melanoma committee 2001/melanoma.pdf · nant melanoma. publication status. dr. whitehead s9622...

OCTOBER 26 - 28, 2001 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.

James Moon, M.S.

Data Coordinators: Camille White, B.S., C.C.R.P.Stephanie Edwards

Protocol Coordinator: Connie Ballon-Almanza, B.S.

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

Radiation Oncology: James G. Douglas, 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: Marie-France Demierre, M.D.

Nurses: Karen L. Mack, R.N.P.Susan Stockton, R.N., B.S.N.

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

2 MELANOMA SOUTHWEST ONCOLOGY GROUP OCTOBER 26 - 28, 2001

CONTENTS

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

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

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

E2697 Biologic Intergroup ..........................................................................................7

E3695 Phase III Intergroup..........................................................................................8

E4697 Phase III Intergroup........................................................................................10

S9430 Phase II Intergroup .........................................................................................12

S9431 Biologic ..........................................................................................................14

S9804 Phase II ...........................................................................................................16

S9903 Phase II ...........................................................................................................21

S0008 Phase III Intergroup ........................................................................................22

S0026 Phase II ...........................................................................................................25

S0116 Phase II ...........................................................................................................26


Melanoma Committee Agenda

Scientific Session

To Be Determined. 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.

Dr. Sosman

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

Dr. Sosman

S0008 Phase III Trial of High Dose Interferon Alpha-2b versus Cis-platin, Vinblastine, DTIC plus IL-2 and Interferon in Patientswith High Risk Melanoma.

Dr. Flaherty

Closed Studies

S9035 Adjuvant Allogeneic Melanoma Vaccine Trial in T3N0M0Melanoma, Phase III. Update and Publication Status.

Drs. Sondak and Sosman

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

Dr. Whitehead

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

Dr. Whitehead

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

Dr. Whitehead


Proposed Studies

E4697 Randomized, Placebo-Controlled Phase III Trial of GM-CSFversus Peptide Vaccine versus GM-CSF + Peptide Vaccine ver-sus Placebo.

Dr. Margolin

S0026 Evaluation of Interferon Alpha-2B and Thalidomide in Patientswith Disseminated Malignant Melanoma, Phase II.

Dr. Hutchins

S0116 Phase II Trial of D1/3-MAGE3-His Fusion Protein with Adju-vant SB-AS02B for Patients with Stage IV, M1a or M1b Meta-static Melanoma.

Dr. Weber

S0201 Intergroup Phase III Adjuvant Trial for Intermediate Risk Mela-noma.

Dr. Sosman

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

20

40

60

80

100

120

140

160

180

Time of registration

JUL 1996JUN 1997

77

49

51

JUL 1997JUN 1998

62

56

42

JUL 1998JUN 1999

71

38

59

JUL 1999JUN 2000

51

42

30

JUL 2000JUN 2001

39

5

14

8

MEMBER AFFILIATES CCOP NON-SWOG

Patient Registration by Study and ArmMELANOMA COMMITTEE

Jan-June2001

July-Dec2000

Jan-June2000

AllPatients

E2697 Melan, Biol Ancillary to E3695 *

DNA Damage Index 5 4 3 12 E3695 Melan, Adv, CVD +/- IFN/IL-2 *

CVD 9 12 10 70CVD + IFN/IL-2 8 11 12 72

17 23 22 142 S9430 Melan,Adv,Comp Surg Res,Ph II

Surgical resection 5 2 8 51

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


Patient Registration by Study and ArmMELANOMA COMMITTEE (Continued)

Jan-June2001

July-Dec2000

Jan-June2000

AllPatients

S9431 Melan, Tissues and Serum

Tissues and serum 5 2 8 53 S9716 Merkel Cell, Adv, CMF, Ph II

CMF 0 0 1 6 S9804 Melan, Adv, Navelbine, Ph II

Navelbine 0 0 16 24 S0008 Melan,Adj,HD IFN v CVD+IFN/IL2

High Dose IFN Alpha-2b 9 1 0 10CVD + IFN/IL-2 9 0 0 9

18 1 0 19


E2697/BIOLOGIC

E2697 Biologic IntergroupCoordinating Group: ECOG

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

Statisticians:P Y Liu, J Moon

Data Coordinators:C White, S Edwards

Date Activated:2/1/2000

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 StatementAs of June 30, 2001, 58 patients have been registeredto this study (12 from the Southwest Oncology Group).All patients enrolled on E3695 need only submit bloodsamples to be eligible. See E2697 protocol for bloodsample submission instructions.

The complete June, 2001 summary of this study fromECOG is available on the Southwest Oncology Groupweb site.

