This study will establish the role of surgical versus nonsurgical approaches in patients whose melanoma has spread to distant sites. Results will help clinicians develop a standardized initial approach that prolongs survival and optimizes quality of…
ID
Source
Brief title
Condition
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
This study is open to patients with Stage IV metastatic melanoma who are able
to have all sites of known disease surgically removed or ablated and have
metastases in no more than 3 visceral organs. Patients with brain or bone
metastases are not eligible for the study. Eligibility
for resection must be confirmed by a participating surgeon who confirms the
potential to resect all known disease.
Secondary outcome
1. To determine whether surgical resection with or without BCG as initial
therapy for Stage IV metastatic melanoma will prolong melanoma-specific
survival (MSS) as compared to initial BMT. Melanoma-specific survival is
defined as the time from randomization to death from melanoma.
2. Time to progression of initial metastatic sites: To determine whether
surgical resection with or without BCG as initial therapy for Stage IV
metastatic melanoma will prolong progression-free survival (PFS) relative to
best medical treatment as initial therapy. For this study, PFS is defined as
the time from randomization to disease recurrence at initial metastatic site in
patients rendered disease-free by surgery, or time from randomization to
RECIST-defined progression of target lesions in patients receiving best medical
therapy or those having residual disease following surgery.
3. Time to development of new metastatic sites: To determine whether surgical
resection with or without adjuvant BCG as initial therapy for Stage IV
metastatic melanoma will prolong time to the development of new metastatic
sites of disease relative to best medical therapy. This endpoint is defined as
the time from randomization to disease recurrence at new metastatic sites in
patients rendered disease-free by surgery, or time from randomization to the
development of new metastatic sites of disease in patients in the best medical
therapy group. Progression of existing lesions in the best medical therapy arm
will not be considered an event for this endpoint (see progression-free
survival above, #2).
4. To determine whether adjuvant treatment with intradermal Bacillus Calmette-
Guérin (BCG) will improve melanoma-specific or disease-free survival in
patients undergoing resection of melanoma metastases.
5. To evaluate the correlation between tumor volume doubling time and PFS as
well as melanoma-specific survival (MSS) in patients with surgery or medical
therapy.
6. To determine whether surgical resection as initial therapy for Stage IV
metastatic melanoma will improve quality of life (QOL) relative to best medical
treatment as initial therapy.
7. To determine the 7. prognostic and predictive value of molecular blood
biomarker measurements of circulating tumor cells (CTC) and circulating DNA
after randomization and after resection in the surgery arm.
8. To determine what proportion of all stage IV patients at the time of initial
diagnosis of distant metastases are possible candidates for surgical resection
of all metastatic disease and what proportion of those undergoing surgery can
be completely resected.
9. To discover predictive immune and molecular biomarkers in patients with
Stage IV metastatic melanoma that may correlate with prognosis and help select
patients for best outcomes following medical or surgical therapy.61, 62
10. To determine whether surgical resection of Stage IV metastatic melanoma
will alter immune responsiveness to urinary tumor associated antigen (UTAA),
ganglioside, or other melanoma antigens relative to best medical therapy
without resection
Background summary
This study will establish the role of surgical versus nonsurgical approaches in
patients whose melanoma has spread to distant sites. Results will help
clinicians develop a standardized initial approach that prolongs survival and
optimizes quality of life. Results also will indicate whether Bacillus
Calmette-Guerin (BCG) postoperative immunotherapy significantly improves the
outcome of patients treated with surgery.
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.
(see prototcol Backroundinformation and scientific rationale pp 15-26)
Study objective
This study will establish the role of surgical versus nonsurgical approaches in
patients whose melanoma has spread to distant sites. Results will help
clinicians develop a standardized initial approach that prolongs survival and
optimizes quality of life. Results also will indicate whether Bacillus
Calmette-Guerin (BCG) postoperative immunotherapy significantly improves the
outcome of patients treated with surgery.
(see prototcol Study objectives pp 27-28))
Study design
This is a Phase III, randomized, international, multicenter study of
metastasectomy 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.
Prior to enrolling in this study, patients with Stage IV melanoma will undergo
a screening phaseto determine if their disease is resectable, thus making them
potentially eligible for the trial. Patients will be assessed clinically and
radiographically to determine the extent of disease, and
all patients must be evaluated by a participating surgeon to determine
resectability as an eligibility criterion (see Chart 1 in Section 4.10.1).
Patients who enroll in the study will be randomly assigned to undergo initial
therapy either by surgical resection (+/- BCG) or best
medical therapy. 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 according to 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, such as DTIC or high-dose IL-2. See
Section 5.3 for discussion of BMT.
All patients will be followed for up to 5 years for clinical and correlative
endpoints, including overall survival, time to development of new metastatic
sites of disease, progression-free survival, melanoma-specific survival,
quality of life, and correlative laboratory studies, including
tumor volume doubling time and development of anti-melanoma antibodies.
