MELANOMA COMMITTEE 2000/Melanoma.pdf · nant Melanoma. Publication Status. Dr. Whitehead S9512 A...

APRIL 15 - 17, 2000 SOUTHWEST ONCOLOGY GROUP MELANOMA 1

MELANOMA COMMITTEE

Chair: Vernon K. Sondak, M.D.Vice Chair: Lawrence E. Flaherty, M.D.

Statisticians: P.Y. Liu, Ph.D.

Joseph M. Unger, M.S.

Data Coordinators: Camille White, B.S., R.R.A.Lauren Crowley, B.A.

Protocol Coordinator: Suzan J. Myers, B.S.

Medical Oncology: Lawrence E. Flaherty, M.D.Pathology: Ralph J. Tuthill, M.D.

Radiation Oncology: Nancy S. Boutin, M.D.Surgery: James A. Warneke, M.D.

Melanoma Biology: Jeffrey A. Sosman, M.D.Non-Melanoma Skin Cancer: Raymond A. Kempf, M.D.

Cancer Control Liaison: James G. Jakowatz, M.D.

Nurse: Pamela Bradley, R.N., O.C.N.

Clinical Research Associates: Renee Robinson, C.C.R.A.Karen Egan, B.A., C.C.R.A.

2 MELANOMA SOUTHWEST ONCOLOGY GROUP APRIL 15 - 17, 2000

CONTENTS

Melanoma Committee Agenda ................................................................................3

Initial Registrations to Therapeutic Studies..............................................................5

Patient Registration by Study and Arm....................................................................5

E1695 Biologic Intergroup......................................................................................7

E2697 Biologic Intergroup......................................................................................8

E3695 Phase III Intergroup .....................................................................................9

S0008 Phase III Intergroup.................................................................................... 11

S9035 Phase III..................................................................................................... 12

S9430 Phase II Intergroup..................................................................................... 16

S9431 Biologic Intergroup .................................................................................... 18

S9512 Phase III Intergroup (E1694) ...................................................................... 20

S9716 Phase II...................................................................................................... 22

S9804 Phase II...................................................................................................... 23


Melanoma Committee Agenda

Scientific SessionS9035 Presentation of Results: Adjuvant Allogeneic Melanoma Vaccine

Trial in T3N0M0 Melanoma, Phase III.Dr. Sondak

Active Studies

E2697 Correlation of DNA Damage Index and Clinical Response in theContext of ECOG Trial E3695.

Dr. Sosman

E3695 A Randomized Phase III Trial of Concurrent Biochemotherapywith Cisplatin, Vinblastine, Dacarbazine, IL-2 and InterferonAlpha-2b versus Cisplatin, Vinblastine, Dacarbazine Alone inPatients with Metastatic Malignant Melanoma.

Dr. Flaherty

S9430 Phase II Trial of Complete Surgical Resection for Stage IVMelanoma with Distant Metastases-Surgical Resection withBiological and Clinical Follow-up.

Drs. Sosman and Warneke

S9431 Molecular, Cytogenetic, and Cellular Biology Studies in Meta-static Melanoma Patients.

Drs. Sosman and Tuthill

S9716 Treatment of Metastatic Merkel Cell Skin Cancer. Dr. Kempf

S9804 Phase II Trial of Navelbine in Disseminated Malignant Mela-noma.

Dr. Whitehead

Closed Studies

E1695 An Evaluation of the Immunologic Mechanism of GM2-KLH/QS-21 Vaccination in the Context of ECOG Trial E1694(S9512).

Dr. Sosman

S9111 Adjuvant Alpha Interferon in Node Positive and High-Risk NodeNegative Melanoma. Phase III. Update and Publication Status.

Dr. Flaherty

S9325 An Evaluation of the In Vivo Mechanism of Interferon Alpha-2b.Biologic. Update and Publication Status.

Dr. Sosman

S9505 Evaluation of Pyrazine Diazohydroxide in Disseminated Malig-nant Melanoma. Publication Status.

Dr. Whitehead

S9512 A Phase III Study of Adjuvant Ganglioside Vaccination GM2-KLH/QS-21 Therapy vs High-dose Interferon Alpha-2b (In-tronA) for High-Risk Melanoma. Update.

Drs. Sosman and Flaherty

S9622 Evaluation of CI-980 in Patients with Disseminated MalignantMelanoma and No Prior Chemotherapy. Publication Status.

Dr. Whitehead


Proposed Studies

S0008 Phase III Trial of High Dose Interferon Alpha-2b vs Cisplatin,Vinblastine, DTIC plus IL-2 and Interferon in Patients with HighRisk Melanoma.

Dr. Flaherty

Replacement Node-Negative Adjuvant Therapy Trials. Drs. Foon, Urba and Sondak

Defined Antigen Vaccines in Stage IV Melanoma. Dr. Weber

Other Possible Interferon Trials. Dr. Sondak

Other Phase II Agents. Dr. Flaherty

Subcommittee Reports

Pathology Dr. Tuthill

Melanoma Biology Dr. Sosman

Non-Melanoma Skin Cancer Dr. Kempf

Working Group Dr. Sondak


Initial Registrations to Therapeutic Studiesby 12 month Intervals

MELANOMA COMMITTEE

0

50

100

150

200

250

300

Time of registration

JAN 95DEC 95

91

140

64

JAN 96DEC 96

91

76

54

JAN 97DEC 97

57

45

46

JAN 98DEC 98

79

44

40

JAN 99DEC 99

59

49

52

MEMBER AFFILIATES CCOP

Patient Registration by Study and ArmMELANOMA COMMITTEE

July-Dec1999

Jan-June1999

July-Dec1998

AllPatients

E3695 Melan, Adv, CVD +/- IFN/IL-2 *

CVD 10 8 13 39CVD + IFN/IL-2 12 10 13 41

22 18 26 80 S9430 Melan, Adv, Comp Surg Res, Ph II

Surgical resection 3 6 6 36 S9431 Melan, Tissues and Serum

Tissues and serum 3 6 6 38 S9512 Melan, Adj, Vaccine YV� �,)1��E��Ph III *

GM2-KLH/QS-21 20 28 28 168+LJK�'RVH� �,)1��E 23 28 23 170

43 56 51 338

* For non-SWOG coordinated studies only SWOG registrations are shown.


