A Trial of Oral 5-azacitidine in Combination With Romidepsin in Advanced Solid Tumors, With an Expansion Cohort in Virally Mediated Cancers and Liposarcoma
Primary Purpose
Solid Tumors, Virally Mediated Cancers and Liposarcoma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
oral 5-azacitidine in combination with romidepsin
Sponsored by
About this trial
This is an interventional treatment trial for Solid Tumors focused on measuring expansion cohort
Eligibility Criteria
Inclusion Criteria:
- 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
- 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.
Exclusion Criteria:
- 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.
- 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
Sites / Locations
- Sidney Kimmel Cancer Center @ Johns Hopkins
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
oral 5-azacitidine + romidepsin
Arm Description
oral 5-azacitidine in combination with romidepsin
Outcomes
Primary Outcome Measures
Incidence of adverse events
Incidence of adverse events, serious adverse events, and dose-limiting adverse events graded according to NCI CTCAE version 4
Maximum Tolerated Dose (MTD)
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
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
Secondary Outcome Measures
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)
Determine whether changes in DNA methylation, histone acetylation, and/or gene expression correlates with clinical response to oral 5-azacitidine and romidepsin
Full Information
NCT ID
NCT01537744
First Posted
February 8, 2012
Last Updated
March 21, 2017
Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
Celgene Corporation
1. Study Identification
Unique Protocol Identification Number
NCT01537744
Brief Title
A Trial of Oral 5-azacitidine in Combination With Romidepsin in Advanced Solid Tumors, With an Expansion Cohort in Virally Mediated Cancers and Liposarcoma
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
Study Type
Interventional
2. Study Status
Record Verification Date
March 2017
Overall Recruitment Status
Completed
Study Start Date
February 2012 (undefined)
Primary Completion Date
March 2016 (Actual)
Study Completion Date
September 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
Celgene Corporation
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Solid Tumors, Virally Mediated Cancers and Liposarcoma
Keywords
expansion cohort
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
oral 5-azacitidine + romidepsin
Arm Type
Experimental
Arm Description
oral 5-azacitidine in combination with romidepsin
Intervention Type
Drug
Intervention Name(s)
oral 5-azacitidine in combination with romidepsin
Other Intervention Name(s)
5-azacytidine, Vidaza, Istodax
Intervention Description
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.
Primary Outcome Measure Information:
Title
Incidence of adverse events
Description
Incidence of adverse events, serious adverse events, and dose-limiting adverse events graded according to NCI CTCAE version 4
Time Frame
From first dose of study treatment to end of study visit, approximately 1.5 years
Title
Maximum Tolerated Dose (MTD)
Description
MTD defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.
Time Frame
First cycle
Title
Clinical responses associated with oral 5-azacitidine and romidepsin
Description
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
Time Frame
Measured every two cycles during study treatment, expected duration ≤1.5 years
Secondary Outcome Measure Information:
Title
Peak plasma concentration (Cmax)
Description
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)
Time Frame
On Day 1 and 8 of Cycle 1
Title
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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
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.
Exclusion Criteria:
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.
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nilofer Azad, MD
Organizational Affiliation
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sidney Kimmel Cancer Center @ Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
31012962
Citation
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.
Results Reference
derived
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A Trial of Oral 5-azacitidine in Combination With Romidepsin in Advanced Solid Tumors, With an Expansion Cohort in Virally Mediated Cancers and Liposarcoma
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