Advanced Solid TumorsPhase 1NCT01306630
A Trial of Tivozanib (AV-951) in Combination With Capecitabine (Xeloda®) in Subjects With Advanced Solid Tumors
A Phase 1 study testing tivozanib (AV-951) and capecitabine (Xeloda®) in people with Advanced Solid Tumors and Locally Advanced or Metastatic Breast or Colorectal Cancer, run by AVEO Pharmaceuticals, Inc. at 3 sites in United States.
Trial summary
This is an open-label, multi-center, dose-finding study of tivozanib administered in combination with capecitabine. During the dose-escalation portion, sequential cohorts of subjects with advanced solid tumors will be enrolled in order to establish the maximum tolerated dose (MTD). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Solid Tumors, Locally Advanced or Metastatic Breast or Colorectal Cancer
- What is being tested?
- tivozanib (AV-951) and capecitabine (Xeloda®)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 3 sitesUnited States
- Study dates
- Nov 2010to Jan 2014
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18 years or older, of either sex, and of any race.
- Histologically or cytologically confirmed solid tumor malignancy.
- Dose escalation cohorts: Advanced solid tumor malignancy (locally advanced or metastatic) that has recurred or progressed following standard therapy or for which no standard therapy currently exists, or for which subject is not a candidate for - standard therapy, or is unwilling to undergo standard therapy.
- MTD expansion cohort: Subjects must have locally advanced or metastatic breast or colorectal cancer with or without prior systemic therapy.
- ECOG performance ≤ 2 (Appendix B) and life expectancy ≥ 3 months.
- Disease that is not amenable to curative surgical intervention, due to either non-resectability of the tumor or medical contraindications.
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- Subjects enrolled in the MTD expansion cohort must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0.
- At least 4 weeks since :
- Vascular endothelial growth factor (VEGF) or VEGF receptor directed therapy
- Chemotherapy (6 weeks since prior mitomycin C or nitrosoureas)
- Immunotherapy (eg, IL-2, IFN, etc.) or biological therapy (eg, monoclonal antibodies)
- Investigational agents
- At least 2 weeks since:
- Systemic hormonal therapy (with the exception of hormone replacement therapy or low dose steroid therapy as described in Drugs and Treatments to be Excluded)
- Herbal preparations (including daily multivitamin/mineral supplements containing herbal components)
- At least 2 weeks since prior radiotherapy to ≤ 25% of bone marrow, or at least 4 weeks since prior radiotherapy to > 25% of bone marrow.
- If female and of child bearing potential, documentation of negative pregnancy test prior to enrollment.
- Sexually active pre-menopausal female subjects (and female partners of male subjects) must use adequate contraceptive measures, while on study and for 30 days after the last dose of study drug. All fertile subjects (and their partners) must agree to use a highly effective method of contraception. Effective birth control includes (a) IUD plus one barrier method; or (b) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). (Note: Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are not considered effective for this study.)
- Adequate hematologic function as evidenced by Hg ≥ 9g/dL, WBC ≥ 3000 per mm3, ANC ≥ 1500 per mm3 and platelet count ≥ 100,000 per mm3.
- Adequate hepatic function as evidenced by a serum bilirubin level ≤1.5 × ULN (except with known Gilbert's Syndrome) and serum AST/ALT levels ≤2.5 × ULN (or ≤5 × ULN for subjects with known hepatic metastasis).
- Adequate renal function as evidenced by a serum creatinine level ≤ 1.5 × ULN (subjects with a serum creatinine level >1.5 x ULN with a calculated creatinine clearance > 50 mL/min according to Cockcroft-Gault equation will be eligible).
- Proteinuria ≤3+ by urinalysis or urine dipstick (subjects with proteinuria >3 + may undergo a 24-hour urine protein and will be eligible if protein is <2 g/24hrs)
- Adequate coagulation parameters: PTT ≤ 1.5 x ULN and INR ≤ 1.5
- Ability to give written informed consent and comply with protocol requirements.
Who cannot join
- 1. Primary CNS malignancies or CNS metastases; subjects with previously treated brain metastasis will be allowed if the brain metastasis has been stable without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery). Subjects with symptoms of CNS metastases or history must have a CT or MRI scan including the brain during Screening.
