Solid TumorsPhase 1NCT01537744
A Trial of Oral 5-azacitidine in Combination With Romidepsin in Advanced Solid Tumors, With an Expansion Cohort in Virally Mediated Cancers and Liposarcoma
A Phase 1 study testing oral 5-azacitidine in combination with romidepsin in people with Solid Tumors and Virally Mediated Cancers and Liposarcoma, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 1 site in United States.
Trial summary
The purpose of this study is to determine whether 5-azacitidine in combination with romidepsin cancer are effective in the treatment of advanced solid tumors. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Solid Tumors, Virally Mediated Cancers and Liposarcoma
- What is being tested?
- oral 5-azacitidine in combination with romidepsin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2012to Sep 2016
- 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
- Understand and voluntarily sign informed consent form (ICF).
- Age ≥ 18 years at time of signing ICF.
- Adhere to study visit schedule and other protocol requirements.
- Histologically or cytologically confirmed metastatic or unresectable solid tumor (phase I dose escalation), OR HPV+ nasopharyngeal cancer, HPV+ cervical cancer or liposarcoma (for expansion cohort).
- Failed at least one previous chemotherapy regimen for metastatic disease if standard therapies exist.
- Measurable disease per RECIST 1.1
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- Life expectancy ≥ 12 weeks
- No previous cancer therapy ≥ 4 weeks.
- ECOG performance status ≤ 1
- Laboratory test results:
- Absolute neutrophil count ≥ 1500/mm³
- Platelet ≥ 100,000/mm³
- Serum creatinine levels < 1.5 X ULN OR creatinine clearance >60 mL/min/1.73 m2 for subjects with creatinine levels > institutional normal
- Serum bilirubin ≤ 1.5 times the upper limit of the normal range for the laboratory (ULN).
- AST (SGOT) and ALT (SGPT) ≤ to 2.5 x ULN
- Disease free of prior malignancies ≥ 5 years (except currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast).
- Women of childbearing potential should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment with 5-azacitidine. All men/women of childbearing potential must use acceptable methods of birth control throughout the study.
Who cannot join
- Serious medical conditions, laboratory abnormality, or psychiatric illness that would prevent the subject from signing ICF.
- Pregnant or breastfeeding women. (Lactating women must agree not to breast feed while taking 5-azacitidine).
- Conditions, including laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret study data.
- Chemotherapy, radiotherapy, or experimental drug or therapy ≤ 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to enrollment or adverse events < grade 1 due to agents administered >4 weeks earlier except for stable grade 2 neuropathy.
- No other concomitant investigational agents.
- Known or suspected hypersensitivity to 5-azacitidine, romidepsin, mannitol or other agents used in this study.
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- Uncontrolled brain metastases.
- Known positive for HIV, infectious hepatitis, type B or C.
- Uncontrolled intercurrent illness
- Known GI disorders precluding oral administration of 5-azacitidine.
- Known cardiac abnormalities such as:
- Congenital long QT syndrome
- QTc interval ≥ 500 milliseconds;
- Myocardial infarction ≤6 months of C1D1. Subjects with a history of myocardial infarction between 6-12 months prior to C1D1 who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event may participate;
- Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min);
- Symptomatic coronary artery disease (CAD), e.g., angina. In any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
- Screening ECG showing evidence of cardiac ischemia (ST depression, depression of ≥2 mm, measured from isoelectric line to the ST segment). If in any doubt, patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
- Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction <40% by MUGA scan or <50% by echocardiogram and/or MRI;
- Known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD);
- Hypertrophic cardiomegaly or restrictive cardiomyopathy;
- Uncontrolled hypertension, i.e., blood pressure (BP) of ≥160/95; patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) and meet all other inclusion criteria; or
- Cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers)
- Patients taking drugs leading to significant QT prolongation
- Concomitant use of CYP3A4 inhibitors
Trial locations and contacts
1 site in 1 country.
United States1 site
Sidney Kimmel Cancer Center @ Johns Hopkins
Baltimore, Maryland, 21231
About this study
Official title: Phase I Trial of Oral 5-azacitidine With Romidepsin in Advanced Solid Tumors, With an Expansion Cohort in Virally Mediated Cancers and Liposarcoma
The purpose of this study is to determine whether 5-azacitidine in combination with romidepsin cancer are effective in the treatment of advanced solid tumors.
Read the detailed description
This is a two part, single-institution, open-label, Phase I dose-escalation study of oral 5-azacitidine in combination with intravenous (IV) romidepsin. Part 1 of the study is a traditional 3 + 3 dose escalation study designed to evaluate the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, pharmacokinetic (PK) profiles, and pharmacodynamic profiles of increasing doses of orally administered 5-azacitidine in combination with a constant dose of IV romidepsin. Part 2 is an expansion cohort study for the preliminary evaluation of efficacy in the treatment of virally mediated cancers and liposarcoma once the MTD has been determined. PK and PD data will also be collected for these subjects.
