Metastatic MelanomaPhase 1/2NCT00925132
Treatment of Resistant Metastatic Melanoma Using Decitabine, Temozolomide and Panobinostat
A Phase 1/2 study testing Temozolomide, Decitabine, Panobinostat in people with Metastatic Melanoma, run by University of Iowa at 1 site in United States.
Trial summary
The purpose of this study is to treat metastatic melanoma with a combination of standard chemotherapy (decitabine and Temozolomide in a dose escalation scheme) with an study drug called panobinostat. This combination is proposed to unlock genes that may contribute to mechanisms that cause tumor growth. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Melanoma
- What is being tested?
- Temozolomide, Decitabine, Panobinostat
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 39 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2009to Dec 2016
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- Male or female patients aged ≥ 18 years old
- ECOG Performance Status of ≤ 2
- Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
- Patients must have measurable disease according to RECIST and CHOI criteria. The minimum target-lesion diameter should have double the CT slice thickness, i.e., 10 mm
- Patients must meet the following laboratory criteria:
- Hematology: Neutrophil count of >1500/mm3;Platelet count of > 100,000/mm3L; Hemoglobin ≥ 9 g/dL Biochemistry:AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x upper limit of normal if the transaminase elevation is due to disease involvement;Serum bilirubin ≤ 1.5 x upper limit of normal;Serum creatinine ≤ 1.5 x upper limit of normal or 24-hour creatinine clearance ≥ 50 ml/min; Total serum calcium (corrected for serum albumin) or ionized calcium ≥ lower limit of normal; Serum potassium ≥ lower limit of normal; Serum sodium ≥ lower limit of normal;Serum albumin ≥ lower limit of normal or 3g/dl;Patients with any elevated alkaline phosphatase due to bone metastasis can be enrolled
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- Baseline ECHO must demonstrate LVEF ≥ the lower limit of the institutional normal.
- TSH and free T4 within normal limits (patients may be on thyroid hormone replacement)
- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 8 days of the first administration of study treatment and must be willing to use two methods of contraception one of them being a barrier method during the study and for 3 months after last study drug administration
- Any patient with the diagnosis of metastatic melanoma from any site. These include untreated patients or those treated with chemotherapy or biochemotherapy.
- Must not have taken a hypomethylating agent or a histone deacetylase agent in the treatment of their disease. Patients who receive targeted agents would only need a 2-week washout period.
- Any patient with metastatic melanoma regardless of prior treatment will be eligible.
- Patients must have had disease progression on or following their most recent treatment regimen or on presentation for the first time with metastatic disease, surgical option can be entertained if this is a localized relapse.
- Patients with CNS disease are eligible for treatment only after their CNS disease has been directly addressed with radiation therapy.
Who cannot join
- Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer
- Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
- Impaired cardiac function including any one of the following: Screening ECG with a QTc > 450 msec confirmed by central laboratory prior to enrollment to the study; Patients with congenital long QT syndrome; History of sustained ventricular tachycardia; Any history of ventricular fibrillation or torsades de pointes; Bradycardia defined as heart rate < 50 beats per minute. Patients with a pacemaker and heart rate ≥ 50 beats per minute are eligible; Patients with a myocardial infarction or unstable angina within 6 months of study entry; Congestive heart failure (NY Heart Association class III or IV);Right bundle branch block and left anterior hemiblock (bifascicular block)
- Uncontrolled hypertension
- Concomitant use of drugs with a risk of causing torsades de pointes
- Concomitant use of CYP3A4 inhibitors
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- Patients with unresolved diarrhea > CTCAE grade 1
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat
- Other concurrent severe and/or uncontrolled medical conditions
- Patients who have received chemotherapy, any investigational drug or undergone major surgery < 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
- Concomitant use of any anti-cancer therapy or radiation therapy.
- Patients who have no measurable disease.
- Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)not willing to use a double barrier method of contraception during the study and 3 months after the end of treatment. One of these methods of contraception must be a barrier method. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months(i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 8 days of the first administration of oral panobinostat.
- Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and 3 months after the end of treatment. One of these methods must be a condom
- Patients with a history of another primary malignancy within 5 years other than curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the skin
- Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required
- Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242
About this study
Official title: Phase Ib/II: Epigenetic Modification of Chemosensitivity and Apoptosis in Metastatic Melanoma: Treatment of a Resistant Disease Using Decitabine, Temozolomide and Panobinostat
The purpose of this study is to treat metastatic melanoma with a combination of standard chemotherapy (decitabine and Temozolomide in a dose escalation scheme) with an study drug called panobinostat. This combination is proposed to unlock genes that may contribute to mechanisms that cause tumor growth.
The primary objectives of this study are:
- To evaluate the safety and tolerability of the proposed schedule of decitabine, temozolomide and panobinostat in the treatment of metastatic melanoma.
- To define any Dose Limiting Toxicity (DLT) and maximum tolerated dose (MTD) of the combination of decitabine, temozolomide and panobinostat.
Read the detailed description
Most chemotherapeutics target rapidly proliferating cells, leaving quiescent cells and those with extended cell cycles unaffected. The investigators propose that this combination of decitabine, temozolomide, and panobinostat will target both melanoma stem cells and rapidly proliferating melanoma cells. The use of two drugs that regulate gene expression epigenetically (panobinostat and decitabine) in combination with a chemotherapeutic agent (temozolomide) is hypothesized to:
- induce expression genes (e.g., Apaf-1) that increase chemosensitivity of tumor cells and enhance apoptosis
- potentiate the cytotoxic effect of temozolomide by epigenetic modulation, and
- induce proliferation and differentiation of tumor stem cells, thus enabling senescence and apoptosis.
Secondary objectives:
- To measure overall survival
- To measure the time to progression of patients treated with this combination in comparison to patients treated historically with DTIC (the current standard of care).
- To evaluate treatment response with FDG PET and compare FDG PET with conventional imaging for treatment response assessment.
- Conditions
- Metastatic Melanoma
- Being tested
- Temozolomide, Decitabine, Panobinostat
- Keywords
- Metastatic, Melanoma, Epigenetic, Temozolomide, Decitabine, Panobinostat, LBH589
- Medical subject headings
- Melanoma, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Temozolomide, Decitabine, PanobinostatDrug
Also called LBH589
Temozolomide - given each cycle.
Decitabine - 6 cohorts with dose escalation.
Panobinostat - 6 cohorts with dose escalation.
| Study group | Role | What they receive |
|---|---|---|
| Temozolomide, Decitabine, Panobinostat | Experimental | Temozolomide - given each cycle.
Decitabine - 6 cohorts with dose escalation.
Panobinostat - 6 cohorts with dose escalation. Receives: Drug: Temozolomide, Decitabine, Panobinostat |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level
A DLT was any Grade 4 toxicity for neutrophils or platelets for ≥ 7 days, Grade 3 toxicity for neutrophils for ≥ 21 days, any Grade 3 solid organ toxicity not explainable by another cause (e.g. neurotoxicity, GI toxicity), metabolic/laboratory toxicity (≥10 x ULN AST) for ≥ 14 days, any Grade 4 infection or QTcF> 500msec EKG. DLTs were assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0.
All adverse events were collected and graded to determine DLTs as assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. DLTs were assessed to determine the recommended Decitabine and Panobinostat dose for the Phase II portion of the trial.
Measured: 6 weeks (one full cycle)
Phase 2 -Number of Patients With a Decrease in Tumor Size Using RECIST and CHOI's Criteria
Tumor response rate was assessed using RECIST criteria in which a complete response was the disappearance of all target lesions; Partial response was a 30% decrease in the sum of the longest dimension (LD) of target lesions, relative to baseline measurement; Progressive disease was an increase of 20% or more in the sum of the LD of target lesions; and Stable disease was a decrease in tumor size of less than 30% or increase of less than 20%.
Tumor response rate was also assessed using CHOI's criteria in which a response was a 10% decrease in tumor size or a 15% decrease in tumor density on contrast-enhanced computed tomography scan.
