NeoplasmsPhase 1NCT01120288
A Pilot Study of EZN-2968, an Antisense Oligonucleotide Inhibitor of HIF-1alpha, in Adults With Advanced Solid Tumors With Liver Metastases
A Phase 1 study testing EZN-2968 in people with Neoplasms and Liver Metastases, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
Background: A protein called HIF is believed to be involved both in forming cancers and helping them to grow after they are formed. EZN-2968 is a new type of cancer drug that goes into the cancer cell and switches off the production of the HIF protein. Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Neoplasms, Liver Metastases
- What is being tested?
- EZN-2968
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- 29 Apr 2010to 24 Sep 2013
- 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 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have histologically or cytologically confirmed diagnosis of solid tumor. The diagnosis should be confirmed by the Laboratory of Pathology, NIH.
- Patients must have disease that is not amenable to potentially curative resection.
- Disease must be amenable to biopsy, and patients must be willing to undergo tumor biopsies.
- Patients must have failed at least one line of prior therapy for metastatic disease or have a disease for which no standard curative therapy exists. Prior anti-angiogenic therapy is allowed.
- Age (Bullet)18 years. Because no dosing or adverse event data are currently available on the use of EZN-2968 in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable.
- Life expectancy of greater than 3 months.
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- ECOG performance status 0-2 (Karnofsky (Bullet)60%).
- Patients must have normal organ and marrow function as defined below:
- absolute neutrophil count (Bullet)1,500/mcL
- platelets (Bullet)100,000/mcL
- total bilirubin 1.5 X ULN
- AST/ALT 2.5 X institutional ULN
- creatinine less than or equal to 1.5 x upper limit of normal
- OR
- creatinine clearance (measured) greater than or equal to 60 mL/minute for patients with creatinine levels >1.5 times upper limit of normal
- INR 1.4
- PTT 40 seconds unless due to lupus anticoagulant
- Urine protein should be screened by urine analysis for urine protein:creatinine (UPC) ratio. For UPC ratio >1, 24-hour urine protein should be obtained and the level should be <500 mg for patient enrollment.
- The effects of EZN-2968 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (abstinence; female use of hormonal methods, or barrier methods of birth control; male use of a condom) prior to study entry, for the duration of study participation, and for 6 months after completion of study. Because there is a risk for adverse events in nursing infants secondary to treatment of the mother with EZN- 2968, breastfeeding should be discontinued while the patient is on this trial and for
- 30 days after completion of treatment on this trial. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
- Ability to understand and the willingness to sign a written informed consent document.
- Willingness to undergo tumor biopsies for research purposes.
Who cannot join
- Patients who have had 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 to eligibility levels (by performance status and laboratory criteria outlined above) due to agents administered more than 4 weeks earlier. Patients may have received investigational agent(s) as part of a Phase 0 study (also referred to as an early Phase I study or pre-Phase I study where a sub-therapeutic dose of drug is administered) at the PI's discretion, up to 2 weeks prior to study entry.
- Patients may not be receiving any other investigational agents.
- Patients with active brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients whose brain metastatic disease status remains stable for (Bullet) 3 months after treatment of the brain metastases without steroids or antiseizure medications may be enrolled at the discretion of the principal investigator.
- Patients requiring therapeutic anticoagulation.
- Hypertension not controlled by medical therapy (hypertension defined as systolic blood pressure >150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to EZN-2968.
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- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. A history of hepatitis is allowed if, following consultation with Liver Diseases Branch, it is felt to be clinically stable.
- Pregnant women are excluded from this study because EZN-2968 has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with EZN-2968, breastfeeding should be discontinued if the mother is treated with EZN-2968.
- HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with EZN-2968.
- Patients with surgical non-healing wounds. Patients with other non-healing wounds will be evaluated and included at the PI s discretion if considered minor.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: A Pilot Study of EZN-2968, an Antisense Oligonucleotide Inhibitor of HIF-1alpha, in Adults With Advance Solid Tumors
Background:
- A protein called HIF is believed to be involved both in forming cancers and helping them to grow after they are formed. EZN-2968 is a new type of cancer drug that goes into the cancer cell and switches off the production of the HIF protein. Researchers are interested in testing EZN-2968 in people who have liver cancer because studies have shown that this drug travels to the liver and stays there when the drug is given through a vein.