Registration by InstitutionRegistrations ending June 30, 2001

InstitutionsTotalReg

Loyola University 2Southeast CCC CCOP 2St Louis CCOP 2Harrington/TexasTech/San Antonio, U of TX 1Kansas, U of 1Mississippi, U of 1Montana CCOP 1Oregon Hlth Sci Univ 1Wichita CCOP 1Total (9 Institutions) 12


E3695/III

E3695 Phase III IntergroupCoordinating Group: ECOG

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


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 GoalsFour hundred sixty-eight eligible patients will be ac-crued to this study over a 40-month period. Interimanalyses will be performed approximately 12, 19, and26 months after the trial opens.

Summary StatementAs of June 30, 2001, 344 patients have been registeredto this study (142 from the Southwest OncologyGroup). In an April 1, 2001 amendment, ECOG in-creased the accrual goal from 264 eligible patients to468 eligible patients.

According to the June, 2001 ECOG report, (data as ofFebruary 19, 2001), 107 patients on the CVD + IL-2/IFN arm have been evaluated for toxicity. There werethree treatment-related deaths, two due to infection,and one due to renal toxicity. Seventy-two (67%) otherpatients experienced, at worst, Grade 4 toxicities,mostly hematologic. On the CVD alone arm 112 pa-tients were evaluated for toxicity. Two treatment re-lated deaths have been reported, one due to cardiacinfarction, the other due to infection. Forty-four (39%)other patients had Grade 4 toxicities, mostly hemato-logic.For more details, please refer to the complete June,2001 summary of this study from ECOG, which isavailable on the Southwest Oncology Group web site.


InstitutionsTotalReg Institutions

TotalReg

Michigan, U of 13 Grand Rapids CCOP 3Wayne State Univ 13 Greater Phoenix CCOP 3City of Hope Med Ctr 7 Loyola University 3San Antonio, U of TX 7 Southeast CCC CCOP 3Arizona, U of 6 Boston Univ Med Ctr 2Utah, U of 6 Kansas, U of 2LSU-Shreveport 5 Montana CCOP 2Atlanta Reg CCOP 4 New Mexico, U of 2BAMC/WHMC 4 Oregon Hlth Sci Univ 2Columbia River CCOP 4 Ozarks Reg CCOP 2Columbia University 4 Puget Sound 2Harrington/TexasTech/San Antonio, U of TX 4 S Georgia Med Ctr/BAMC/WHMC 2St Louis CCOP 4 St Mary's Hospital/Colorado, U of 2U of Tennessee MC/San Antonio, U of TX 4 Tulane University 2Wichita CCOP 4 All Other Institutions 18Cleveland Clinic OH 3 Total (48 Institutions) 142


E4697/III

E4697 Phase III IntergroupCoordinating Group: ECOG

A Randomized, Placebo-Controlled Phase III Trial of Yeast Derived GM-CSFVersus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus

Placebo in Patients with "No Evidence of Disease" after Complete SurgicalResection of "Locally Advanced" and/or Stage IV Melanoma


Study Coordinators:D Lawson (ECOG), K Margolin



ObjectivesTo compare overall survival, two year survival, andtime to progression of patients with completely re-sected Stage IV melanoma or Stage III melanoma withgross extranodal extension, satellites, and/or intransitlesions, or with other high risks when treated with GM-CSF versus no GM-CSF.

To compare overall survival, two year survival, andtime to progression of HLA-A2 positive patientstreated with peptide vaccination versus no peptide vac-cination.

To perform descriptive evaluations of overall survivaland time to progression of HLA-A2 positive patientstreated with GM-CSF plus peptide vaccination versuspeptide vaccination alone, GM-CSF plus peptide vac-cination versus GM-CSF alone, and GM-CSF pluspeptide vaccination versus placebo. In addition, fordescriptive purposes, survival and time to progressionof HLA-A2 positive patients not receiving peptide vac-cination will be compared to that of HLA-A2 negativepatients not receiving peptide vaccination.

To investigate the influence of GM-CSF on circulatingdendritic cell numbers and subpopulations in peripheralblood of patients receiving and not receiving GM-CSF.

To investigate, in HLA-A2 positive patients, whetherimmunization with peptides with or without GM-CSFelicits a measurable T-cell response as assessed byELISPOT and the MHC tetramer assay, and to investi-gate the functionality of these cells by intracellularcytokine staining.

Patient PopulationPatients must have completely resected disease withone of the following: any locoregional recurrence afterprior adjuvant interferon or failure on S0008, any localrecurrence of disease after adequate surgical excisionof the original primary, mucosal melanoma, or StageIV melanoma of cutaneous, ocular, mucosal, or un-known primary. Provided they are ineligible for S0008or are considered medically unfit to receive standardhigh-dose interferon, patients with any clinically evi-dent satellite or intransit disease, Stage III disease withgross extracapsular extension, recurrence in a previ-ously resected nodal basin, four or more involvedlymph nodes (or matted lymph nodes), or an ulceratedprimary with lymph node involvement are eligible forthis study. Patients must have been surgically renderedfree of disease with negative margins on resectedspecimens. Patients rendered free of disease by non-surgical means are not eligible.

