Treatment of Resistant Metastatic Melanoma Using Decitabine, Temozolomide and Panobinostat

NCT00925132 | Terminated Phase 1 Results DMC

• 1 other identifier: 200807728
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Metastatic Melanoma

Keywords

Metastatic; Melanoma; Epigenetic; Temozolomide; Decitabine; Panobinostat; LBH589

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  12 weeks (2 cycles)

Secondary Outcomes (1)

• Phase 2 - Number of Participants With Disease Progression

  5 years

Study Arms (1)

Temozolomide, Decitabine, Panobinostat

EXPERIMENTAL

Temozolomide - given each cycle. Decitabine - 6 cohorts with dose escalation. Panobinostat - 6 cohorts with dose escalation.

Drug: Temozolomide, Decitabine, Panobinostat

Interventions

Temozolomide, Decitabine, Panobinostat DRUG

Temozolomide - given each cycle. Decitabine - 6 cohorts with dose escalation. Panobinostat - 6 cohorts with dose escalation.

Also known as: LBH589

Temozolomide, Decitabine, Panobinostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• University of Iowa: lead
• Holden Comprehensive Cancer Center: collaborator
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

Related Publications (1)

• 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.

  PMID: 25062770 DERIVED

MeSH Terms

Conditions

Melanoma; Neoplasm Metastasis

Interventions

Temozolomide; Decitabine; Panobinostat

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azacitidine; Aza Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Hydroxamic Acids; Hydroxylamines; Amines; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

This study was closed to enrollment early as there was a change in the number of approved drugs for metastatic melanoma, making Temozolomide as a chemotherapy agent, an unlikely treatment for metastatic melanoma.

Results Point of Contact

• Title: Mohammed Milhem
• Organization: University of Iowa

319-356-2324

Study Officials

• Mohammed Milhem, MD

  University of Iowa

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Associate Professor

Study Record Dates

• First Submitted: June 18, 2009
• First Posted: June 19, 2009
• Study Start: December 1, 2009
• Primary Completion: November 1, 2014
• Study Completion: December 1, 2016
• Last Updated: July 2, 2017
• Results First Posted: July 2, 2017

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)