Patient Registration by Study and ArmMELANOMA COMMITTEE (Continued)

July-Dec1999

Jan-June1999

July-Dec1998

AllPatients

S9716 Merkel Cell, Adv, CMF, Ph II

CMF 1 3 1 5 S9804 Melan, Adv, Navelbine, Ph II

Navelbine 7 1 0 8


E1695 Biologic Intergroup

Coordinating Group: ECOG

An Evaluation of the Immunologic Mechanism of GM2-KLH/QS-21 Vaccinationin the Context of ECOG Trial E1694 (S9512). Limited Institution.

Intergroup Participants:ECOG, SWOG, MDACC, MSKCC

Study Coordinators:J Kirkwood (ECOG), V Sondak, J Sosman,P Chapman (MSKCC), M Ross (MDACC)

Statisticians:PY Liu, J Unger

Data Coordinators:C White, L Crowley

Date Activated:11/01/1998

Date Closed:10/15/1999

ObjectivesTo determine the correlation between the developmentof serologic response to autologous melanoma andanti-GM2 antibody reactivity induced by immunizationagainst GMK or treatment with IFN alpha-2b.

To determine the correlation between development ofT-cell response to autologous melanoma and anti-GM2reactivity induced by immunization against GMK ortreatment with IFN alpha-2b.

To determine the correlation between the developmentof serologic and cellular immune reactivity againstautologous tumor and relapse-free or overall survivalof patients participating in the GMK and IFN arms ofS9512.

Patient PopulationPatients must be about to undergo surgery for mela-noma metastatic to regional lymph nodes and mustplan to be registered on and meet the eligibility re-quirements of S9512. Patients with stage T4N0M0primary melanoma are not eligible.

Specimens must be submitted per protocol.

Accrual GoalsIt is expected that 172 eligible patients will be accrued.

Summary StatementThis study was permanently closed on October 15,1999. No patients were registered through SWOG.


E2697/BIOLOGIC

E2697 Biologic Intergroup


Correlation of DNA Damage Index and Clinical Response in the Context ofECOG Trial E3695

Intergroup Participants:ECOG, SWOG

Study Coordinators:M Atkins (ECOG), J Sosman




ObjectivesTo determine the extent of cisplatin-induced DNAdamage in vitro in PBMC obtained from melanomapatients prior to treatment with chemotherapy or bio-chemotherapy and correlate the extent of DNA damagewith clinical response.

To determine the optimum cisplatin concentration withwhich to treat PBMC in vitro that will provide thehighest positive and negative predictive value for re-sponse to both chemotherapy and biochemotherapy.

Patient PopulationPatients must have been randomized to the parent pro-tocol E3695.

Accrual GoalsThe accrual goal is 200 patients (100 from the chemo-therapy group and 100 from the biochemotherapygroup of E3695).

Summary StatementThis study was activated on February 1, 2000.


E3695/III

E3695 Phase III Intergroup


A Randomized Phase III Trial of Concurrent Biochemotherapy with Cisplatin,Vinblastine, Dacarbazine, IL-2 and Interferon Alpha-2b versus Cisplatin,

Vinblastine, Dacarbazine Alone in Patients with MetastaticMalignant Melanoma

Intergroup Participants:ECOG, SWOG

Study Coordinators:M Atkins (ECOG), L Flaherty, V Sondak




Schema

RANDOMIZE

DTIC/CDDP/Vinblastine (CVD)

DTIC/CDDP/Vinblastine/IL-2/IFN Alpha-2b and G-CSF

ObjectivesTo determine whether an inpatient biochemotherapy ofCVD + IL-2/interferon alpha-2b/G-CSF is superior toCVD alone based on survival in patients with meta-static malignant melanoma.

To determine whether this inpatient biochemotherapyis superior to CVD alone based on response rate, re-sponse duration, time to treatment failure, percent CRand percent durable CR.

To determine the feasibility of administering this inpa-tient biochemotherapy regimen to patients with meta-static malignant melanoma in an intergroup multicentersetting.

To determine the toxicity of this inpatient biochemo-therapy regimen relative to CVD alone.

Patient PopulationPatients must have histologically confirmed, surgicallyincurable metastatic malignant melanoma. Patientsmust not have active brain metastases or leptomenin-

geal disease. Patients with history of brain metastasesmust be three months from definitive therapy and haveno evidence of active disease or edema on brain MRI.Patients must have measurable disease.

Patients must not have received any prior systemictherapy for metastatic disease. Patients must not havehad prior radiotherapy to areas of measurable diseaseunless they have clearly progressive disease in this siteor there is measurable disease outside the area of priorradiation.

Patients must have ECOG performance status of 0 or 1and adequate hematologic, renal, cardiac, pulmonary,and hepatic functions. Patients must be age 18 years orolder. Patients with organ allografts or seizure disor-ders, patients requiring corticosteroids, and patientsknown to be positive for HIV antibody are ineligible.


