Combretastatin A4 PhosphatePhase 1/2NCT01570790
Combretastatin A4 Phosphate in Patients With Neovascular Age-Related Macular Degeneration
A Phase 1/2 study testing Combretastatin A-4 phosphate in people with Combretastatin A4 Phosphate and Age-related Macular Degeneration, run by Johns Hopkins University at 1 site in United States.
Trial summary
The purpose of the study is assess safety, bioactivity, and maximal tolerated dose of repeated weekly intravenous infusion of combretastatin A-4 phosphate (CA4P) in patients with neovascular age-related macular degeneration Read more about this study
- Who is it for?
- Ages 50 years and older
- Conditions the study is for
- Combretastatin A4 Phosphate, Age-related Macular Degeneration, AMD
- What is being tested?
- Combretastatin A-4 phosphate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- May 2003to Jun 2005
- Phase
- Phase 1/2
- 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 50 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 50 years or older;
- 12-lead electrocardiogram (ECG) performed at least 2 weeks but less than 4 weeks prior to entry into the study showing a QTc <440 with no evidence of current or prior myocardial ischemia, infarction or significant arrhythmia as determined by review and signature of the cardiologist.
- Adequate bone marrow function:
- Absolute granulocyte count ≥1500 cells/mm3; Platelet count ≥100,000 cells/mm3; Hemoglobin ≥9.0gm/ dL;
- PT/PTT within the institution upper limit of normal (ULN) or INR <1.1 ;
- Adequate hepatic function:
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- Total bilirubin within the institution ULN; Alanine and aspartate aminotransferase (ALT/AST) <3 times the institutional ULN;
- Adequate renal function: serum creatinine ≤2.0 mg/dL;
- Ophthalmic criteria:
- Best corrected visual acuity in the study eye of ≤20/40 and ≥20/800 in the fellow eye.
- Subfoveal choroidal neovascularization (as illustrated by fluorescein angiography) secondary to age-related macular degeneration, with a total lesion size of ≤12 total disc areas, of which at least 50% must be active CNV.
- Subretinal hemorrhage ≤50% of total lesion size;
- For patients with minimally classic and purely occult CNV, there must be documented evidence of ≥2 lines of vision loss (ETDRS) during the previous 12 weeks;
- Clear ocular media and adequate papillary dilatation to permit good quality stereoscopic fundus photography;
- Male fertile patients must abstain from sexual intercourse or use effective birth control;
- Women must be post-menopausal for at least 12 months prior to study entry, or surgically sterile, or must be using two forms of effective contraception.
- Able to return for all study visits within required visit windows;
- Be able to give written informed consent.
Who cannot join
- Previous subfoveal thermal laser therapy;
- Any subfoveal scarring or atrophy, or >25% of the total lesion size is made up of scarring or atrophy;
- Significant media opacities, including cataract, which can interfere with visual acuity, assessment of toxicity, or fundus photography;
- Presence of other causes of choroidal neovascularization, including pathologic myopia (spherical equivalent of ≥-8.0 diopters, or axial length of ≥25mm), ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, and multifocal choroiditis and other uveitic entities;
- Any condition that might interfere with assessment of the progression of CNV;
- Any intraocular surgery in the study eye within 12 weeks of screening for the study;
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- Other treatment for AMD of the study eye within 12 weeks prior to screening;
- Known allergy to fluorescein;
- Any current or history of significant gastrointestinal, oral, or nasal bleeding;
- Serious intercurrent infections or other nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this therapy;
- Grade 2 (CTC v.3.0) or greater pre-existing peripheral neuropathy;
- Psychiatric disorders or other conditions rendering patients incapable of complying with the requirements of the protocol;
- Pregnant or breast-feeding women;
- History of angina, myocardial infarction, CHF, non-controlled atrial arrhythmias or clinically significant arrhythmias including conduction abnormality, nodal junctional arrhythmias and dysrhythmias, sinus bradycardia or tachycardia, supraventricular arrhythmias, atrial fibrillation or flutter, syncope or vasovagal episodes;
- Abnormal cardiac stress test;
- Uncontrolled hypertension (consistently >150/100mmHg irrespective of medication);
- Uncontrolled hypokalemia and/or hypomagnesemia;
- ECG with evidence of prior myocardial infarction, QTc > 450 msec or other clinically significant abnormalities;
- Drug(s) known to prolong the QTc interval;
- Patients with conditions associated with QTc prolongation;
- Any investigational drug or device within 4 weeks prior to screening;
- Decreased ejection fraction ≤50% or prior myocardial infarction.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: An Open Label, Pilot (Phase I/II), Dose-Escalation Safety and Tolerability Study of Combretastatin A4 Phosphate in Patients With Neovascular Age-Related Macular Degeneration.
