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Phase Ib/II: Epigenetic Modification of Chemosensitivity and Apoptosis in Metastatic Melanoma: Treatment of a Resistant Disease Using Decitabine, Temozolomide and Panobinostat


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Metastatic Melanoma

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Trial Information

Phase Ib/II: Epigenetic Modification of Chemosensitivity and Apoptosis in Metastatic Melanoma: Treatment of a Resistant Disease Using Decitabine, Temozolomide and Panobinostat


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.


Inclusion Criteria:



1. Male or female patients aged ≥ 18 years old

2. ECOG Performance Status of ≤ 2

3. Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed

4. 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

5. 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

6. Baseline ECHO must demonstrate LVEF ≥ the lower limit of the institutional normal.

7. TSH and free T4 within normal limits (patients may be on thyroid hormone replacement)

8. 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

9. Any patient with the diagnosis of metastatic melanoma from any site. These include
untreated patients or those treated with chemotherapy or biochemotherapy.

10. Must not have taken a hypomethylating agent or a histone deacetylase agent in the
treatment of their disease.

11. Any patient with metastatic melanoma regardless of prior treatment will be eligible.

12. 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.

13. Patients with CNS disease are eligible for treatment only after their CNS disease has
been directly addressed with radiation therapy.

Exclusion Criteria:

1. Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer

2. Patients who will need valproic acid for any medical condition during the study or
within 5 days prior to first panobinostat treatment

3. 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)

4. Uncontrolled hypertension

5. Concomitant use of drugs with a risk of causing torsades de pointes

6. Concomitant use of CYP3A4 inhibitors

7. Patients with unresolved diarrhea > CTCAE grade 1

8. Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of oral panobinostat

9. Other concurrent severe and/or uncontrolled medical conditions

10. 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.

11. Concomitant use of any anti-cancer therapy or radiation therapy.

12. Patients who have no measurable disease.

13. 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.

14. 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

15. 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

16. Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C;
baseline testing for HIV and hepatitis C is not required

17. Patients with any significant history of non-compliance to medical regimens or with
inability to grant a reliable informed consent

Type of Study:

Interventional

Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase I - to evaluate the safety and tolerability of the proposed schedule of decitabine, temozolomide and panobinostat in the treatment of metastatic melanoma.

Outcome Time Frame:

15 months

Safety Issue:

Yes

Authority:

United States: Food and Drug Administration

Study ID:

200807728

NCT ID:

NCT00925132

Start Date:

January 2010

Completion Date:

June 2014

Related Keywords:

  • Metastatic Melanoma
  • Metastatic
  • Melanoma
  • Epigenetic
  • Temozolomide
  • Decitabine
  • Panobinostat
  • LBH589
  • Melanoma

Name

Location

University of Iowa Hospitals and ClinicsIowa City, Iowa  52242