E3695/III

Stratification/Descriptive FactorsPatients will be stratified by (1) performance status: 0vs 1; (2) prior interferon: yes vs no; and (3) number ofinvolved sites: 1 vs 2 or 3 vs 4 or more.

Accrual GoalsTwo hundred sixty-four eligible patients will be ac-crued to this study over a 22 month period. Interimanalyses will be performed approximately 12, 19, and26 months after the trial opens.

Summary StatementAs of December 31, 1999, 176 patients were registeredto this study (80 from the Southwest Oncology Group).

Based on an August, 1999 ECOG report, 46 patients onthe CVD + IL-2/IFN arm have been evaluated for tox-icity. There was one treatment-related death (due toinfection). Thirty-one other patients had Grade 4 tox-icities. Grade 4 toxicities occurring more than onceincluded leukopenia (17), thrombocytopenia (16),granulocytopenia (14), vomiting (3), pulmonary toxic-ity (3), neuro-clinical toxicity (3), cardiac toxicity (2),hypocalcemia (2), and hypomagnesia (2). Fifty-onepatients on the CVD alone arm were evaluated fortoxicity. Twenty patients had Grade 4 toxicities. Grade4 toxicities occurring more than once included granu-locytopenia (14), leukopenia (4), and pulmonary toxic-ity (2).

Registration by Institution

Initial Registration

Registrations ending December 31, 1999

InstitutionsTotalReg Institutions

TotalReg

Wayne State Univ 8 S Georgia Med Ctr/BAMC/WHMC 2Arizona, U of 6 St Mary’s Hospital/Colorado, U of 2Michigan, U of 5 St. Louis CCOP 2Columbia Univ 4 Tulane University 2LSU-Shreveport 4 Akron Gen Med Ctr/Cleveland Clinic 1San Antonio, U of TX 4 Atlanta Reg CCOP 1U of Tennessee MC/San Antonio, U of TX 4 Cleveland Clinic 1BAMC/WHMC 3 Dixie Medical Center/Utah, U of 1City of Hope Med Ctr 3 Grand Rapids CCOP 1Columbia River CCOP 3 Irvine, U of CA 1Utah, U of 3 Loyola University 1Wichita CCOP 3 Northwest CCOP 1Boston Univ Med Ctr 2 Salem Hospital/Oregon Hlth Sci Univ 1Greater Phoenix CCOP 2 Sinai Hospital/Temple University 1Harrington/TexasTech/San Antonio, U of TX 2 Southeast CCC CCOP 1New Mexico, U of 2 W A Foote Mem Hosp/Michigan, U of 1Puget Sound 2 Total (33 Institutions) 80


S0008/III

S0008 Phase III Intergroup

Coordinating Group: SWOG

Phase III Trial of High Dose Interferon Alpha-2b vs Cisplatin, Vinblastine,DTIC plus IL-2 and Interferon in Patients with High Risk Melanoma

Intergroup Participants:SWOG, ECOG

Study Coordinators:L Flaherty, J Thompson, J Kirkwood (ECOG)



ObjectivesTo compare overall survival and disease-free survivalbetween patients with high risk melanoma who receivehigh dose interferon alpha-2b versus cisplatin, vinblas-tine, DTIC plus IL-2 and interferon.

To evaluate the toxicities of these two regimens in thispatient population.

Patient PopulationPatients must have melanoma of cutaneous origin or ofunknown primary which fulfill one of the followingcriteria: one clinically apparent (overt, macrometasta-sis) regional lymph node metastasis (N1B); OR, two tofour clinically undetectable (occult, all micrometasta-ses) regional lymph node metastases (N2A) or two tofour regional lymph node metastases (N2B) with oneor more which are clinically apparent (overt, macro-metastasis) or any satellite/in-transit metastasis withoutregional lymph node metastasis (N2C); OR, five ormore regional lymph node metastases (all microme-tastases or any macrometastasis) or 1 or more mattednodes or any satellite/in-transit metastasis with anyregional lymph node metastasis (N3); OR, nodal recur-rence in the basin of a previous complete lymphade-nectomy (NR) or intransit recurrence after previouscomplete lymphadenectomy (IR). Patients are eligiblefor this trial either at initial presentation of their pri-mary melanoma or at the time of the first clinicallydetected nodal or in-transit recurrence. Patients withmelanoma of ocular, mucosal, or other non-cutaneousorigin are not eligible. Patients with distant metastasesare not eligible.

Patients at initial presentation of melanoma must haveadequate wide excision of the primary lesion, if pres-

ent. A full lymphadenectomy is required for all patientsincluding those with positive sentinel nodes and thosewith positive in-transit metastasis. Patients must beregistered within 56 days of either lymphadenectomyOR surgery for nodal or in-transit recurrence if com-plete lymphadenectomy has previously been per-formed. Patients must not have had prior radiotherapy,chemotherapy (including infusion or perfusion ther-apy), or any immunotherapy including interferon, in-terleukins, levamisole or other biologic response modi-fiers for any type of cancer.

Patients must be 18 years of age or older, have a Zu-brod performance status of 0-1, and have adequate re-nal, hepatic, hematologic, cardiac, and pumonary func-tion. Patients must not have autoimmune disorders,conditions of immunosuppression or treatment withcorticosteroids. Patients with known AIDS or HIV-1associated complex or known to be HIV antibody sero-positive or Hepatitis positive are not eligible for thisstudy.

Stratification/Descriptive FactorsPatients are stratified by the following patient groups:initial presentation of melanoma (N1B) versus initialpresentation of melanoma (N2) versus initial presenta-tion of melanoma (N3) versus nodal recurrence (NR)or in-transit recurrence (IR) after previous completelymphadenectomy.