- 2. Significant cardiovascular disease, including:
- Active clinically symptomatic left ventricular failure
- Uncontrolled hypertension: Systolic blood pressure > 140 mmHg or diastolic blood pressure >90 mmHg on 2 or more antihypertensive medications. Note: Initiation or adjustment of antihypertensive medication(s) is permitted during the screening period, in order to control a subject's BP prior to initiating treatment. Blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour. The SBP / DBP values from each blood pressure assessment must be ≤ 140/90 mmHg in order for a subject to be eligible for the study
- Myocardial infarction, severe or unstable angina within 6 months prior to administration of first dose of study drug
- History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation)
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- Cardiac arrhythmias requiring anti-arrhythmic medications
- History of coronary or peripheral artery bypass graft within 6 months
- 3. Significant thromboembolic or vascular disorders within 6 months prior to first dose of study drug; this does NOT include catheter-related thrombosis. Significant thromboembolic or vascular disorders include but are not limited to:
- Deep vein thrombosis
- Pulmonary embolism
- Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
- Symptomatic peripheral vascular disease
- 4. Subjects with non-healing wounds, active peptic ulcers, or unhealed bone fractures.
- 5. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
- 6. Known hypersensitivity to fluoropyrimidine therapy or to 5-fluorouracil.
- 7. Known inability to tolerate capecitabine (Xeloda®) due to unacceptable toxicities.
- 8. Serious active infection, (including active Hepatitis B or Hepatitis C) or infection requiring parenteral antibiotics.
- 9. Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug.
- 10. Significant bleeding disorders within 6 months prior to first dose of study drug, including but not limited to:
- Hematemesis, hematochezia, melena or other gastrointestinal bleeding
- Hemoptysis or other pulmonary bleeding
- Hematuria or other genitourinary bleeding
- 11. Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer and ductal or lobular carcinoma in situ of the breast. Subjects are not considered to have a currently active malignancy if they have completed anti-cancer therapy and have been disease free for >2 years.
- 12. Pregnant or lactating females.
- 13. Known concomitant genetic or acquired immune suppression disease such as HIV.
- 14. Centrally located lung cancer, or evidence of solid tumor invading major blood vessels on imaging.
- 15. Malabsorption, uncontrolled vomiting or diarrhea, or any disease significantly affecting gastrointestinal function that could interfere with absorption of study drugs, or inability to swallow oral drugs.
- Drugs and Treatments to be Excluded
- Chemotherapy, biological therapy (including cytokines, signal transduction inhibitors, monoclonal antibodies), immunotherapy or any other therapy for solid tumors.
- Systemic hormonal therapy, with the exception of:
- Hormonal therapy for appetite stimulation or contraception
- Nasal, ophthalmic, inhaled and topical steroid preparations
- Androgen suppression therapy for non-metastatic prostate carcinoma
- Hormone replacement therapy for conditions such as adrenal insufficiency, hypothyroidism, diabetes, etc.
- Low-dose maintenance steroid therapy (equivalent of prednisone ≤ 10 mg/day) for other conditions
- Treatment with radiotherapy (limited radiotherapy involving ≤ 25% of bone marrow may be allowed for palliative purposes after consultation with the medical monitor. Treatment with study drugs (tivozanib and capecitabine) must be stopped during radiotherapy).
- Herbal preparations/supplements (including daily multivitamin/mineral supplement containing herbal components).
- Treatment with full dose oral anticoagulants such as warfarin, acenocoumarol, fenprocoumon, or similar agents. If previously receiving these types of agents, a minimum washout of 1 week and documented INR of ≤ 1.5 will be required prior to start of therapy. Full dose anticoagulation with low molecular weight heparin or unfractionated heparin administered subcutaneously is allowed. Low dose oral anticoagulation (eg, 1-2 mg/day warfarin) is allowed provided INR remains ≤ 1.5 during the study.
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Study site
Fort Myers, Florida, 33908
Study site
Nashville, Tennessee, 37203
Study site
Scottsdale, Arizona, 85258
About this study
Official title: A Phase 1b, Open-Label, Dose-Escalating Trial of Tivozanib (AV-951) in Combination With Capecitabine (Xeloda®) in Subjects With Advanced Solid Tumors
This is an open-label, multi-center, dose-finding study of tivozanib administered in combination with capecitabine. During the dose-escalation portion, sequential cohorts of subjects with advanced solid tumors will be enrolled in order to establish the maximum tolerated dose (MTD). If the MTD is not reached, the recommended Phase 2 dose (RP2D) will be determined. In the expansion cohort, subjects with locally advanced or metastatic breast or colon cancer will be enrolled at MTD (or RP2D) to further evaluate safety and activity of this combination in these tumor types.