- Plasma samples will be obtained, prior and during treatment, to assess the methylation status of free tumor DNA circulating in the blood
- Archival tissue will be obtained on all participants for future correlative studies, such as baseline gene expression, methylation patterns.
- Participants with accessible, biopsiable tumors will also undergo pre-treatment and post-treatment (~cycle 2D1) biopsies for correlative studies in the expansion cohort.
- Being tested
- oral 5-azacitidine in combination with romidepsin
- Keywords
- expansion cohort
- Medical subject headings
- Liposarcoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
oral 5-azacitidine in combination with romidepsinDrug
Also called 5-azacytidine, Vidaza, Istodax
DOSING REGIMEN(S):
Table 1: Dose Escalation Schedule Dose Level Dose and Schedule a, c 5-Azacitidine (PO) Romidepsin (IV)
Level -1b 100mg daily days 1-14 8mg/m2 days 8 and 15
Level 1 200mg daily days 1-14 8mg/m2 days 8 and 15
Level 2 300mg daily days 1-14 8mg/m2 days 8 and 15
Level 3 300mg daily days 1-21 8mg/m2 days 8 and 15
Level 4d MTD 8mg/m2 days 8, 15, and 22
- Each cycle will last 28 days.
- Subjects will be enrolled in Level -1 if the MTD is reached in the subjects enrolled in Level 1.
- On days when both agents are administered, oral 5-azacitidine should be administered at the start of the romidepsin infusion.
- Level 4 is optional and decisions whether to initiate this level will be based on discussions between the study investigator and Celgene.
| Study group | Role | What they receive |
|---|---|---|
| oral 5-azacitidine + romidepsin | Experimental | oral 5-azacitidine in combination with romidepsin Receives: Drug: oral 5-azacitidine in combination with romidepsin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of adverse events
Incidence of adverse events, serious adverse events, and dose-limiting adverse events graded according to NCI CTCAE version 4
Measured: From first dose of study treatment to end of study visit, approximately 1.5 years
Maximum Tolerated Dose (MTD)
MTD defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.
Measured: First cycle
Clinical responses associated with oral 5-azacitidine and romidepsin
Clinical responses associated with oral 5-azacitidine and romidepsin treatment in subjects with advanced solid malignancies according to RECIST criteria [Time Frame: measured every two cycles during study treatment, expected duration ≤1.5 years
Measured: Measured every two cycles during study treatment, expected duration ≤1.5 years
Secondary outcomes (2)
Peak plasma concentration (Cmax)
Peak plasma concentration (Cmax), area under the concentration versus time curve (AUC) from time 0-infinity, elimination half-life (t1/2), clearance, and volume of distribution (Vd)
Measured: On Day 1 and 8 of Cycle 1
Determine whether changes in DNA methylation, histone acetylation, and/or gene expression correlates with clinical response to oral 5-azacitidine and romidepsin
Measured: Weekly during cycle 1 and at the start of each subsequent cycle while on study
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Feb 2012 (estimated)
- Study startFeb 2012
- Primary completionMar 2016
- Study completionSep 2016
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 Solid TumorsStudies of the same condition, open and under way.
- More trials run by Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsThe 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Celgene Corporation
- Responsible party
- Sponsor
- Investigators
- Nilofer Azad, MD, Principal investigator, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01537744
- Sponsor's protocol ID
- J11102
- Other IDs
- NA_00052054
- Status last verified
- Mar 2017
- First submitted
- 8 Feb 2012
- Last updated
- 24 Mar 2017
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Gaillard SL, Zahurak M, Sharma A, Durham JN, Reiss KA, Sartorius-Mergenthaler S, Downs M, Anders NM, Ahuja N, Rudek MA, Azad N. A phase 1 trial of the oral DNA methyltransferase inhibitor CC-486 and the histone deacetylase inhibitor romidepsin in advanced solid tumors. Cancer. 2019 Aug 15;125(16):2837-2845. doi: 10.1002/cncr.32138. Epub 2019 Apr 23.
PubMed 31012962
Study at a glance
From the registry record, last updated by the sponsor on 24 Mar 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Trial of Oral 5-azacitidine With Romidepsin in Advanced Solid Tumors, With an Expansion Cohort in Virally Mediated Cancers and Liposarcoma
- ClinicalTrials.gov ID
- NCT01537744
- Acronym / sponsor ID
- J11102
- Keywords
- expansion cohort
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsUniversity, hospital or other
- Collaborators
- Celgene Corporation
- Study start
- Feb 2012
- Primary completion
- Mar 2016 (actual)
- Study completion
- Sep 2016 (actual)
- First posted
- 23 Feb 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 this study is to determine whether 5-azacitidine in combination with romidepsin cancer are effective in the treatment of advanced solid tumors.