The purpose of the study is assess safety, bioactivity, and maximal tolerated dose of repeated weekly intravenous infusion of combretastatin A-4 phosphate (CA4P) in patients with neovascular age-related macular degeneration
Read the detailed description
The study is designed as a single escalating dose with cohorts of five subjects. Escalation to the next cohort was based on the presence of no more than one subject with a dose limiting toxicity (DLT). The first cohort is to receive 27 mg/m2 intravenous infusion of of CA4P, 36mg/m2 to the second cohort, and 45mg/m2 to the third cohort. CA4P will be infused at baseline and every week for a total of 4 doses. Follow up visits will be scheduled at week 8 and 12.
Safety data will be collected during the 12-week duration of the study and will be assessed using the common terminology criteria of adverse events (CTCAE v3.0). Bioactivity data will be assessed by measuring change in best corrected visual acuity, changes in central retinal thickness as measured by Optical coherence tomography, and changes in the amount of leakage on fluorescein angiography.
DLTs were defined as specific events that are considered to be probably or definitely related to CA4P. Major DLTs included QTc interval ≥ 500 msec (based on measurements provided by the core laboratory for ECG analysis), Grade-2 or greater ventricular arrhythmia, unexplained syncope, Grade-3 or greater toxicity, delayed recovery postponing re-treatment by >14 days, and ocular toxicity such as keratopathy, uveitis, optic neuropathy, and retinopathy, at the discretion of the investigator.
- Conditions
- Combretastatin A4 Phosphate, Age-related Macular Degeneration, AMD, CNV, Choroidal Neovascularization
- Being tested
- Combretastatin A-4 phosphate
- Medical subject headings
- Macular Degeneration, Choroidal Neovascularization
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Combretastatin A-4 phosphateDrug
Also called fosbretabulin disodium
27 mg/m2 CA4P IV infusion at baseline and every week for 4 doses
Combretastatin A-4 PhosphateDrug
Also called fosbretabulin disodium
36 mg/m2 CA4P IV infusion at baseline and every week for 4 doses
Combretastatin A-4 PhosphateDrug
Also called fosbretabulin disodium
45 mg/m2 CA4P IV infusion at baseline and every week for 4 doses
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 | Experimental | Not described Receives: Drug: Combretastatin A-4 phosphate |
| Cohort 2 | Experimental | Not described Receives: Drug: Combretastatin A-4 Phosphate |
| Cohort 3 | Experimental | Not described Receives: Drug: Combretastatin A-4 Phosphate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety and Tolerability
To report frequency and severity of adverse events, as defined by the common terminology criteria of adverse events (CTCAE v.3.0; National Cancer Institute), and to determine the degree of relationship of adverse events to the study drug (CA4P).
Measured: 12 weeks after the first infusion of the Study Drug
Dose Limiting Toxicities (DLT)
DLT is defined as any of the following adverse events if ≥Grade-2 in severity: ventricular arrhythmia, second or third degree AV block, severe sinus bradycardia < 45 bpm, tachycardia >120 bpm, supraventricular arrhythmia > 24 hours, ventricular tachycardia (>9 beats in a row), any length of torsades de pointes, unexplained recurrent syncope, QTc prolongation ≥500 msec on > 2 consecutive ECGs, Grade-2 or greater myocardial infarction, or ocular toxicities deemed by the investigator not acceptable for the patients to receive further treatments.
