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A Phase II, Pharmacokinetic (PK), Pharmacodynamic (PD) and Biological Correlative Study of the Efficacy and Safety of Dual Antiangiogenic Inhibition Using Bevacizumab and Sorafenib in Patients With Advanced Malignant Melanoma


Phase 2
18 Years
N/A
Not Enrolling
Both
Melanoma (Skin)

Thank you

Trial Information

A Phase II, Pharmacokinetic (PK), Pharmacodynamic (PD) and Biological Correlative Study of the Efficacy and Safety of Dual Antiangiogenic Inhibition Using Bevacizumab and Sorafenib in Patients With Advanced Malignant Melanoma


OBJECTIVES:

Primary

- Determine the clinical biologic activity of sorafenib tosylate and bevacizumab, defined
as the sum of complete response, partial response, and prolonged stable disease for ≥
16 weeks, in patients with unresectable stage III or stage IV malignant melanoma
previously treated with at least 2 regimens of immunotherapy, cytokines, biologic
therapy, or vaccine therapy or in previously untreated patients who are not appropriate
candidates to receive aldesleukin-based treatment.

Secondary

- Evaluate the safety and tolerability of sorafenib tosylate and bevacizumab in these
patients.

- Evaluate the biologic activity of this regimen, in terms of time to progression,
progression-free survival at 6 months, and overall survival, in these patients.

- Describe significant pharmacokinetic interactions between bevacizumab and sorafenib
tosylate.

- Characterize the pharmacodynamic relationships between the plasma concentration of
sorafenib tosylate and bevacizumab and the effects of treatment on normal organ
function and tumor tissue in these patients.

- Identify predictive biomarkers of response to this regimen in these patients.

- Correlate changes in biological measurements with patient outcomes.

OUTLINE: This is an open-label, multicenter study.

Patients receive oral sorafenib tosylate on days 1-5, 8-12, 15-19, and 22-26 and bevacizumab
IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days in the absence of
unacceptable toxicity or disease progression.

Blood samples and tumor biopsies are obtained periodically for pharmacokinetic and
pharmacodynamic studies. Samples are examined by liquid chromatography, mass spectrometry,
immunohistochemistry, gene expression analysis, DNA mutation analysis, and genomic analysis
for biological markers.

After completion of study treatment, patients are followed for 4 weeks.

PROJECTED ACCRUAL: A total of 45 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed melanoma

- Unresectable (stage III) or metastatic (stage IV) disease

- Measurable disease, defined as ≥ 1 lesion that can be accurately and serially
measured in ≥ 1 dimension as ≥ 20 mm with conventional techniques or as ≥ 10 mm with
spiral CT scan

- Cutaneous lesions measuring ≥ 1 cm will be considered measurable disease

- No primary ocular melanoma

- No active CNS metastatic brain or meningeal tumors

- Prior CNS disease allowed provided it was definitely treated ≥ 3 months ago AND
there is no CNS disease by MRI or CT scan within the past 4 weeks

- No residual disease

PATIENT CHARACTERISTICS:

- Life expectancy > 12 weeks

- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

- WBC ≥ 3,000/mm³

- Absolute neutrophil count ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN

- Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min

- Serum amylase < 1.5 times ULN OR lipase < 1.5 times ULN

- Urine protein:creatinine ratio < 1.0 OR urine protein < 1,000 mg by 24-hour urine
collection

- No significant traumatic injury in the past 28 days

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 6 months after
completion of study treatment

- No history of allergic reactions attributed to compounds of similar chemical or
biological composition to sorafenib tosylate and bevacizumab or other agents used in
the study

- No known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

- None of the following medical conditions:

- New York Heart Association class III-IV congestive heart failure

- Cardiac arrhythmias, including atrial fibrillation if not adequately controlled

- Active coronary artery disease or ischemia (e.g., unstable angina,
cerebrovascular accident, transient ischemic attack, or myocardial infarction
within the past 6 months)

- Uncontrolled hypertension

- Clinically significant peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

- No seizure disorder requiring medication (e.g., antiepileptics)

- No history of or suspected HIV infection or clinically significant hepatitis B or C

- No serious or nonhealing wound, ulcer, or bone fracture

- No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within
the past 28 days

- No active clinically serious infections

- No dysphagia (difficulty swallowing)

- No substance abuse

- No medical, psychological, or social condition that may preclude study participation
or evaluation of the study results

- No prior or concurrent cancer that is distinct in primary site or histology from the
cancer being evaluated except cervical carcinoma in situ, treated basal cell
carcinoma, superficial bladder tumors (Ta, Tis, or T1) or any cancer treated with
intent to cure, rather than for palliation, < 3 years prior to study entry

PRIOR CONCURRENT THERAPY:

- No more than 2 prior immunotherapy, cytokine therapy, biologic therapy, or vaccine
therapy regimens (e.g., aldesleukin) for advanced or metastatic disease

- Prior single-agent immunotherapy or combinations of immunotherapy as first
treatment for advanced or metastatic disease allowed

- Prior immunotherapy, cytokine therapy, biologic therapy, or vaccine therapy
regimens in the adjuvant setting allowed

- No immunotherapy, cytokine therapy, biologic therapy, or vaccine therapy (e.g.,
aldesleukin) for advanced or metastatic disease within the past 4 weeks

- No prior organ allograft or stem cell transplantation

- No prior Ras-pathway inhibitors (including trastuzumab [Herceptin®], farnesyl
transferase inhibitors, or MEK inhibitors)

- No prior treatment with a drug that targets vascular endothelial growth factor (e.g.,
bevacizumab)

- No prior thalidomide or sorafenib tosylate

- No chemotherapy or radiotherapy within the past 4 weeks (6 weeks for nitrosoureas or
mitomycin C) and recovered

- Radiographic evidence of progression required for prior irradiated lesions

- No major surgical procedure or open biopsy within the past 28 days

- No Hypericum perforatum (St. John's wort) or rifampin within the past 3 weeks

- Concurrent full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 allowed
provided the following criteria are met:

- Patient has an in-range INR (usually between 2 and 3) on a stable dose of oral
anticoagulant or on a stable dose of low molecular weight heparin

- Patient has no active bleeding or pathological condition that carries a high
risk of bleeding (e.g., tumor involving major vessels or known varices)

- No other concurrent investigational agents

- No other concurrent anticancer agents or therapies

- No concurrent carbamazepine, phenytoin, or phenobarbital (drugs that induce CYP450 3A
activity)

- No concurrent St. John's wort or rifampin

- No concurrent radiotherapy

- No concurrent major surgery

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Response

Outcome Description:

Clinical biologic activity of treatment, defined as the sum of complete response, partial response, and prolonged stable disease for ≥ 16 weeks, upon treatment with the combination of sorafenib and bevacizumab, in patients with advanced metastatic melanoma previously treated with immunotherapy or in previously untreated patients who are not appropriate candidates to receive IL-2-based treatment.

Outcome Time Frame:

4 months

Safety Issue:

No

Principal Investigator

John Sarantopoulos, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Texas Health Science Center San Antonio

Authority:

United States: Food and Drug Administration

Study ID:

CDR0000502282

NCT ID:

NCT00387751

Start Date:

August 2006

Completion Date:

February 2009

Related Keywords:

  • Melanoma (Skin)
  • stage III melanoma
  • stage IV melanoma
  • recurrent melanoma
  • Melanoma

Name

Location

Brooke Army Medical CenterFort Sam Houston, Texas  78234-6200
Cancer Therapy and Research CenterSan Antonio, Texas  78229