Accrual GoalsThe accrual goal for this study is 410 eligible patients.Interim analyses will be performed when 80% of pa-tients have been accrued and when 2/3 of the antici-pated deaths on the control arm have been observed.


S9035/III

S9035 Phase III

Randomized Trial of Adjuvant Immunotherapy with an Allogeneic MelanomaVaccine for Patients with Intermediate Thickness, Node Negative

Malignant Melanoma (T3N0M0)

Study Coordinators:V Sondak, R Kempf, R Tuthill, J Sosman





Schema

Observation

RANDOMIZE

Vaccine Treatment x Two Years

Objectives

To compare the disease-free survival and overall sur-vival between patients with T3N0M0 malignant mela-noma who receive adjuvant immunotherapy with anallogeneic melanoma vaccine vs no adjuvant treatment.

To evaluate the toxicity of adjuvant immunotherapywith an allogeneic melanoma vaccine in patients withT3N0M0 malignant melanoma.

To explore the interaction between the patients’ de-fined HLA types (i.e., whether they are compatiblewith the HLA phenotypes of the vaccine) and the vac-cine treatment effectiveness in terms of disease-freesurvival and overall survival.

Patient Population

Patients must have histologically diagnosed cutaneousmalignant melanoma with depth 1.51 to 4.00 mm orClark’s level IV if Breslow’s depth unknown. Patientswho meet the criteria for Breslow Thickness are eligi-ble even if the tumor is not Clark’s Level IV. Patientsmust have complete resection of all known sites ofmelanoma with no evidence of residual or metastaticmelanoma or nodal involvement.

Patients must be registered within 56 days after lastsurgery. Patients must not have had prior chemother-apy, hormonal therapy, radiation therapy, or biologicresponse modifiers for this disease. Node dissection isnot required.

Patients must have passed their 18th birthdays, have aSWOG performance status of 0-1, and have adequaterenal, hepatic, hematologic, and cardiac function. Pa-tients who are expected to require treatment with corti-costeroids are ineligible.

Peripheral blood for HLA phenotyping must beplanned to be drawn prior to treatment and submittedaccording to protocol.

Stratification/Descriptive Factors

Patients are stratified by 1) sex: male vs female; 2)primary tumor thickness: T3a (1.5-3.0 mm) vs T3b(>3.0-4.0 mm) vs Clark’s level IV, Breslow’s Thick-ness unknown; and 3) prior lymph node dissection: novs yes.


S9035/III

Accrual Goals

The accrual goal for this study is 572 eligible patients.Interim analyses will be performed when ¼, ½, and ¾of the expected events have occurred.

Summary Statement

This study was permanently closed on November 15,1996, after reaching full accrual. Six hundred andeighty-nine patients were registered. Eighty-nine pa-tients were ineligible due to not having T3N0M0 dis-ease (76), inadequate margins at surgical excision (8),prestudy alkaline phosphatase above institutional nor-mal limits (3), and Mohs surgery.

Six eligible patients on the vaccine arm refused treat-ment immediately after registration. These patients arecoded as having major protocol deviations and are notevaluable for toxicity. Two other eligible patients onthe vaccine arm received chemotherapy during vaccinetreatment. These patients are also coded as major pro-tocol deviations. In addition, seven eligible patientsrefused after being randomized to the observation armand received treatment off protocol. These seven pa-

tients are also coded as having major protocol devia-tions.

All patients are off protocol treatment. Thirty-threepatients were removed from treatment due to toxicityor side effects.

Two hundred and ninety-four patients have been evalu-ated for vaccine toxicity. Twenty-six patients experi-enced Grade 3 toxicities. The Grade 3 “other” toxicitiesinclude one patient with spontaneous abortion in thefirst trimester of pregnancy (an “Endocrine-other”toxicity) and one patient with a GI bleed (a “GI-other”toxicity). The most common toxicities were abscess,granuloma, malaise/fatigue/lethargy, flu-like toxicities(fever without infection, chills, and myalgia/arthralgia),and local pain, erythema, and swelling at the injectionsite.

A total of 553 patients had HLA typing completed.

The results of this study will be presented at the Mela-noma Committee Meeting of the Spring 2000 SWOGGroup Meeting.



TotalReg

Puget Sound 42 Upstate Carolina 10Irvine, U of CA 32 Arkansas, U of 9Oregon Hlth Sci Univ 28 San Antonio, U of TX 9Kaiser Foundatn Hosp/Davis, U of CA 25 Virginia Mason CCOP 9Boston Univ Med Ctr 20 Grand Rapids CCOP 8Northwest CCOP 18 Loyola University 8Michigan, U of 15 St Charles Med Ctr/Puget Sound 8Utah, U of 15 Wichita CCOP 8Ohio State U 12 Central IL CCOP 7Dayton CCOP 11 Dixie Medical Center/Utah, U of 7Greater Phoenix CCOP 11 Scott & White/TX A&M 7Harris Methodist/San Antonio, U of TX 11 Wayne State Univ 7Kansas City CCOP 11 Cleveland Clinic 6St Elizabeth Med Ctr/Kentucky, U of 11 Mississippi, U of 6Atlanta Reg CCOP 10 Sacred Heart Med Ctr/Puget Sound 6Columbia River CCOP 10 Thompson Ca Surv Ctr/San Antonio, U of TX 6Harrington/TexasTech/San Antonio, U of TX 10 All Other Institutions 266Riverside Methodist/Ohio State U 10 Total (148 Institutions) 689

Registration, Eligibility, and Evaluability

Data as of February 11, 2000

TOTAL Vaccine Observation NUMBER REGISTERED 689 346 343

INELIGIBLE 89 46 43ELIGIBLE 600 300 300

TOXICITY ASSESSMENTEvaluable 294 294 0Not Evaluable 6 6 0Not Applicable 300 0 300


