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A Phase I Study of Intralesional Administration of an Adenovirus Vector Expressing the HSV-1 Thymidine Kinase Gene (AdV.RSV-TK) in Combination With Escalating Doses of Ganciclovir in Patients With Cutaneous Metastatic Malignant Melanoma

Phase 1
18 Years
Not Enrolling
Melanoma (Skin)

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Trial Information

A Phase I Study of Intralesional Administration of an Adenovirus Vector Expressing the HSV-1 Thymidine Kinase Gene (AdV.RSV-TK) in Combination With Escalating Doses of Ganciclovir in Patients With Cutaneous Metastatic Malignant Melanoma

OBJECTIVES: I. Determine the maximum tolerated dose of ganciclovir administered IV every 12
hours for 7 days in combination with adenovirus RSV-TK administered by direct intralesional
injection in patients with cutaneous or subcutaneous metastatic malignant melanoma. II.
Determine the dose limiting toxicities of this regimen in this patient population. III.
Evaluate the response (both local and at distant metastatic sites), duration of response,
response by ganciclovir dose, and any impact local treatment with adenovirus RSV-TK and
ganciclovir "suicide" gene therapy may have on overall survival in these patients.

OUTLINE: This is a dose escalation study of ganciclovir. Patients are stratified according
to response of the index lesion and other metastatic disease sites. Patients receive an
intratumoral injection of adenovirus RSV-TK on day 1. Ganciclovir IV is administered every
12 hours on days 3-10 for a total of 14 doses. Patients sustaining a partial response (PR)
or complete response (CR) may be retreated 2 weeks after documented PR or CR. Cohorts of 3-6
patients receive escalating doses of ganciclovir until the maximum tolerated dose (MTD) is
determined. The MTD is defined as the dose preceding that at which 2 of 6 patients
experience dose limiting toxicities. Patients are followed at 3 weeks, 4 weeks, 60 days,
then every 2 months for 6 months, and then every 3 months for 1.5 years.

PROJECTED ACCRUAL: A maximum of 27 patients will be accrued for this study.

Inclusion Criteria

DISEASE CHARACTERISTICS: Histologically confirmed advanced stage IV malignant melanoma M1
All pathologic subtypes eligible Tridimensionally measurable disease At least 1 discreet
easily accessible and measurable cutaneous or subcutaneous lesion of a volume no greater
than 3 cm3 by physical examination using Vernier calipers Ulcerated or necrotic lesions
may not serve as index lesion Not a candidate for curative surgical resection Visceral
metastases, including brain lesions, eligible provided no rapidly progressive CNS
metastases likely to result in death within 3 months

PATIENT CHARACTERISTICS: Age: 18 and over Performance status: Karnofsky 60-100% Life
expectancy: Greater than 3 months Hematopoietic: Absolute neutrophil count at least
1,800/mm3 Platelet count at least 100,000/mm3 Hemoglobin at least 9.0 g/dL Hepatic: BUN no
greater than 1.5 times upper limit of normal (ULN) Bilirubin no greater than 1.5 times ULN
Renal: Creatinine no greater than 1.8 mg/dL OR Creatinine clearance at least 70 mL/min
Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective
contraception during and for 3 months after study No other clinically significant medical
disease that is poorly controlled and/or expected to impact patient survival or that would
preclude study therapy No significant cognitive impairment No serious active infection
requiring intravenous antibiotic or antiviral therapy No clinical AIDS No primary
immunodeficiencies No other concurrent active malignancy No history of sensitivity to
ganciclovir or other antiviral drugs of this family No prior severe reaction to adenovirus
or herpes virus infection (e.g., toxic epidermal necrolysis or Stevens-Johnson syndrome)

PRIOR CONCURRENT THERAPY: Biologic therapy: At least 4 weeks since prior biological
response modifier therapy (e.g., interleukin-2, interferon) and recovered No prior gene
therapy using adenoviral based vectors, chimeric adenoviral based vectors, HSV-tk or other
thymidine kinase based therapy No concurrent biological response modifier therapy No other
concurrent gene therapy including ribozyme and antisense based therapy Chemotherapy: At
least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas, melphalan, or mitomycin)
and recovered No concurrent antineoplastic chemotherapy Endocrine therapy: Concurrent
replacement or therapeutic corticosteroids allowed Radiotherapy: Prior radiotherapy
allowed provided index lesion not within radiation field Recovered from prior radiotherapy
No concurrent radiotherapy except for CNS metastases provided index lesion not within
radiation field Surgery: See Disease Characteristics Recovered from prior surgery Other:
No other concurrent ganciclovir, acyclovir, or similar antiviral drug No concurrent
immunosuppressive therapy (e.g., organ allograft)

Type of Study:


Study Design:

Primary Purpose: Treatment

Principal Investigator

John C. Morris, MD

Investigator Role:

Study Chair

Investigator Affiliation:

NCI - Metabolism Branch;MET


United States: Federal Government

Study ID:




Start Date:

March 2000

Completion Date:

Related Keywords:

  • Melanoma (Skin)
  • stage IV melanoma
  • recurrent melanoma
  • lentigo maligna malignant melanoma
  • superficial spreading malignant melanoma
  • acral lentiginous malignant melanoma
  • nodular malignant melanoma
  • Melanoma



Baylor College of Medicine Houston, Texas  77030
Clinical Genetherapy Branch Bethesda, Maryland  20892
Metabolism Branch Bethesda, Maryland  20892