Neuroendocrine TumorsPhase 1NCT03014297
Fosbretabulin With Everolimus in Neuroendocrine Tumors With Progression
A Phase 1 study testing everolimus and fosbretabulin in people with Neuroendocrine Tumors and Everolimus, run by Lowell Anthony, MD at 1 site in United States.
Trial summary
This is a single center, open label, phase I study involving grade I-III gastroenteropancreatic neuroendocrine tumors, consisting of a dose escalation Part A followed by an expansion cohort Part B. On Part A Patients will be treated with daily oral everolimus. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Neuroendocrine Tumors, Everolimus
- What is being tested?
- everolimus and fosbretabulin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteUnited States
- Study dates
- 6 Mar 2017to 16 Nov 2018
- 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
- Patients must have histologically confirmed neuroendocrine tumor (grades 1-3) that is metastatic or unresectable, and for which standard curative or palliative measures do not exist or are no longer effective.
- Prior treatment with fosbretabulin is allowed, if not given in combination with everolimus.
- Prior treatment with everolimus is allowed, if the patient was able to tolerate 10 mg daily everolimus with acceptable side effects, and if everolimus was not given in combination with fosbretabulin. A 1 week washout period will be required if patient was previously on everolimus.
- Age ≥18 years.
- ECOG performance status ≤2.
- Life expectancy greater than 6 months.
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- Progressive disease based on radiological imaging within 12 months. RECIST 1.1 would be used to assess measurable disease burden.
- Patients must have normal organ and marrow function as defined below:
- absolute neutrophil count ≥1,000/mcL
- platelets ≥75,000/mcL
- total bilirubin ≤2.5 × institutional upper limit of normal
- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
- creatinine within normal institutional limits OR
- creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
- Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
- Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of fosbretabulin and everolimus administration.
- Ability to understand and the willingness to sign a written informed consent document.
Who cannot join
- Patients who have had prior everolimus but were not able to tolerate a 10 mg daily dose.
- Prior chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
- Child Pugh Class B or greater hepatic dysfunction.
- Patients who are receiving any other investigational agents.
- Patients with known brain metastases because of their poor prognosis and likelihood to develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to fosbretabulin
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- Uncontrolled hypertension (HTN); sustained blood pressure (BP) greater than 150/100 mmHg
- Must not have had any unstable angina or myocardial infarction within 4 months prior to enrollment to treatment, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker.
- Must not have any evidence of other clinically active cancer and have no history of prior malignancy within the past 3 years with the exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less and with stable prostatespecific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival for the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal glands or pancreas.
- Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
- Pregnant women are excluded from this study because everolimus and fosbretabulin have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events to nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated with everolimus and fosbretabulin.
- HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with everolimus and fosbretabulin. In addition, these patients are at increased risk of lethal infections when treated with marrowsuppressive therapy. Appropriate studies will be initiated for patients receiving combination antiretroviral therapy when indicated.
- History of prior cerebrovascular event, (including transient ischemic attack) within 6 months of start of screening.
- Current thrombotic or hemorrhagic disorder/event or history of prior event within 6 months of start of Screening
- Corrected QT interval ([QTc] Fridericia) > 480 ms
- Significant vascular disease or recent peripheral arterial thrombosis
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Kentucky Markey Cancer Center
Lexington, Kentucky, 40502
About this study
Official title: A Phase 1 Study of Fosbretabulin in Combination With Everolimus in Neuroendocrine Tumors (Grades 1-3) That Have Progressed After at Least One Prior Regimen for Metastatic Disease
This is a single center, open label, phase I study involving grade I-III gastroenteropancreatic neuroendocrine tumors, consisting of a dose escalation Part A followed by an expansion cohort Part B. On Part A Patients will be treated with daily oral everolimus. Fosbretabulin will be administered IV either q3 weekly or q weekly based on PO CRM cohort. Part B: Once the investigators have established an MTD in Part A, the investigators will be treating 15 more patients at that dose combination. The primary and secondary objectives of the expansion cohort will be similar to Part A of the study, i.e., to establish a safety profile of the experimental drug combination and to collect and assess efficacy data. Patients will be treated with concurrent everolimus and fosbretabulin for 12 weeks.
Read the detailed description
A variety of treatment options are available for NETs with carcinoid syndrome including surgical and medical therapies. Most subjects require somatostatin analogs to control the symptoms of carcinoid syndrome. Subjects who no longer respond to somatostatin and other liver-directed therapies, who experience progression of disease and increasing symptoms have limited options, including participation in a clinical trial. Recently everolimus and sunitinib have been approved for the treatment of subjects with progressive locally advanced or metastatic neuroendocrine tumors. Based on the preclinical data in models of NETs and the clinical activity seen in NETS and other tumor types that have existing tumor vascculature, this study will examine the effectiveness of fosbretabulin given in combination with everolimus in subjects with GI-NETs and PNETs.The vasoconstrictive effect of fosbretabulin is potent, though short-lived (4-8 hours), with no cumulative adverse effect. Everolimus inhibits angiogenesis, slows tumor growth and has a prolonged half-life (30 hours). Combining these two agents with distinctly different mechanisms of action may improve tumor control without additional toxicities, and has the potential of reducing drug resistance.
- Conditions
- Neuroendocrine Tumors, Everolimus
- Being tested
- everolimus, fosbretabulin
- Medical subject headings
- Neuroendocrine Tumors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
everolimusDrug
everolimus
fosbretabulinDrug
fosbretabulin
| Study group | Role | What they receive |
|---|---|---|
| everolimus + fosbretabulin | Experimental | everolimus + fosbretabulin Receives: Drug: everolimus; Drug: fosbretabulin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD)
To establish the maximum tolerated dose of the combination of everolimus plus fosbretabulin in neuroendocrine tumors (Grades 1-3) who have progressed after at least one prior regimen for metastatic disease.