S9035/III

Patient Characteristics


Vaccine(n=300)

Observation(n=300)

AGE

Median 51.0 51.0Minimum 18 21Maximum 85 84

SEX

Males 176 59% 177 59%Females 124 41% 123 41%

RACE

White (Non-Hispanic) 293 98% 295 98%Black (Non-Hispanic) 1 0% 1 0%Hispanic 4 1% 3 1%Asian or Pacific Islander 1 0% 1 0%American Indian 1 0% 0 0%

TUMOR THICKNESS

T3a, 1.5 - 3.0 mm 235 78% 238 79%T3b, >3.0 - 4.0 mm 57 19% 51 17%Clark level 4, depth unknown 8 3% 11 4%

LYMPH NODE DISSECTION

Yes 74 25% 71 24%No 226 75% 229 76%

Treatment Summary


Vaccine NUMBER ON PROTOCOL TREATMENT 0

NUMBER OFF PROTOCOL TREATMENT 300

REASON OFF TREATMENT Treatment completed as planned 168 Toxicity or side effects 33 Refusal unrelated to toxicity 35 Progression/relapse 59 Death 0 Other - not protocol specified 5

MAJOR PROTOCOL DEVIATIONS 8


S9035/III

Number of Patients with a Given Type and Degree of Toxicity


Vaccine Vaccine(n=294) (n=294)

Grade GradeTOXICITY Unk 0 1 2 3 4 5 TOXICITY Unk 0 1 2 3 4 5

Abdominal pain 0 290 3 1 0 0 0

Hypotension 0 292 1 1 0 0 0

Abscess 0 182 0 112 0 0 0 Impotence/loss of libido 0 293 1 0 0 0 0Alk phos or 5’nucleotidase inc 0 280 13 1 0 0 0 Increased urgency/frequency 0 293 1 0 0 0 0Alopecia 0 292 2 0 0 0 0 Infection 0 273 6 14 1 0 0Anemia 0 284 6 4 0 0 0 Insomnia 0 287 7 0 0 0 0Anorexia 0 282 12 0 0 0 0 Leukopenia 0 284 8 1 1 0 0Anxiety/depression 2 285 7 0 0 0 0 Local 1 35 177 72 9 0 0Bilirubin increase 0 283 0 10 1 0 0 Lymphopenia 0 280 8 6 0 0 0Blistering 0 292 2 0 0 0 0 Malaise/fatigue/lethargy 0 188 84 19 3 0 0Bone pain 0 292 1 1 0 0 0 Menses changes 0 292 2 0 0 0 0CNS - other 0 293 1 0 0 0 0 Metabolic – other 1 292 1 0 0 0 0Cardiac - dysrhythmia 1 288 4 1 0 0 0 Mucositis – other 1 291 1 1 0 0 0Cardiac - other 0 293 1 0 0 0 0 Myalgia/arthralgia 1 206 57 29 1 0 0Chills 2 224 46 22 0 0 0 Nausea 1 248 35 9 1 0 0Clotting - other 0 293 1 0 0 0 0 Neurosensory - other 1 293 0 0 0 0 0Conjunctivitis/keratitis 1 291 2 0 0 0 0 Other flu-like symptoms 3 281 8 2 0 0 0Constipation 1 292 1 0 0 0 0 Pain 1 246 37 9 1 0 0Cough 0 285 7 2 0 0 0 Paresthesia 0 292 2 0 0 0 0Creatinine increase 0 286 8 0 0 0 0 Personality change 0 290 3 1 0 0 0Dermatologic - other 0 283 8 3 0 0 0 Pharynx/esophagitis 0 287 4 3 0 0 0Desquamation 0 291 3 0 0 0 0 Pruritis 0 290 3 1 0 0 0Diarrhea 0 275 14 3 2 0 0 Respiratory infection 0 288 5 1 0 0 0Disorientation 0 292 2 0 0 0 0 Skin rash/urticaria 0 278 9 5 2 0 0Dizziness/vertigo 0 286 7 0 1 0 0 Somnolence/agitation 0 292 2 0 0 0 0Dry skin 1 291 2 0 0 0 0 Stomatitis 0 289 4 1 0 0 0Dyspnea 0 288 0 5 1 0 0 Sweats 0 275 13 6 0 0 0Edema 0 283 7 4 0 0 0 Taste 0 293 1 0 0 0 0Endocrine - other 0 293 0 0 1 0 0 Thrombocytopenia 0 282 9 1 2 0 0Erythema 0 252 20 22 0 0 0 Transaminase (SGOT, SGPT) inc 0 278 16 0 0 0 0Eye - other 0 293 0 1 0 0 0 Urinary tract infection 0 293 1 0 0 0 0Facial flushing 0 288 6 0 0 0 0 Vision 0 291 0 0 3 0 0Fever without infection 2 199 41 49 3 0 0 Vomiting 1 287 3 3 0 0 0GI - other 0 293 0 0 1 0 0 Weakness 0 283 8 3 0 0 0Gastritis/ulcer 0 293 1 0 0 0 0 Weight gain 0 287 7 0 0 0 0Granulocytopenia 0 290 4 0 0 0 0 Weight loss 0 284 7 3 0 0 0Granuloma 0 170 0 124 0 0 0 Wound Infection 0 293 0 1 0 0 0Headache 2 243 37 11 1 0 0 Miscellaneous - other 2 278 14 0 0 0 0Hearing 0 293 0 1 0 0 0Hematuria 0 293 1 0 0 0 0 MAXIMUM GRADEHemorrhage (clinical) 0 292 2 0 0 0 0 ANY TOXICITYHot flashes 0 293 1 0 0 0 0 Number 0 13 68 187 26 0 0


S9430/II

S9430 Phase II Intergroup


A Phase II Trial of Complete Surgical Resection for Stage IV Melanoma:Surgical Resection with Biological Evaluation and Clinical Follow-Up


Study Coordinators:V Sondak, J Sosman, J Warneke, J Kirkwood (ECOG)




ObjectivesTo assess the overall survival and progression-freesurvival of patients with metastatic melanoma (beyondthe draining lymph nodes) following complete surgicalresection of all known disease.