Patients receiving BCG will also undergo immunologic evaluations to determine
reactivity to PPD skin testing. Patients in the surgical resection arms should
have their operations completed within 3 weeks after randomization. If upon
operation, these patients are found to have unresectable disease, they will
receive best available medical or radiation therapy. Two post-surgery visits
will be required for BCG administration. The first dose of BCG will be given no
earlier than 4 weeks
after surgery, and the second BCG dose will follow 2 weeks later. Follow-up
visits will then occur at months 2, 4, 6, 8, 10, and 12 in year 1; months 3, 6,
9, and 12 in year 2; months 4, 8 and 12 in year 3; then every 6 months for
years 4 and 5. The follow-up schedule will be based
on the patient*s surgery date (Day 0) and, for BCG patients, recovery from
surgery (see Study Calendar, Appendix 1). The treatment schedule for medical
therapy patients will be determined by the regimen they receive, but they
should be examined and scanned at least as often as the
above stated follow-up regimen.
Patients receiving medical therapy will follow the treatment schedule according
to theirdesignated regimen, but will still need to be seen at a participating
study site for follow-up visits at least every 2 months in year 1; every 3
months in year 2; every 4 months in year 3; and every
6 months for years 4-5 (see Study Calendar, Appendix 1, for a detailed
schedule). The followupschedule will be based on the patient*s start date for
medical therapy (Day 0).
Patients in any treatment arm whose disease progresses or recurs after initial
treatment may undergo salvage therapy as appropriate. Salvage treatments may
include additional surgical resection for those in the surgery arms whose
disease, according to the judgment of the clinical investigator, is still
resectable. Those in the surgery arms whose disease is not resectable will
receive the best available medical therapy. Patients in the best medical
therapy arm who progress and/or recur may continue with a different medical
therapy or may undergo surgical
resection if their disease is still resectable, according to the judgment of
the clinical investigator. The medical and surgical oncologist team will
determine whether patients with stable disease orpartial responses should
continue their medical therapy.
(see prototcol Study design29-30)
Study burden and risks
Surgery: Potential risks from undergoing surgery for this study are the
standard risks of surgical resection and depend on the site of the metastases
to be resected.
BCG; Nearly all patients receiving BCG experience local erythema, induration,
and inflammation of the skin at the injection sites. When injected
intradermally, the expected reaction is a small red papule that scales, forms a
localized abscess, ulcerates and dries, leaving a small pink or bluish sc
Systemic treatment: Potential risks from medical therapy will vary depending on
the regimen used and individual patient sensitivity but generally include
weight loss, loss of appetite, nausea and/or vomiting, fatigue, decrease in
blood counts, hair loss, as well as others specific to individual drugs.
Additional side effects depend on the regimen of drugs to be used for the
chosen medical or adjuvant therapy.
2200 santa Monica Boulevard
Santa Monica, CA 90404
US
2200 santa Monica Boulevard
Santa Monica, CA 90404
US
Listed location countries
Age
Inclusion criteria
Inclusion Criteria
All of the following inclusion criteria must be met and certification of eligibility must be
obtained from the Principal Investigator in order for the patient to be eligible. A completed,
signed and dated consent form is also required prior to randomization and prior to the
performance of any protocol-related procedures.;1. Patients must be at least 18 years of age and have a minimum life expectancy
(excluding melanoma) of 5 years.
2. All known disease must be surgically resectable in the opinion of a participating
surgeon.
3. Patients 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.
4. Patients may have up to 3 visceral organs involved. Any number of lesions up to
6 is allowed.
5. Patients must provide informed written consent for participation.
6. Patients must have ECOG performance status of 0 or 1.
7. Patients 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.
8. Laboratory values within 30 days of randomization:
a. WBC >3,000/mm3
b. Lymphocytes >800/mm3
c. Platelets >100,000/mm3
d. Creatinine <2.0 mg/dL
e. Bilirubin <2.0 mg/dL
f. Alkaline phosphatase < 2X upper
g. SGOT < 2X ULN
h. SGPT < 2X ULN
i. LDH < 1.5X ULN
Exclusion criteria
Exclusion Criteria
If any of the following exclusion criteria is met, the patient is ineligible for the study.
1. Unresectable metastatic disease or more than 4 months since stage IV
diagnosis.
2. Brain or bone metastatic sites.
3. History of primary uveal or mucosal melanoma.
4. Another concomitant diagnosis that limits life expectancy to less than 5 years.
5. 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.
6. More than 3 involved visceral organ sites or more than 6 metastatic lesions.
7. Psychiatric disorder or organic brain syndrome that might preclude participation
in the protocol.
8. 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.
9. Serious cardiac, gastrointestinal, hepatic or pulmonary disease that would make
surgical resection high-risk.
10. Pregnancy
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-021030-56-NL |
| ClinicalTrials.gov | NCT01013623 |
| CCMO | NL31661.042.10 |