disease.
Time frame: every 8 weeks, assessed approximately up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX/Bevacizumab and Axitinib | Time To Progression (TTP) | 8.8 months |