To determine the ability of the Southwest OncologyGroup Melanoma Committee to enroll patients withmetastatic melanoma who can be resected to a "dis-ease-free" state, in order to assess the feasibility of fu-ture trials of specific interventions in this patientpopulation.

Patient PopulationPatients must have histologically confirmed Stage IVmelanoma that is deemed to be surgically resectable.Patients with multiple resected sites or metastaticmelanoma from an unknown primary site are eligibleas long as all known disease will be grossly resected.Patients with recurrence in iliac lymph nodes followinginguinal lymph node dissection are eligible.

Prior non-protocol surgery is allowed, but must havebeen completed at least 14 days prior to registration.Prior radiation therapy, chemotherapy, or immunother-

apy are allowed, but must have been completed at least28 days prior to registration. Patients must have aSWOG performance status of 0-2. Simultaneous regis-tration to S9431 is required.

Patients must be registered prior to protocol surgery.

Stratification/Descriptive FactorsPatients will be described by (1) prior surgery: yes vsno; (2) prior systemic therapy: yes vs no; (3) perform-ance status: 0-1 vs 2; (4) TNM class: M1a vs. M1b; (5)primary site: known vs unknown; and (6) prior adju-vant interferon: yes vs no.

Accrual GoalsThe accrual goal is 50 eligible patients with gross dis-ease completely resected.

Summary StatementAs of December 31, 1999, 36 patients were registeredto this study, all from SWOG. ECOG joined the studyon October 1, 1999.

Twenty-three patients have had their surgical treatmentevaluated. Three patients did not have disease com-pletely resected and are not analyzable.


S9430/II




TotalReg

Michigan, U of 12 Montana CCOP 1Oregon Hlth Sci Univ 11 New Mexico, U of 1City of Hope Med Ctr 4 Puget Sound 1Wichita CCOP 2 Salem Hospital/Oregon Hlth Sci Univ 1Arizona, U of 1 South Alabama CCOP 1Carilion Medical Ctr/Temple University 1 Total (11 Institutions) 36


Registrations ending December 31, 1999; Data as of January 12, 2000

Surgical resection(n=33)

AGE Median 53.0 Minimum 18 Maximum 79 SEX Male 22 67% Female 11 33% RACE White (Non-Hispanic) 32 97% American Indian 1 3% PRIOR SURGERY Yes 31 94% No 2 6% PRIOR TREATMENT Yes 14 42% No 19 58% PERFORMANCE STATUS 0 or 1 33 100% 2 0 0% TNM CLASSIFICATION M1a 22 67% M1b 11 33% PRIMARY SITE Known 31 94% Unknown 2 6% PRIOR ADJUVANT IFN Yes 13 39% No 20 61%


S9431/BIOLOGIC

S9431 Biologic Intergroup


Cytogenetic, Molecular and Cellular Biology Studies in Metastatic MelanomaPatients, Ancillary


Study Coordinators:J Sosman, V Sondak, R Tuthill, R Whitehead, C Fenoglio-Preiser, T McConnell, R Magenis, J Kirkwood (ECOG)




ObjectivesTo characterize the frequency of non-random cytoge-netic abnormalities in regional and distant melanomametastases and explore their association with clinicaloutcome of melanoma patients enrolled onto SouthwestOncology Group trials.

To characterize the frequency of specific genetic al-terations at either the DNA, mRNA, or protein leveland explore the association of these abnormalities withclinical outcome in patients with regional and distantmetastases who are enrolled on Southwest OncologyGroup melanoma trials.

To characterize the host immunologic response tometastatic melanoma by determining whether the in-vivo pattern of cytokine expression is consistent withspecific subsets of T helper cells (TH1 or TH2) withinmelanoma deposits.

To explore whether host immunologic response variesbased on the site of metastatic disease and/or correlateswith clinical outcome in patients enrolled on SouthwestOncology Group trials.

To obtain paraffin embedded tumor blocks, peripheralblood, and sera from patients with metastatic mela-noma to form a tissue, cell and serum bank for futurestudies.

Patient PopulationTo be eligible for S9431, the patient must have beenregistered, or is planned to be registered within 56days, to a Southwest Oncology Group melanomatreatment protocol. Patients for whom the only regis-tration is to a non-SWOG coordinated study are noteligible.

Summary StatementAs of December 31, 1999, 38 patients were registeredto this study, all from SWOG. One patient with noregistration to a SWOG-coordinated treatment trial wasineligible. Thirty-six patients were from treatment trialS9430 and one was from treatment trial S9350. ECOGjoined the study on October 1, 1999.

Investigators are reminded that this study is open topatients from any Southwest Oncology Group-coordinated melanoma treatment trial (for example,relapsing patients from S9035 are eligible).