Read the detailed description
This is a Phase Ib, open-label, multi-center, dose-escalation study of orally administered tivozanib in combination with capecitabine to approximately 24 subjects with advanced solid tumors and, in the expanded MTD cohort, subjects with locally advanced or metastatic breast or colorectal cancer. This study is designed to evaluate the safety, tolerability, dose-limiting toxicities, maximum tolerated dose, pharmacokinetic, and antineoplastic activity. The number of cohorts evaluated and the maximum doses to be administered will depend upon the observed tolerability. Dose level "0", tivozanib HCl 1.5 mg and capecitabine 1000 mg/m² BID, is the starting dose level. Once assigned to a cohort, each subject will continue to be treated at the same dose level and schedule throughout the course of the study.
- Being tested
- tivozanib (AV-951) and capecitabine (Xeloda®)
- Keywords
- AV-951, tivozanib, capecitabine (Xeloda®)
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
tivozanib (AV-951) and capecitabine (Xeloda®)Drug
Tivozanib 1.0 mg or 1.5 mg oral once daily for 2 weeks followed by 1 week off. Capecitabine 825 mg/m2, 1000 mg/m2, or 1250 mg/m2, oral twice daily for 2 weeks followed by 1 week off. 1 cycle= 3 weeks. Cycles will be repeated in the absence of disease progression or unacceptable toxicity.
| Study group | Role | What they receive |
|---|---|---|
| tivozanib + capecitabine | Other | Not described Receives: Drug: tivozanib (AV-951) and capecitabine (Xeloda®) |
What is being measured
The primary outcome is the main question the study is designed to answer.
To determine the safety, tolerability, and maximum tolerated dose of tivozanib when administered in combination with capecitabine (Xeloda®) to subjects with advanced solid tumors
Assessment of any dose-limiting toxcities
Measured: daily for 6 weeks
Secondary outcomes (2)
Evaluate the pharmacokinetics of tivozanib, and capecitabine and its metabolites by measuring the serum plasma concentrations of tivozanib and capecitabine in the blood over time.
PK parameters of tivozanib and capecitabine will be calculated from serum and plasma levels. These will be summarized descriptively and presented by visit and dose cohort. PK parameters will be calculated using non compartmental and/or compartmental models and PK parameters will be summarized and presented. The mean (± STDEM) concentration-time profiles of tivozanib, capecitabine, and their metabolite(s) will be presented for each dose.
Measured: Cycle 1 (Days 1, 2, 8, 14, and 15), Cycle 2 (Days 1 and 14), Cycles 3, 5, 7, and 9 (Day 1 only).
To evaluate the antineoplastic activity of tivozanib and capecitabine, when given together, to slow the growth of or shrink tumor as measured by CT/MRI imaging assessment and according to RECIST criteria.
Disease and response assessments will be determined using Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Disease assessment is to include disease classification, tumor marker assessments, and diagnostic imaging / measurement of marker lesions. Computerized tomography (CT) will be considered the standard method for evaluating disease status. All subjects should have a CT scan (or MRI) of the head, chest, abdomen, and pelvis at baseline. The location and dimensions of "marker" lesions will be documented.
Measured: every 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Mar 2011 (estimated)
- Study startNov 2010
- Primary completionJan 2014
- Study completionJan 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced Solid TumorsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- AVEO Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Shefali Agarwal, M.D., Study director, AVEO Pharmaceuticals, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01306630
- Sponsor's protocol ID
- AV-951-10-114
- Status last verified
- Jan 2014
- First submitted
- 3 Nov 2010
- Last updated
- 27 Jan 2014
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Jan 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1b, Open-Label, Dose-Escalating Trial of Tivozanib (AV-951) in Combination With Capecitabine (Xeloda®) in Subjects With Advanced Solid Tumors
- ClinicalTrials.gov ID
- NCT01306630
- Acronym / sponsor ID
- AV-951-10-114
- Keywords
- AV-951, tivozanib, capecitabine (Xeloda®)
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- AVEO Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- Nov 2010
- Primary completion
- Jan 2014 (actual)
- Study completion
- Jan 2014 (actual)
- First posted
- 2 Mar 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is an open-label, multi-center, dose-finding study of tivozanib administered in combination with capecitabine. During the dose-escalation portion, sequential cohorts of subjects with advanced solid tumors will be enrolled in order to establish the maximum tolerated dose (MTD). If the MTD is not reached, the recommended Phase 2 dose (RP2D) will be determined. In the expansion cohort, subjects with locally advanced or metastatic breast or colon cancer will be enrolled at MTD (or RP2D) to further evaluate safety and activity of this combination in these tumor types.