Measured: 12 weeks after the first infusion of the study drug
Secondary outcomes (3)
Maximum Tolerated Dose
Maximum Tolerated Dose (MTD) of intravenous infusion of combretastatin A-4 phosphate in patients with neovascular age related macular degeneration. The MTD is defined as the maximum dose level of CA4P administered at which, DLT is observed in fewer than 2 patients at a given cohort.
Measured: 12 weeks after the first infusion of the study drug
Change in Best Corrected Visual Acuity
Difference change from baseline in Best corrected visual acuity, as measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, at week 4 and week 12.
Measured: 4 and 12 weeks after first infusion of the study drug
Change in Central Retinal Thickness
Difference change from baseline in central retinal thickness as measured by Optical Coherence Tomography at week 4 and week 12.
Measured: 4 and 12 weeks following the first infusion of CA4P
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Apr 2012 (estimated)
- Study startMay 2003
- Primary completionJun 2005
- Study completionJun 2005
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Combretastatin A4 PhosphateStudies of the same condition, open and under way.
- More trials run by Johns Hopkins UniversityThe sponsor's other registered studies.
- 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 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Quan D Nguyen, MD, MSc, Principal investigator, Wilmer Eye Institute - Johns Hopkins University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01570790
- Sponsor's protocol ID
- FBO-206
- Status last verified
- Dec 2017
- First submitted
- 2 Apr 2012
- Last updated
- 6 Dec 2017
- Results posted
- No
- Data monitoring committee
- No
Publications
Ibrahim MA, Do DV, Sepah YJ, Shah SM, Van Anden E, Hafiz G, Donahue JK, Rivers R, Balkissoon J, Handa JT, Campochiaro PA, Nguyen QD. Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin A-4 phosphate. BMC Pharmacol Toxicol. 2013 Jan 14;14:7. doi: 10.1186/2050-6511-14-7.
PubMed 23316779
Study at a glance
From the registry record, last updated by the sponsor on 6 Dec 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open Label, Pilot (Phase I/II), Dose-Escalation Safety and Tolerability Study of Combretastatin A4 Phosphate in Patients With Neovascular Age-Related Macular Degeneration.
- ClinicalTrials.gov ID
- NCT01570790
- Acronym / sponsor ID
- FBO-206
- Conditions
- Combretastatin A4 Phosphate, Age-related Macular Degeneration, AMD, CNV, Choroidal Neovascularization
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Study start
- May 2003
- Primary completion
- Jun 2005 (actual)
- Study completion
- Jun 2005 (actual)
- First posted
- 4 Apr 2012 (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.
The purpose of the study is assess safety, bioactivity, and maximal tolerated dose of repeated weekly intravenous infusion of combretastatin A-4 phosphate (CA4P) in patients with neovascular age-related macular degeneration
Detailed description
The study is designed as a single escalating dose with cohorts of five subjects. Escalation to the next cohort was based on the presence of no more than one subject with a dose limiting toxicity (DLT). The first cohort is to receive 27 mg/m2 intravenous infusion of of CA4P, 36mg/m2 to the second cohort, and 45mg/m2 to the third cohort. CA4P will be infused at baseline and every week for a total of 4 doses. Follow up visits will be scheduled at week 8 and 12.
Safety data will be collected during the 12-week duration of the study and will be assessed using the common terminology criteria of adverse events (CTCAE v3.0). Bioactivity data will be assessed by measuring change in best corrected visual acuity, changes in central retinal thickness as measured by Optical coherence tomography, and changes in the amount of leakage on fluorescein angiography.
DLTs were defined as specific events that are considered to be probably or definitely related to CA4P. Major DLTs included QTc interval ≥ 500 msec (based on measurements provided by the core laboratory for ECG analysis), Grade-2 or greater ventricular arrhythmia, unexplained syncope, Grade-3 or greater toxicity, delayed recovery postponing re-treatment by >14 days, and ocular toxicity such as keratopathy, uveitis, optic neuropathy, and retinopathy, at the discretion of the investigator.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Experimental | Drug: Combretastatin A-4 phosphate |
| Cohort 2 | Experimental | Drug: Combretastatin A-4 Phosphate |
| Cohort 3 | Experimental | Drug: Combretastatin A-4 Phosphate |
Who may qualify
- Ages
- 50 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- Age 50 years or older;
- 12-lead electrocardiogram (ECG) performed at least 2 weeks but less than 4 weeks prior to entry into the study showing a QTc <440 with no evidence of current or prior myocardial ischemia, infarction or significant arrhythmia as determined by review and signature of the cardiologist.