S9431/BIOLOGIC




TotalReg

Oregon Hlth Sci Univ 13 Montana CCOP 1Michigan, U of 12 New Mexico, U of 1City of Hope Med Ctr 4 Puget Sound 1Wichita CCOP 2 Salem Hospital/Oregon Hlth Sci Univ 1Arizona, U of 1 South Alabama CCOP 1Carilion Medical Ctr/Temple University 1 Total (11 Institutions) 38


S9512/III

S9512 Phase III Intergroup (E1694)


A Phase III Study of Adjuvant Ganglioside Vaccination GM2-KLH/QS-21Therapy vs High-Dose Interferon Alpha-2b (IntronA) for High-Risk

Melanoma (T4 > 4 mm Primary or Regional Lymph Node Metastasis)

Intergroup Participants:ECOG (E1694), SWOG, CALGB (509801), MDACC,MSKCC

Study Coordinators:J Kirkwood (ECOG), V Sondak, J Sosman,P Chapman (MSKCC), M Ross (MDACC),M Ernstoff (CALGB)





Schema

RANDOMIZE

GM2-KLH/QS-21 Immunization

High-Dose Interferon Alpha-2b

ObjectivesTo compare the effect of immunization with GM2-KLH/QS-21 on the relapse-free survival of high riskmelanoma patients in relation to high dose Interferon(IFN Alpha-2b).

To compare the effect of GM2-KLH/QS-21 immuni-zation on overall survival of high risk melanoma pa-tients in relation to high-dose IFN Alpha-2b.

To determine the correlation between pre-existing orvaccine induced IgM antibody response against GM2and relapse-free as well as overall survival of high riskmelanoma patients on the vaccine arm.

Patient PopulationPatients must have either T4 N0 M0-deep primarymelanoma (> 4.0 mm Breslow depth) with or withoutlymphadenectomy; or T1-4 N1 M0-primary melanomawith regional lymph node metastases found histologi-cally at lymphadenectomy, but clinically undetectable

(occult); or T1-4 N1-2 M0-primary melanoma withclinically apparent (overt) regional lymph node metas-tases confirmed by lymphadenectomy; or T1-4 N1-2M0-clinically detected recurrence of melanoma at theproximal regional lymph node(s) basin, confirmed bylymphadenectomy; or TX N1-2 M0-clinically detectedsingle site of nodal metastatic melanoma arising froman unknown primary, confirmed by lymphadenectomy;or T1-4 N1-2 M0-clinically or histologically detectedprimary melanoma involving multiple regional nodalgroups, confirmed by lymphadenectomy. Patients withprimary melanoma WHO DO NOT undergo lymphnode dissection (T4 only) must be randomized within56 days of their wide excision and no longer than 70days after their primary lesion biopsy. Patients withprimary melanoma WHO DO undergo lymph nodedissection must be randomized within 56 days of thelymphadenectomy, 70 days of wide excision and nolonger than 84 days after the primary lesion biopsy.Patients with nodal recurrence must complete lymph-


S9512/III

adenectomy and be randomized within 56 days of thelymphadenectomy and no longer than 70 days after thebiopsy that established the recurrence. Patients withclinical, radiological, laboratory, or pathological evi-dence of incompletely resected melanoma are ineligi-ble.

Patients must have undergone an adequate wide exci-sion of the primary lesion. A full lymphadenectomy isrequired for all patients undergoing lymph node sur-gery (i.e., all those except T4 N0 patients). Patientswith soft tissue involvement by gross extranodal exten-sion of tumor, or patients with any gross extracapsularinvasion or grossly apparent satellite lesions, are noteligible. Patients who have received prior radiotherapy,chemotherapy (including infusion or perfusion ther-apy), or immunotherapy are ineligible.

Patients must be at least 18 years old, have an ECOGperformance status of 0 or 1, and have adequate he-matologic, renal, hepatic, and psychiatric function.Patients with a history of congestive heart failure(NYHA class > 2) are ineligible. Patients must nothave autoimmune disorders, conditions of immunosup-pression, or require treatment with corticosteroids. Pa-tients must not be HIV or hepatitis seropositive. Pa-tients with a history of CNS demyelinating, inflamma-tory disease, or hereditary or acquired peripheral neu-ropathy are not eligible. Patients with recurrent mela-noma at regional lymph nodes who were previouslyentered on this study, or patients with regional recur-

rence in transit, are ineligible. Patients must not have ahistory of severe allergic reaction to shellfish.

Stratification/Descriptive FactorsPatients will be stratified by (1) number of nodes posi-tive at lymphadenectomy: 0 vs 1 vs 2-3 vs >=4 (pa-tients with clinical T4 N0 M0 disease who have notundergone lymphadenectomy will be stratified with theN0 group); and (2) sex: male vs female.

Accrual GoalsSeven hundred and sixty-six eligible patients will beaccrued to this study. Interim analyses will be per-formed when 25%, 50%, and 75% of the expected re-lapses have been observed.

Summary StatementThis study was permanently closed on October 15,1999, after reaching its accrual goal. Eight hundred andeighty patients were registered (338 by the SouthwestOncology Group).

According to an August, 1999 ECOG report, 312 pa-tients on the high-dose interferon arm have been evalu-ated for toxicity. Fifty-two patients experienced Grade4 toxicity. The most common Grade 4 toxicity wasgranulocytopenia (26). Other Grade 4 toxicities occur-ing more than once include neuro-psych (5), diarrhea(4), vomiting (4), neuro-clinical (3), liver (2), and in-fection (2). On the vaccine arm, 341 patients wereevaluated for toxicity. Five patients had Grade 4 toxic-ity and 38 patients had Grade 3 toxicity.



