Stage IV Surgery Versus Best Medical Therapy

This study is designed to examine the impact of surgical resection versus medical therapy as
initial treatment therapy for patients with Stage IV melanoma. Surgical resection is thought
to be efficacious in highly selected patients with solitary metastases, but not in patients
with multiple sites of metastases. Even in those with solitary metastases, there is
considerable debate among major melanoma centers over whether undergoing initial systemic
medical therapy prior to surgical resection should be preferred to initial surgical
resection upon Stage IV diagnosis. According to Dr. Dan Coit, Co-leader of the Melanoma
Disease Management Team at Memorial Sloan Kettering Cancer Institute in New York, a trial of
initial medical therapy is their standard approach on the multidisciplinary melanoma service
even for patients with solitary distant metastases (personal communication, 15 Dec 2009).

Many who favor upfront medical therapy believe that delay before surgical resection may
avoid unnecessary surgery by identifying patients who progress early due to the outgrowth of
occult metastases at multiple sites, which may make the patient unresectable.

This is a Phase III, randomized, international, multicenter study of metastasectomy with or
without BCG versus best medical therapy as initial therapy in Stage IV melanoma. This study
has three arms: surgical resection plus BCG as an immune adjuvant, surgical resection plus
observation, and best medical therapy (BMT). Since no systemic medical therapy has been
demonstrated to be superior to DTIC and multiple new therapies are being evaluated, the
choice as to what constitutes best medical therapy will be determined by the individual
investigator based on the standard of care for systemic medical therapy at that particular
multicenter site. Best systemic medical therapy may include clinical trials of new agents or
standard non-protocol treatments (e.g., DTIC or Temodar according to the standard of care at
the multi-center site).

Patients who progress on the best medical treatment arm may switch to a different medical
therapy or, if appropriate, have surgical therapy; similarly, surgery patients may have
additional surgical resection or receive medical therapy.

Inclusion Criteria:

- Patients must provide informed written consent for participation.

- At least 18 years of age

- Have a minimum life expectancy (excluding melanoma) of 5 years.

- All known disease must be surgically resectable in the opinion of a participating
surgeon.

- Must have a histologic diagnosis of Stage IV melanoma arising from a primary
cutaneous site or visceral metastasis from an unknown primary site and be within 4
months of initial stage IV diagnosis.

- Up to 3 visceral organs involved

- Up to 6 lesions allowed

- Must have ECOG performance status of 0 or 1.

- Must be in good general health with no serious co-morbid illness. Good clinical
judgment must be exercised in careful selection of patients who are candidates for
surgical resection of distant metastases.

- Laboratory values within 30 days of randomization:

1. WBC >3,000/mm3

2. Lymphocytes >800/mm3

3. Platelets >100,000/mm3

4. Creatinine <2.0 mg/dL

5. Bilirubin <2.0 mg/dL

6. Alkaline phosphatase < 2X upper limit of normal (ULN)

7. SGOT < 2X ULN

8. SGPT < 2X ULN

9. LDH < 1.5X ULN

Exclusion Criteria:

- Unresectable metastatic disease or more than 4 months since stage IV diagnosis.

- Brain or bone metastatic sites.

- History of primary uveal or mucosal melanoma.

- Another concomitant diagnosis that limits life expectancy to less than 5 years.

- Chronic immunosuppression due to inherited, acquired or iatrogenic immune defect.
This includes active HIV, hepatitis, or use of immunosuppressive medications as a
component of anti-rejection therapy for organ transplant, as treatment for an
autoimmune disease.

- More than 3 involved visceral organ sites or more than 6 metastatic lesions.

- Psychiatric disorder or organic brain syndrome that might preclude participation in
the protocol.

- Diagnosis of other malignancy in the past 5 years except adequately treated low grade
malignancies such as basal cell carcinoma, cutaneous squamous cell carcinoma,
carcinoma-in-situ of the cervix, or other neoplasm that will not limit life
expectancy to less than 5 years.

- Serious cardiac, gastrointestinal, hepatic or pulmonary disease that would make
surgical resection high-risk.

- Pregnancy