Read more
Objectives:
- To determine the safety and effectiveness of EZN-2968 on liver cancer.
Eligibility:
- Individuals 18 years of age and older who have been diagnosed with liver cancer that has not responded to standard treatments.
Design:
- Participants will have an initial screening visit with a physical examination, blood and urine tests, and imaging studies to assess tumor size. Tumor biopsies may also be taken for research purposes.
- Participants will have an undefined number of 6-week treatment cycles of EZN-2968, given once a week for 3 weeks followed by 3 weeks without the drug.
- During each cycle, participants will have additional blood tests and imaging scans to assess tumor response to treatment.
- Cycles of treatment with EZN-2968 may continue until the treatment is not effective, illness requires participants to stop taking the study drug, or the participant chooses to withdraw from the study.
Read the detailed description
Background:
- Hypoxia-inducible factor-1 (HIF-1) facilitates the adaptation of normal and tumor tissue to oxygen deprivation. HIF-1 is frequently overexpressed in cancer cells, where it is involved in the upregulation of many gene products essential for invasion, migration, angiogenesis, and survival, including vascular endothelial growth factor (VEGF). Blocking HIF-1 activity inhibits the expression of VEGF, resulting in the inhibition of tumor growth in vitro and in vivo.
- EZN-2968 is an antisense oligonucleotide that specifically targets HIF-1 alpha, one of the subunits of HIF-1. Safety and preliminary suggestion of activity have been demonstrated in two Phase I trials; one patient with hepatocellular carcinoma, one with renal cell cancer, and one with angiosarcoma of the face treated with EZN-2968 had objective evidence of shrinkage of large masses. In vivo data show evidence of intracellular uptake of EZN-2968 into tumor cells, and in the Phase I trial, preliminary data show that eleven patients had prolonged stable disease (>90 days duration on study), three of which had objective evidence of tumor shrinkage, thus demonstrating proof of principle for this approach.
Primary Objective:
- Determine the modulation of HIF-1alpha mRNA in tumor biopsies pre- and post-administration of EZN-2968.
Secondary Objectives:
- Assess the safety of EZN-2968 in patients with advanced solid tumors.
- Determine the modulation of HIF-1 alpha protein levels in tumor biopsies pre- and post-administration of EZN-2968.
- Evaluate anti-tumor response as determined by RECIST.
- Evaluate the expression of HIF-1 alpha target genes by real-time PCR in tumor biopsies.
- Assess tumor angiogenesis using DCE-MRI.
Eligibility:
- Adult patients with histologically or cytologically confirmed solid malignancies will be included in the study.
- Patients must have disease that is not amenable to potentially curative resection.
- Patients must have failed at least one line of prior therapy for metastatic disease or have a disease for which no standard curative therapy exists.
- Lesion must be amenable to biopsy.
Design:
- EZN-2968 will be administered as a 2-hour IV infusion at a dose of 18 mg/kg once a week for 3 consecutive weeks followed by a 3-week period without drug. Each cycle will be 6 weeks, i.e., 3 weeks of therapy followed by 3 weeks without drug.
- Tumor biopsies and other correlative imaging and pharmacodynamic studies will be performed at baseline and after the third dose. Tumor restaging will be performed every 2 cycles.
- Conditions
- Neoplasms, Liver Metastases
- Being tested
- EZN-2968
- Keywords
- Anti-Angiogenesis, Targeted Therapy, HIF, Antisense, VEGF, Cancer, Solid Tumor, Liver Metastasis
- Medical subject headings
- Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EZN-2968Drug
What is being measured
The primary outcome is the main question the study is designed to answer.
Determine the modulation of HIF-1 alpha mRNA in tumor biopsies pre- and post- administration of EZN-2968.
Measured: 1-2 years
Secondary outcomes (1)
Assess the safety of EZN-2968 in patients with liver-predominant solid tumors. Determine the modulation of HIF-1 alpha protein levels in tumor biopsies pre- and post-administration of EZN-2968.