Detailed description
This is a two part, single-institution, open-label, Phase I dose-escalation study of oral 5-azacitidine in combination with intravenous (IV) romidepsin. Part 1 of the study is a traditional 3 + 3 dose escalation study designed to evaluate the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, pharmacokinetic (PK) profiles, and pharmacodynamic profiles of increasing doses of orally administered 5-azacitidine in combination with a constant dose of IV romidepsin. Part 2 is an expansion cohort study for the preliminary evaluation of efficacy in the treatment of virally mediated cancers and liposarcoma once the MTD has been determined. PK and PD data will also be collected for these subjects.
- Plasma samples will be obtained, prior and during treatment, to assess the methylation status of free tumor DNA circulating in the blood
- Archival tissue will be obtained on all participants for future correlative studies, such as baseline gene expression, methylation patterns.
- Participants with accessible, biopsiable tumors will also undergo pre-treatment and post-treatment (~cycle 2D1) biopsies for correlative studies in the expansion cohort.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| oral 5-azacitidine + romidepsin | Experimental | Drug: oral 5-azacitidine in combination with romidepsinoral 5-azacitidine in combination with romidepsin |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Understand and voluntarily sign informed consent form (ICF).
- Age ≥ 18 years at time of signing ICF.
- Adhere to study visit schedule and other protocol requirements.
- Histologically or cytologically confirmed metastatic or unresectable solid tumor (phase I dose escalation), OR HPV+ nasopharyngeal cancer, HPV+ cervical cancer or liposarcoma (for expansion cohort).
- Failed at least one previous chemotherapy regimen for metastatic disease if standard therapies exist.
Key exclusion criteria (24 listed)
- Serious medical conditions, laboratory abnormality, or psychiatric illness that would prevent the subject from signing ICF.
- Pregnant or breastfeeding women. (Lactating women must agree not to breast feed while taking 5-azacitidine).
- Conditions, including laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret study data.
- Chemotherapy, radiotherapy, or experimental drug or therapy ≤ 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to enrollment or adverse events < grade 1 due to agents administered >4 weeks earlier except for stable grade 2 neuropathy.
- No other concomitant investigational agents.
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 |
|---|---|---|
| oral 5-azacitidine in combination with romidepsinAlso: 5-azacytidine, Vidaza, IstodaxDOSING REGIMEN(S): Table 1: Dose Escalation Schedule Dose Level Dose and Schedule a, c 5-Azacitidine (PO) Romidepsin (IV) Level -1b 100mg daily days 1-14 8mg/m2 days 8 and 15 Level 1 200mg daily days 1-14 8mg/m2 days 8 and 15 Level 2 300mg daily days 1-14 8mg/m2 days 8 and 15 Level 3 300mg daily days 1-21 8mg/m2 days 8 and 15 Level 4d MTD 8mg/m2 days 8, 15, and 22 1. Each cycle will last 28 days. 2. Subjects will be enrolled in Level -1 if the MTD is reached in the subjects enrolled in Level 1. 3. On days when both agents are administered, oral 5-azacitidine should be administered at the start of the romidepsin infusion. 4. Level 4 is optional and decisions whether to initiate this level will be based on discussions between the study investigator and Celgene. | Drug | oral 5-azacitidine + romidepsin |
Primary outcome
Incidence of adverse events
Time frame: From first dose of study treatment to end of study visit, approximately 1.5 years
Incidence of adverse events, serious adverse events, and dose-limiting adverse events graded according to NCI CTCAE version 4
Maximum Tolerated Dose (MTD)
Time frame: First cycle
MTD defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.
Clinical responses associated with oral 5-azacitidine and romidepsin
Time frame: Measured every two cycles during study treatment, expected duration ≤1.5 years
Clinical responses associated with oral 5-azacitidine and romidepsin treatment in subjects with advanced solid malignancies according to RECIST criteria [Time Frame: measured every two cycles during study treatment, expected duration ≤1.5 years
2 secondary outcomes
Peak plasma concentration (Cmax)
Time frame: On Day 1 and 8 of Cycle 1
Determine whether changes in DNA methylation, histone acetylation, and/or gene expression correlates with clinical response to oral 5-azacitidine and romidepsin
Time frame: Weekly during cycle 1 and at the start of each subsequent cycle while on study
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 24 Mar 2017.
- Derived from this study: PubMed 31012962Gaillard SL, Zahurak M, Sharma A, Durham JN, Reiss KA, Sartorius-Mergenthaler S, Downs M, Anders NM, Ahuja N, Rudek MA, Azad N. A phase 1 trial of the oral DNA methyltransferase inhibitor CC-486 and the histone deacetylase inhibitor romidepsin in advanced solid tumors. Cancer. 2019 Aug 15;125(16):2837-2845. doi: 10.1002/cncr.32138. Epub 2019 Apr 23.
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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.
Nilofer Azad, MD principal investigator
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
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 oral 5-azacitidine in combination with romidepsin in people with Solid Tumors and Virally Mediated Cancers and Liposarcoma, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 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 24 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 24 Mar 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 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?
Incidence of adverse events (time frame: From first dose of study treatment to end of study visit, approximately 1.5 years). The study lists 3 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 NCT01537744, 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 24 Mar 2017.