- Adequate bone marrow function:
- Absolute granulocyte count ≥1500 cells/mm3; Platelet count ≥100,000 cells/mm3; Hemoglobin ≥9.0gm/ dL;
- PT/PTT within the institution upper limit of normal (ULN) or INR <1.1 ;
Key exclusion criteria (22 listed)
- Previous subfoveal thermal laser therapy;
- Any subfoveal scarring or atrophy, or >25% of the total lesion size is made up of scarring or atrophy;
- Significant media opacities, including cataract, which can interfere with visual acuity, assessment of toxicity, or fundus photography;
- Presence of other causes of choroidal neovascularization, including pathologic myopia (spherical equivalent of ≥-8.0 diopters, or axial length of ≥25mm), ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, and multifocal choroiditis and other uveitic entities;
- Any condition that might interfere with assessment of the progression of CNV;
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 |
|---|---|---|
| Combretastatin A-4 phosphateAlso: fosbretabulin disodium27 mg/m2 CA4P IV infusion at baseline and every week for 4 doses | Drug | Cohort 1 |
| Combretastatin A-4 PhosphateAlso: fosbretabulin disodium36 mg/m2 CA4P IV infusion at baseline and every week for 4 doses | Drug | Cohort 2 |
| Combretastatin A-4 PhosphateAlso: fosbretabulin disodium45 mg/m2 CA4P IV infusion at baseline and every week for 4 doses | Drug | Cohort 3 |
Primary outcome
Safety and Tolerability
Time frame: 12 weeks after the first infusion of the Study Drug
To report frequency and severity of adverse events, as defined by the common terminology criteria of adverse events (CTCAE v.3.0; National Cancer Institute), and to determine the degree of relationship of adverse events to the study drug (CA4P).
Dose Limiting Toxicities (DLT)
Time frame: 12 weeks after the first infusion of the study drug
DLT is defined as any of the following adverse events if ≥Grade-2 in severity: ventricular arrhythmia, second or third degree AV block, severe sinus bradycardia < 45 bpm, tachycardia >120 bpm, supraventricular arrhythmia > 24 hours, ventricular tachycardia (>9 beats in a row), any length of torsades de pointes, unexplained recurrent syncope, QTc prolongation ≥500 msec on > 2 consecutive ECGs, Grade-2 or greater myocardial infarction, or ocular toxicities deemed by the investigator not acceptable for the patients to receive further treatments.
3 secondary outcomes
Maximum Tolerated Dose
Time frame: 12 weeks after the first infusion of the study drug
Change in Best Corrected Visual Acuity
Time frame: 4 and 12 weeks after first infusion of the study drug
Change in Central Retinal Thickness
Time frame: 4 and 12 weeks following the first infusion of CA4P
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 6 Dec 2017.
- Derived from this study: PubMed 23316779Ibrahim MA, Do DV, Sepah YJ, Shah SM, Van Anden E, Hafiz G, Donahue JK, Rivers R, Balkissoon J, Handa JT, Campochiaro PA, Nguyen QD. Vascular disrupting agent for neovascular age related macular degeneration: a pilot study of the safety and efficacy of intravenous combretastatin A-4 phosphate. BMC Pharmacol Toxicol. 2013 Jan 14;14:7. doi: 10.1186/2050-6511-14-7.
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.
Quan D Nguyen, MD, MSc principal investigator
Wilmer Eye Institute - Johns Hopkins University School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Combretastatin A-4 phosphate in people with Combretastatin A4 Phosphate and Age-related Macular Degeneration, run by Johns Hopkins University at 1 site 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 18 inclusion and 22 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 6 Dec 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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 combined 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.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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?
Safety and Tolerability (time frame: 12 weeks after the first infusion of the Study Drug). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01570790, which also lists 1 linked publication.
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 6 Dec 2017.