TotalReg

Arkansas, U of 17 Our Lady of Lourdes/LSU-Shreveport 5Dayton CCOP 13 Ozarks Reg CCOP 5Oregon Hlth Sci Univ 12 Scott & White CCOP 5Michigan, U of 11 Sinai Hospital/Temple University 5Atlanta Reg CCOP 10 St Joseph Reg Hlth/Arkansas, U of 5Virginia Mason CCOP 10 St. Louis CCOP 5Grand Rapids CCOP 9 Carilion Medical Ctr/Temple University 4Hawaii, U of 9 Central IL CCOP 4Kaiser Foundatn Hosp/Davis, U of CA 9 Cleveland Clinic 4Wayne State Univ 9 Greater Phoenix CCOP 4Wichita CCOP 9 Irvine, U of CA 4City of Hope Med Ctr 8 Northwest CCOP 4Puget Sound 8 Presbyterian Hosp/San Antonio, U of TX 4San Antonio, U of TX 7 SW Reg Cancer Ctr/San Antonio, U of TX 4Columbus CCOP 6 St Mary’s Hospital/Colorado, U of 4LSU-Shreveport 6 Upstate Carolina 4Montana CCOP 6 All Other Institutions 98Ohio State U 6 Total (94 Institutions) 338Kansas City CCOP 5


S9716/II

S9716 Phase II

A Phase II Trial of Cyclophosphamide, Methotrexate and 5-Fluorouracil (CMF)in Neuroendocrine Carcinoma of the Skin (Merkel Cell Carcinoma)

Study Coordinators:R Kempf, R Tuthill

Statisticians:J Unger, PY Liu



ObjectivesTo investigate the ability of the Southwest OncologyGroup Melanoma Committee to enroll patients withMerkel Cell Carcinoma that is either local/regional ormetastatic.

To estimate the survival rate and the clinical responserate (confirmed and unconfirmed complete and partialresponses) of the intravenous combination of cyclo-phosphamide, methotrexate and 5-fluorouracil admin-istered to patients with Merkel Cell Carcinoma.

Patient PopulationPatients must have histologically proven diagnosis ofMerkel Cell Carcinoma that is unresectable, either lo-cal/regional or metastatic. Patients with treated andstable CNS metastases are eligible as long as they haveanother site that is measurable. Patients must have bi-dimensionally measurable disease.

Patients must not have received prior chemotherapy formetastatic disease. Patients may have received prioradjuvant chemotherapy, as long as it did not includeany of the agents in this study. Patients who have re-ceived prior biologic therapy or immunotherapy are not

eligible. Prior surgery and radiation therapy are al-lowed, but must have been completed at least 14 daysprior to registration.

Patients must have a SWOG performance status of 0-1and adequate hematologic, hepatic, and renal functions.Patients with pleural effusions or ascites are not eligi-ble.

Stratification/Descriptive FactorsPatients will be stratified by local/regional vs meta-static disease.

Accrual GoalsForty eligible patients with local/regional disease andforty eligible patients with metastatic disease will beaccrued.

Summary StatementAs of December 31, 1999, five patients were registeredto this study, two with local/regional disease and threewith metastatic disease.

Two patients have been evaluated for toxicity. NoGrade 3 or 4 toxicities have been reported.



InstitutionsTotalReg

Boston Univ Med Ctr 1Grand Rapids CCOP 1Kansas, U of 1Keesler USAF Med Ctr/Mississippi, U of 1Ozarks CGOP/Kansas, U of 1 Total (5 Institutions) 5


S9804/II

S9804 Phase II

Evaluation of Vinorelbine Tartrate (Navelbine) in Patients with DisseminatedMalignant Melanoma and One Prior Systemic Therapy

Study Coordinator:R Whitehead

Statisticians:J Unger, PY Liu



ObjectivesTo evaluate the response rate (confirmed and uncon-firmed complete and partial responses) of patients withdisseminated malignant melanoma when treated withvinorelbine tartrate (Navelbine).

To assess the qualitative and quantitative toxicities ofvinorelbine administered in a Phase II study.

Patient PopulationPatients must have histologically proven malignantmelanoma which is Stage IV. Patients with currentevidence of brain metastases are not eligible. Patientswith a history of brain metastases are eligible ONLY ifthey have had a complete resection of disease in thebrain and then had whole brain radiation therapy. Pa-tients must have bi-dimensionally measurable disease.

Patients must have received at least one prior systemictherapy (chemotherapy, biologic/immunotherapy, or acombination regimen) for metastatic disease. Patients

must not have received adjuvant chemotherapy. Priorradiation therapy, surgery, hormonal therapy, isolationlimb perfusion, and adjuvant biologic/immunotherapyare allowed, but must have been completed at least 28days prior to registration.

Patients must have a SWOG performance status of 0-2and adequate hematologic, renal, and hepatic functions.Patients with AIDS or HIV-1 associated complex orpatients known to be HIV antibody seropositive are noteligible.

Accrual GoalsTwenty eligible patients will be registered. If one ormore responses are observed, 20 additional patientswill be accrued.

Summary StatementAs of December 31, 1999, eight patients were regis-tered to this study.



InstitutionsTotalReg

Alabama Oncology LLC/Tulane University 1MD Anderson, Florida/Arkansas, U of 1Merle West Med Ctr/Davis, U of CA 1Northwest Med Ctr/Arkansas, U of 1St Lukes/Mt States/Utah, U of 1St Mary Med Ctr/Los Angeles, U of CA 1St Mary’s Hospital/Colorado, U of 1Wichita CCOP 1 Total (8 Institutions) 8


S9804/II


Registrations ending December 31, 1999; Data as of January 12, 2000

Navelbine(n=8)

AGE

Median 55.5Minimum 44Maximum 62

SEX

Male 6 75%Female 2 25%

RACE

White (Non-Hispanic) 8 100%

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