Tumor response rates were assessed in order to determine effectiveness of the treatment regimen which was defined by the response rate of at least 30% as measured by either the RECIST or Choi's criteria, and ineffective if the rate is less than 15% on both.
Measured: 12 weeks (2 cycles)
Secondary outcomes (1)
Phase 2 - Number of Participants With Disease Progression
Number of participants who died or had disease progression
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jun 2009 (estimated)
- Study startDec 2009
- Primary completionNov 2014
- Study completionDec 2016
Why it stopped: Change in the number of approved drugs for metastatic melanoma
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Metastatic MelanomaStudies of the same condition, open and under way.
- More trials run by University of IowaThe 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 39 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Iowa
- Sponsor type
- University, hospital or other
- Collaborators
- Holden Comprehensive Cancer Center, Novartis Pharmaceuticals
- Responsible party
- Principal investigator, Mohammed M Milhem, University of Iowa
- Investigators
- Mohammed Milhem, MD, Principal investigator, University of Iowa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00925132
- Sponsor's protocol ID
- 200807728
- Status last verified
- Jun 2017
- First submitted
- 18 Jun 2009
- Last updated
- 2 Jul 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Xia C, Leon-Ferre R, Laux D, Deutsch J, Smith BJ, Frees M, Milhem M. Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide). Cancer Chemother Pharmacol. 2014 Oct;74(4):691-7. doi: 10.1007/s00280-014-2501-1. Epub 2014 Jul 26.
PubMed 25062770
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase Ib/II: Epigenetic Modification of Chemosensitivity and Apoptosis in Metastatic Melanoma: Treatment of a Resistant Disease Using Decitabine, Temozolomide and Panobinostat
- ClinicalTrials.gov ID
- NCT00925132
- Acronym / sponsor ID
- 200807728
- Conditions
- Metastatic Melanoma
- Keywords
- Metastatic, Melanoma, Epigenetic, Temozolomide, Decitabine, Panobinostat, LBH589
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Change in the number of approved drugs for metastatic melanoma
- Enrolment
- 39 participants (actual)
- Lead sponsor
- University of IowaUniversity, hospital or other
- Collaborators
- Holden Comprehensive Cancer Center, Novartis Pharmaceuticals
- Study start
- Dec 2009 (actual)
- Primary completion
- Nov 2014 (actual)
- Study completion
- Dec 2016 (actual)
- First posted
- 19 Jun 2009 (estimated)
- Results
- Posted 2 Jul 2017
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 treat metastatic melanoma with a combination of standard chemotherapy (decitabine and Temozolomide in a dose escalation scheme) with an study drug called panobinostat. This combination is proposed to unlock genes that may contribute to mechanisms that cause tumor growth.
The primary objectives of this study are:
- To evaluate the safety and tolerability of the proposed schedule of decitabine, temozolomide and panobinostat in the treatment of metastatic melanoma.
- To define any Dose Limiting Toxicity (DLT) and maximum tolerated dose (MTD) of the combination of decitabine, temozolomide and panobinostat.
Detailed description
Most chemotherapeutics target rapidly proliferating cells, leaving quiescent cells and those with extended cell cycles unaffected. The investigators propose that this combination of decitabine, temozolomide, and panobinostat will target both melanoma stem cells and rapidly proliferating melanoma cells. The use of two drugs that regulate gene expression epigenetically (panobinostat and decitabine) in combination with a chemotherapeutic agent (temozolomide) is hypothesized to:
- induce expression genes (e.g., Apaf-1) that increase chemosensitivity of tumor cells and enhance apoptosis
- potentiate the cytotoxic effect of temozolomide by epigenetic modulation, and
- induce proliferation and differentiation of tumor stem cells, thus enabling senescence and apoptosis.
Secondary objectives:
- To measure overall survival
- To measure the time to progression of patients treated with this combination in comparison to patients treated historically with DTIC (the current standard of care).
