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Phase 1/2 Study Epigenetic Modification of BRAF-mutated Metastatic Melanoma: Treatment of a Resistant Disease Using Decitabine Combined With Vemurafenib

Phase 1/Phase 2
18 Years
Not Enrolling
Metastatic Melanoma, Melanoma, BRAF-mutated Metastatic Melanoma, V600EBRAF-mutated Metastatic Melanoma

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Trial Information

Phase 1/2 Study Epigenetic Modification of BRAF-mutated Metastatic Melanoma: Treatment of a Resistant Disease Using Decitabine Combined With Vemurafenib

Primary Objectives Evaluate the safety and tolerability of the proposed schedule of
Decitabine and Vemurafenib in the treatment of metastatic melanoma.

Ensure appropriate demethylation occurs. This will be assessed by measuring the percentage
of Hemoglobin F by HPLC before and 2, 4 and 8 weeks after treatment with Decitabine,
assuming a dose-limiting toxicity (DLT) or the maximum-tolerated dose (MTD) does not occur.
This data will be used to calculate the ideal cohort for the phase II portion.

Assess tumor response rates by Response Evaluation Criteria in Solid Tumors "RECIST"

Secondary Objectives To measure the time to progression of patients treated with this
combination in comparison to patients treated historically with Vemurafenib alone (the
current standard of care in BRAF-mutated patients).

Inclusion Criteria

Inclusion criteria:

Male or female >/= 18 years old ECOG Performance Status of
Meet the following lab criteria:

Hematology Neutrophil count >1500/mm3 Platelet count >100,000/mm3 Hemoglobin >/= 9 g/dL
Biochemistry AST/ALT transaminase elevation is due to disease involvement Serum bilirubin creatinine /= 50 ml/min by Cockcroft-Gault
equation Total serum calcium (corrected for serum albumin) >/= 8.5 mg/dL or ionized
calcium >/= 3.8 mg/dL Serum potassium >/= LLN Serum sodium >/= LLN Serum albumin >/= 3g/dl
Baseline MUGA or ECHO must demonstrate LVEF >/= the lower limit of the institutional

TSH and free T4 within normal limits, may be on thyroid hormone replacement Women of
childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of
the first dose of study drug. Willing to use 2 methods of contraception, one being a
barrier method during the study and for 3 months after last study drug dose.

Any patient with metastatic melanoma (any site) whose tumor is V600EBRAF positive,
regardless of prior treatment.

Prior treatment with Vemurafenib will be allowed Must not have taken a hypomethylating
agent. Must have had disease progression on or following most recent treatment regimen or
on presentation for the first time with metastatic disease.

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

Exclusion criteria:

Prior Decitabine for the treatment of cancer

Impaired cardiac function including any one of the following:

Screening ECG with a QTc > 460 msec confirmed by central lab prior to enrollment;
congenital long QT syndrome; History of sustained ventricular tachycardia; History of
ventricular fibrillation/torsades de pointes; Bradycardia defined as heart rate (hr) < 50
beats per minute; Patients with a pacemaker and hr >/= 50 beats per minute are eligible;
Patients with a myocardial infarction or unstable angina within 6 mos of study entry; CHF
(NYHA class III or IV); Right bundle branch block and left anterior hemiblock;
Uncontrolled hypertension Concomitant use of drugs with a risk of causing torsades de
pointes Concomitant use of CYP3A4, CYP1A2, or CYP2D6 substrates Unresolved diarrhea >
CTCAE grade 1 Impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of Vemurafenib Other concurrent severe or uncontrolled
medical conditions Patients who have received prior therapies will be allowed to enroll
after a wash-out period: Chemotherapy - 3 week (wk) wash-out; Oral agents - 2 wk wash-out
(Except Vemurafenib, no wash-out period); Investigational agents - 3 wk wash-out;
Immunotherapy - 4 wk wash-out; Palliative radiation therapy to bone/brain - 2 wk wash-out;
Major radiation or surgical procedure - 3 wk wash-out Concomitant use of any anti-cancer
or radiation therapy. No measurable disease Pregnant, breast-feeding women or WOCBP not
willing to use a double barrier method of contraception during the study and 3 months
after the end of treatment. One method of contraception must be a barrier method. WOCBP
are defined as sexually mature women who have not undergone a hysterectomy or have not
been naturally postmenopausal for at least 12 consecutive months (who has had menses any
time in the preceding 12 consecutive months).

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 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 Known positivity for
HIV or hepatitis C Any significant history of non-compliance to medical regimens or with
inability to grant a reliable informed consent

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose-limiting toxicities per CTCAE 4.0;

Outcome Time Frame:

After one cycle (28 days)

Safety Issue:


Principal Investigator

Mohammed Milhem, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Iowa


United States: Food and Drug Administration

Study ID:




Start Date:

July 2013

Completion Date:

Related Keywords:

  • Metastatic Melanoma
  • Melanoma
  • BRAF-mutated Metastatic Melanoma
  • V600EBRAF-mutated Metastatic Melanoma
  • Metastatic melanoma
  • melanoma
  • BRAF-mutated Metastatic Melanoma
  • V600EBRAF-mutated metastatic melanoma
  • Decitabine
  • Vemurafenib
  • Melanoma



University of Iowa Hospitals & Clinics Iowa City, Iowa  52242