Detailed description
This is a Phase Ib, open-label, multi-center, dose-escalation study of orally administered tivozanib in combination with capecitabine to approximately 24 subjects with advanced solid tumors and, in the expanded MTD cohort, subjects with locally advanced or metastatic breast or colorectal cancer. This study is designed to evaluate the safety, tolerability, dose-limiting toxicities, maximum tolerated dose, pharmacokinetic, and antineoplastic activity. The number of cohorts evaluated and the maximum doses to be administered will depend upon the observed tolerability. Dose level "0", tivozanib HCl 1.5 mg and capecitabine 1000 mg/m² BID, is the starting dose level. Once assigned to a cohort, each subject will continue to be treated at the same dose level and schedule throughout the course of the study.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| tivozanib + capecitabine | Other | Drug: tivozanib (AV-951) and capecitabine (Xeloda®) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- Age 18 years or older, of either sex, and of any race.
- Histologically or cytologically confirmed solid tumor malignancy.
- Dose escalation cohorts: Advanced solid tumor malignancy (locally advanced or metastatic) that has recurred or progressed following standard therapy or for which no standard therapy currently exists, or for which subject is not a candidate for - standard therapy, or is unwilling to undergo standard therapy.
- MTD expansion cohort: Subjects must have locally advanced or metastatic breast or colorectal cancer with or without prior systemic therapy.
- ECOG performance ≤ 2 (Appendix B) and life expectancy ≥ 3 months.
Key exclusion criteria (39 listed)
- 1. Primary CNS malignancies or CNS metastases; subjects with previously treated brain metastasis will be allowed if the brain metastasis has been stable without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery). Subjects with symptoms of CNS metastases or history must have a CT or MRI scan including the brain during Screening.
- 3. Significant thromboembolic or vascular disorders within 6 months prior to first dose of study drug; this does NOT include catheter-related thrombosis. Significant thromboembolic or vascular disorders include but are not limited to:
- 4. Subjects with non-healing wounds, active peptic ulcers, or unhealed bone fractures.
- 5. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
- 6. Known hypersensitivity to fluoropyrimidine therapy or to 5-fluorouracil.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| tivozanib (AV-951) and capecitabine (Xeloda®)Tivozanib 1.0 mg or 1.5 mg oral once daily for 2 weeks followed by 1 week off. Capecitabine 825 mg/m2, 1000 mg/m2, or 1250 mg/m2, oral twice daily for 2 weeks followed by 1 week off. 1 cycle= 3 weeks. Cycles will be repeated in the absence of disease progression or unacceptable toxicity. | Drug | tivozanib + capecitabine |
Primary outcome
To determine the safety, tolerability, and maximum tolerated dose of tivozanib when administered in combination with capecitabine (Xeloda®) to subjects with advanced solid tumors
Time frame: daily for 6 weeks
Assessment of any dose-limiting toxcities
2 secondary outcomes
Evaluate the pharmacokinetics of tivozanib, and capecitabine and its metabolites by measuring the serum plasma concentrations of tivozanib and capecitabine in the blood over time.
Time frame: Cycle 1 (Days 1, 2, 8, 14, and 15), Cycle 2 (Days 1 and 14), Cycles 3, 5, 7, and 9 (Day 1 only).
To evaluate the antineoplastic activity of tivozanib and capecitabine, when given together, to slow the growth of or shrink tumor as measured by CT/MRI imaging assessment and according to RECIST criteria.
Time frame: every 6 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jan 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Shefali Agarwal, M.D. study director
AVEO Pharmaceuticals, Inc.
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing tivozanib (AV-951) and capecitabine (Xeloda®) in people with Advanced Solid Tumors and Locally Advanced or Metastatic Breast or Colorectal Cancer, run by AVEO Pharmaceuticals, Inc. at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 39 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Jan 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To determine the safety, tolerability, and maximum tolerated dose of tivozanib when administered in combination with capecitabine (Xeloda®) to subjects with advanced solid tumors (time frame: daily for 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jan 2014.