- To evaluate treatment response with FDG PET and compare FDG PET with conventional imaging for treatment response assessment.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Temozolomide, Decitabine, Panobinostat | Experimental | Drug: Temozolomide, Decitabine, PanobinostatTemozolomide - given each cycle. Decitabine - 6 cohorts with dose escalation. Panobinostat - 6 cohorts with dose escalation. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Male or female patients aged ≥ 18 years old
- ECOG Performance Status of ≤ 2
- Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
- Patients must have measurable disease according to RECIST and CHOI criteria. The minimum target-lesion diameter should have double the CT slice thickness, i.e., 10 mm
- Patients must meet the following laboratory criteria:
Key exclusion criteria (17 listed)
- Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer
- Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
- Impaired cardiac function including any one of the following: Screening ECG with a QTc > 450 msec confirmed by central laboratory prior to enrollment to the study; Patients with congenital long QT syndrome; History of sustained ventricular tachycardia; Any history of ventricular fibrillation or torsades de pointes; Bradycardia defined as heart rate < 50 beats per minute. Patients with a pacemaker and heart rate ≥ 50 beats per minute are eligible; Patients with a myocardial infarction or unstable angina within 6 months of study entry; Congestive heart failure (NY Heart Association class III or IV);Right bundle branch block and left anterior hemiblock (bifascicular block)
- Uncontrolled hypertension
- Concomitant use of drugs with a risk of causing torsades de pointes
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 |
|---|---|---|
| Temozolomide, Decitabine, PanobinostatAlso: LBH589Temozolomide - given each cycle. Decitabine - 6 cohorts with dose escalation. Panobinostat - 6 cohorts with dose escalation. | Drug | Temozolomide, Decitabine, Panobinostat |
Primary outcome
Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level
Time frame: 6 weeks (one full cycle)
A DLT was any Grade 4 toxicity for neutrophils or platelets for ≥ 7 days, Grade 3 toxicity for neutrophils for ≥ 21 days, any Grade 3 solid organ toxicity not explainable by another cause (e.g. neurotoxicity, GI toxicity), metabolic/laboratory toxicity (≥10 x ULN AST) for ≥ 14 days, any Grade 4 infection or QTcF> 500msec EKG. DLTs were assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. All adverse events were collected and graded to determine DLTs as assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. DLTs were assessed to determine the recommended Decitabine and Panobinostat dose for the Phase II portion of the trial.
Phase 2 -Number of Patients With a Decrease in Tumor Size Using RECIST and CHOI's Criteria
Time frame: 12 weeks (2 cycles)
Tumor response rate was assessed using RECIST criteria in which a complete response was the disappearance of all target lesions; Partial response was a 30% decrease in the sum of the longest dimension (LD) of target lesions, relative to baseline measurement; Progressive disease was an increase of 20% or more in the sum of the LD of target lesions; and Stable disease was a decrease in tumor size of less than 30% or increase of less than 20%. Tumor response rate was also assessed using CHOI's criteria in which a response was a 10% decrease in tumor size or a 15% decrease in tumor density on contrast-enhanced computed tomography scan. Tumor response rates were assessed in order to determine effectiveness of the treatment regimen which was defined by the response rate of at least 30% as measured by either the RECIST or Choi's criteria, and ineffective if the rate is less than 15% on both.
1 secondary outcome
Phase 2 - Number of Participants With Disease Progression
Time frame: 5 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 25062770Xia C, Leon-Ferre R, Laux D, Deutsch J, Smith BJ, Frees M, Milhem M. Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide). Cancer Chemother Pharmacol. 2014 Oct;74(4):691-7. doi: 10.1007/s00280-014-2501-1. Epub 2014 Jul 26.
- 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.
Mohammed Milhem, MD principal investigator
University of Iowa
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 Temozolomide, Decitabine, Panobinostat in people with Metastatic Melanoma, run by University of Iowa 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 14 inclusion and 17 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 2 Jul 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?
Yes. Results are posted in the registry (first posted 2 Jul 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Phase I - Number of Participants With Dose Limiting Toxicities (DLTs) at a Given Dose Level (time frame: 6 weeks (one full cycle)). 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 NCT00925132, 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 2 Jul 2017.