Measured: 1-2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 May 2010 (estimated)
- Study start29 Apr 2010
- Study completion24 Sep 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for NeoplasmsStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The 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
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Shivaani Kummar, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01120288
- Sponsor's protocol ID
- 100113
- Other IDs
- 10-C-0113
- Status last verified
- 6 Mar 2014
- First submitted
- 7 May 2010
- Last updated
- 5 Jul 2018
- Results posted
- No
Publications
Wenger RH, Rolfs A, Marti HH, Guenet JL, Gassmann M. Nucleotide sequence, chromosomal assignment and mRNA expression of mouse hypoxia-inducible factor-1 alpha. Biochem Biophys Res Commun. 1996 Jun 5;223(1):54-9. doi: 10.1006/bbrc.1996.0845.
PubMed 8660378Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001 Apr;13(2):167-71. doi: 10.1016/s0955-0674(00)00194-0.
PubMed 11248550Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003 Oct;3(10):721-32. doi: 10.1038/nrc1187.
PubMed 13130303
Study at a glance
From the registry record, last updated by the sponsor on 5 Jul 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study of EZN-2968, an Antisense Oligonucleotide Inhibitor of HIF-1alpha, in Adults With Advance Solid Tumors
- ClinicalTrials.gov ID
- NCT01120288
- Acronym / sponsor ID
- 100113
- Conditions
- Neoplasms, Liver Metastases
- Keywords
- Anti-Angiogenesis, Targeted Therapy, HIF, Antisense, VEGF, Cancer, Solid Tumor, Liver Metastasis
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 29 Apr 2010
- Study completion
- 24 Sep 2013 (actual)
- First posted
- 10 May 2010 (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.
Background:
- A protein called HIF is believed to be involved both in forming cancers and helping them to grow after they are formed. EZN-2968 is a new type of cancer drug that goes into the cancer cell and switches off the production of the HIF protein. Researchers are interested in testing EZN-2968 in people who have liver cancer because studies have shown that this drug travels to the liver and stays there when the drug is given through a vein.
Objectives:
- To determine the safety and effectiveness of EZN-2968 on liver cancer.
Eligibility:
- Individuals 18 years of age and older who have been diagnosed with liver cancer that has not responded to standard treatments.
Design:
- Participants will have an initial screening visit with a physical examination, blood and urine tests, and imaging studies to assess tumor size. Tumor biopsies may also be taken for research purposes.
- Participants will have an undefined number of 6-week treatment cycles of EZN-2968, given once a week for 3 weeks followed by 3 weeks without the drug.
- During each cycle, participants will have additional blood tests and imaging scans to assess tumor response to treatment.
- Cycles of treatment with EZN-2968 may continue until the treatment is not effective, illness requires participants to stop taking the study drug, or the participant chooses to withdraw from the study.
Detailed description
Background:
- Hypoxia-inducible factor-1 (HIF-1) facilitates the adaptation of normal and tumor tissue to oxygen deprivation. HIF-1 is frequently overexpressed in cancer cells, where it is involved in the upregulation of many gene products essential for invasion, migration, angiogenesis, and survival, including vascular endothelial growth factor (VEGF). Blocking HIF-1 activity inhibits the expression of VEGF, resulting in the inhibition of tumor growth in vitro and in vivo.
- EZN-2968 is an antisense oligonucleotide that specifically targets HIF-1 alpha, one of the subunits of HIF-1. Safety and preliminary suggestion of activity have been demonstrated in two Phase I trials; one patient with hepatocellular carcinoma, one with renal cell cancer, and one with angiosarcoma of the face treated with EZN-2968 had objective evidence of shrinkage of large masses. In vivo data show evidence of intracellular uptake of EZN-2968 into tumor cells, and in the Phase I trial, preliminary data show that eleven patients had prolonged stable disease (>90 days duration on study), three of which had objective evidence of tumor shrinkage, thus demonstrating proof of principle for this approach.
Primary Objective:
- Determine the modulation of HIF-1alpha mRNA in tumor biopsies pre- and post-administration of EZN-2968.