Measured: 12 weeks
Secondary outcomes (2)
Incidence of Toxicities
Incidence of patients reporting at least one adverse event per NCI CTCAE v4.0
Measured: 12 weeks
Anti-tumor activity
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes.
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jan 2017 (estimated)
- Study start6 Mar 2017
- Primary completion5 Jun 2018
- Study completion16 Nov 2018
Why it stopped: Part I completed. Part 2 will not be done due to sponsor decision.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Neuroendocrine 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
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Lowell Anthony, MD
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Lowell Anthony, MD, University of Kentucky
- Investigators
- Lowell Anthony, MD, Principal investigator, University of Kentucky
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03014297
- Sponsor's protocol ID
- MCC-16-GI-99-PMC
- Status last verified
- Aug 2019
- First submitted
- 21 Dec 2016
- Last updated
- 8 Aug 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 Study of Fosbretabulin in Combination With Everolimus in Neuroendocrine Tumors (Grades 1-3) That Have Progressed After at Least One Prior Regimen for Metastatic Disease
- ClinicalTrials.gov ID
- NCT03014297
- Acronym / sponsor ID
- MCC-16-GI-99-PMC
- Conditions
- Neuroendocrine Tumors, Everolimus
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Part I completed. Part 2 will not be done due to sponsor decision.
- Enrolment
- 17 participants (actual)
- Lead sponsor
- Lowell Anthony, MDUniversity, hospital or other
- Study start
- 6 Mar 2017 (actual)
- Primary completion
- 5 Jun 2018 (actual)
- Study completion
- 16 Nov 2018 (actual)
- First posted
- 9 Jan 2017 (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 a single center, open label, phase I study involving grade I-III gastroenteropancreatic neuroendocrine tumors, consisting of a dose escalation Part A followed by an expansion cohort Part B. On Part A Patients will be treated with daily oral everolimus. Fosbretabulin will be administered IV either q3 weekly or q weekly based on PO CRM cohort. Part B: Once the investigators have established an MTD in Part A, the investigators will be treating 15 more patients at that dose combination. The primary and secondary objectives of the expansion cohort will be similar to Part A of the study, i.e., to establish a safety profile of the experimental drug combination and to collect and assess efficacy data. Patients will be treated with concurrent everolimus and fosbretabulin for 12 weeks.
Detailed description
A variety of treatment options are available for NETs with carcinoid syndrome including surgical and medical therapies. Most subjects require somatostatin analogs to control the symptoms of carcinoid syndrome. Subjects who no longer respond to somatostatin and other liver-directed therapies, who experience progression of disease and increasing symptoms have limited options, including participation in a clinical trial. Recently everolimus and sunitinib have been approved for the treatment of subjects with progressive locally advanced or metastatic neuroendocrine tumors. Based on the preclinical data in models of NETs and the clinical activity seen in NETS and other tumor types that have existing tumor vascculature, this study will examine the effectiveness of fosbretabulin given in combination with everolimus in subjects with GI-NETs and PNETs.The vasoconstrictive effect of fosbretabulin is potent, though short-lived (4-8 hours), with no cumulative adverse effect. Everolimus inhibits angiogenesis, slows tumor growth and has a prolonged half-life (30 hours). Combining these two agents with distinctly different mechanisms of action may improve tumor control without additional toxicities, and has the potential of reducing drug resistance.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| everolimus + fosbretabulin | Experimental | Drug: everolimus, Drug: fosbretabulineverolimus + fosbretabulin |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Patients must have histologically confirmed neuroendocrine tumor (grades 1-3) that is metastatic or unresectable, and for which standard curative or palliative measures do not exist or are no longer effective.
- Prior treatment with fosbretabulin is allowed, if not given in combination with everolimus.
- Prior treatment with everolimus is allowed, if the patient was able to tolerate 10 mg daily everolimus with acceptable side effects, and if everolimus was not given in combination with fosbretabulin. A 1 week washout period will be required if patient was previously on everolimus.
- Age ≥18 years.
- ECOG performance status ≤2.
Key exclusion criteria (16 listed)
- Patients who have had prior everolimus but were not able to tolerate a 10 mg daily dose.
- Prior chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
- Child Pugh Class B or greater hepatic dysfunction.
- Patients who are receiving any other investigational agents.
- Patients with known brain metastases because of their poor prognosis and likelihood to develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
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 |
|---|---|---|
| everolimuseverolimus | Drug | everolimus + fosbretabulin |
| fosbretabulinfosbretabulin | Drug | everolimus + fosbretabulin |
Primary outcome
Maximum Tolerated Dose (MTD)
Time frame: 12 weeks
To establish the maximum tolerated dose of the combination of everolimus plus fosbretabulin in neuroendocrine tumors (Grades 1-3) who have progressed after at least one prior regimen for metastatic disease.
2 secondary outcomes
Incidence of Toxicities
Time frame: 12 weeks
Anti-tumor activity
Time frame: 12 weeks
Results and safety
The study was stopped early (reason given: Part I completed. Part 2 will not be done due to sponsor decision.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Aug 2019.
- Individual participant dataSharing planned: No
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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.
Lowell Anthony, MD principal investigator
University of Kentucky
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing everolimus and fosbretabulin in people with Neuroendocrine Tumors and Everolimus, run by Lowell Anthony, MD 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 17 inclusion and 16 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: stopped early, as of the sponsor's last update on 8 Aug 2019. 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 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 was stopped early (reason given: Part I completed. Part 2 will not be done due to sponsor decision.). Results are not available in the source record.
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?
Maximum Tolerated Dose (MTD) (time frame: 12 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 8 Aug 2019.