Secondary Objectives:
- Assess the safety of EZN-2968 in patients with advanced solid tumors.
- Determine the modulation of HIF-1 alpha protein levels in tumor biopsies pre- and post-administration of EZN-2968.
- Evaluate anti-tumor response as determined by RECIST.
- Evaluate the expression of HIF-1 alpha target genes by real-time PCR in tumor biopsies.
- Assess tumor angiogenesis using DCE-MRI.
Eligibility:
- Adult patients with histologically or cytologically confirmed solid malignancies will be included in the study.
- Patients must have disease that is not amenable to potentially curative resection.
- Patients must have failed at least one line of prior therapy for metastatic disease or have a disease for which no standard curative therapy exists.
- Lesion must be amenable to biopsy.
Design:
- EZN-2968 will be administered as a 2-hour IV infusion at a dose of 18 mg/kg once a week for 3 consecutive weeks followed by a 3-week period without drug. Each cycle will be 6 weeks, i.e., 3 weeks of therapy followed by 3 weeks without drug.
- Tumor biopsies and other correlative imaging and pharmacodynamic studies will be performed at baseline and after the third dose. Tumor restaging will be performed every 2 cycles.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- Patients must have histologically or cytologically confirmed diagnosis of solid tumor. The diagnosis should be confirmed by the Laboratory of Pathology, NIH.
- Patients must have disease that is not amenable to potentially curative resection.
- Disease must be amenable to biopsy, and patients must be willing to undergo tumor biopsies.
- Patients must have failed at least one line of prior therapy for metastatic disease or have a disease for which no standard curative therapy exists. Prior anti-angiogenic therapy is allowed.
- Age (Bullet)18 years. Because no dosing or adverse event data are currently available on the use of EZN-2968 in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable.
Key exclusion criteria (10 listed)
- Patients who have had 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 to eligibility levels (by performance status and laboratory criteria outlined above) due to agents administered more than 4 weeks earlier. Patients may have received investigational agent(s) as part of a Phase 0 study (also referred to as an early Phase I study or pre-Phase I study where a sub-therapeutic dose of drug is administered) at the PI's discretion, up to 2 weeks prior to study entry.
- Patients may not be receiving any other investigational agents.
- Patients with active brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients whose brain metastatic disease status remains stable for (Bullet) 3 months after treatment of the brain metastases without steroids or antiseizure medications may be enrolled at the discretion of the principal investigator.
- Patients requiring therapeutic anticoagulation.
- Hypertension not controlled by medical therapy (hypertension defined as systolic blood pressure >150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
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 |
|---|---|---|
| EZN-2968 | Drug | – |
Primary outcome
Determine the modulation of HIF-1 alpha mRNA in tumor biopsies pre- and post- administration of EZN-2968.
Time frame: 1-2 years
1 secondary outcome
Assess the safety of EZN-2968 in patients with liver-predominant solid tumors. Determine the modulation of HIF-1 alpha protein levels in tumor biopsies pre- and post-administration of EZN-2968.
Time frame: 1-2 years
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 5 Jul 2018.
- Background: PubMed 8660378Wenger RH, Rolfs A, Marti HH, Guenet JL, Gassmann M. Nucleotide sequence, chromosomal assignment and mRNA expression of mouse hypoxia-inducible factor-1 alpha. Biochem Biophys Res Commun. 1996 Jun 5;223(1):54-9. doi: 10.1006/bbrc.1996.0845.
- Background: PubMed 11248550Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001 Apr;13(2):167-71. doi: 10.1016/s0955-0674(00)00194-0.
- Background: PubMed 13130303Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003 Oct;3(10):721-32. doi: 10.1038/nrc1187.
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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.
Shivaani Kummar, M.D. principal investigator
National Cancer Institute (NCI)
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 EZN-2968 in people with Neoplasms and Liver Metastases, run by National Cancer Institute (NCI) 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 22 inclusion and 10 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 5 Jul 2018. 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 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?
Determine the modulation of HIF-1 alpha mRNA in tumor biopsies pre- and post- administration of EZN-2968. (time frame: 1-2 years). 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 NCT01120288, which also lists 3 linked publications.
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 5 Jul 2018.