Patients must not have received any adjuvant therapy,(chemotherapy, biologic, or limb perfusion), after theresection(s) that makes them eligible for this trial. Onesystemic treatment after prior surgery is allowed. Pre-vious radiation therapy, including after the resection, isallowed. Patients must not have had any prior treatmentwith GM-CSF or any peptides used in this protocol.

Patients HLA-A2 status must be known. Patients mustbe ≥ 18 years of age, have an ECOG performancestatus of 0-1, and must be able to self-administer orarrange for administration of subcutaneous injections.Patients must have adequate hematologic and hepaticfunction. Patients must not have an active infectionrequiring treatment with parenteral antibiotics. Patients


E4697/III

must not have autoimmune disorders, conditions ofimmunosuppression or treatment with steroids. Re-placement doses of steroids for patients with adrenalinsufficiency are allowed.

Stratification/Descriptive FactorsPatients are stratified by (1) HLA-A2 status: positivevs negative; (2) site of metastases: visceral vs non-visceral vs both; and (3) number of metastatic lesions:1 vs 2-3 vs 4 or more.

RandomizationPatients who are HLA-A2 positive will be randomizedusing a factorial design to receive either GM-CSF pluspeptide vaccine, GM-CSF placebo plus peptide vac-cine, GM-CSF plus peptide placebo, or GM-CSF pla-cebo plus peptide placebo.

Patients who are HLA-A2 negative will be randomizedto receive either GM-CSF or GM-CSF placebo.

Accrual GoalsThe accrual goal is 540 eligible patients, with 90 eligi-ble patients per treatment arm.

Summary StatementECOG activated this study on December 29, 1999. Asof June 30, 2001, 83 patients have been registered. Atthis writing, this study has not yet opened in SouthwestOncology Group.

According to a June, 2001 ECOG report, (data as ofFebruary 19, 2001), 33 patients have been evaluatedfor toxicity. Three (9%) Grade 3 toxicities have beenobserved.

The complete June, 2001 summary of this study fromECOG is available on the Southwest Oncology Groupweb site.


S9430/II

S9430 Phase II IntergroupCoordinating Group: SWOG

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

Intergroup Participants:SWOG, ECOG

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

Statisticians:J Moon, P Y Liu



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) Metastatic Disease status:visceral vs non-visceral; (5) primary site: known vsunknown; and (6) prior adjuvant interferon: yes vs no.

Accrual GoalsThe accrual goal is 100 eligible patients with grossdisease completely resected.

Summary StatementAs of June 30, 2001, 51 patients were registered to thisstudy. One patient is currently listed as ineligible dueto insufficient data. ECOG joined the study on March24, 2000. In a July 15, 2000 revision, the accrual goalwas increased from 50 to 100 eligible patients withgross disease completely resected.

Four eligible patients are not analyzable: two who didnot have disease completely resected and two whosespecimen was free of tumor.

Out of thirty-five analyzable patients evaluated, twoexperienced surgical toxicities: one patient with Grade1 hemorrhage and Grade 1 wound infection, the otherwith Grade 1 wound infection.


S9430/II



TotalReg

Michigan, U of 16 Carilion Medical Ctr/Temple University 1Oregon Hlth Sci Univ 15 Kansas City CCOP 1City of Hope Med Ctr 4 Montana CCOP 1Wayne State Univ 3 New Mexico, U of 1Salem Hospital/Oregon Hlth Sci Univ 2 Puget Sound 1Utah, U of 2 South Alabama CCOP 1Wichita CCOP 2 Total (14 Institutions) 51Arizona, U of 1

Registration, Eligibility, and EvaluabilityRegistrations ending June 30, 2001; Data as of July 20, 2001

Surgicalresection

Surgicalresection

NUMBER REGISTERED 51 TOXICITY ASSESSMENT 46

INELIGIBLE 1 Evaluable 35Insufficient Documentation 1 Too Early 11

Reversible 1ELIG./ PEND. ELIG. 50

Analyzable, Pend. Elig. 3Not Analyzable 4

Patient CharacteristicsRegistrations ending June 30, 2001; Data as of July 20, 2001

Surgical resection(n=46)

Surgical resection(n=46)

AGE PERFORMANCE STATUSMedian 53.0 0 or 1 46 100%Minimum 18 2 0 0%Maximum 79

METASTATIC DISEASESEX Non-visceral 30 65%

Males 33 72% Visceral 16 35%Females 13 28%

PRIMARY SITERACE Known 46 100%

White (Non-Hispanic) 44 96% Unknown 0 0%Black (Non-Hispanic) 1 2%American Indian 1 2% PRIOR ADJUVANT INTERFERON

Yes 19 41%PRIOR SURGERY No 27 59%

Yes 44 96%No 2 4%

PRIOR TREATMENTYes 20 43%No 26 57%


S9431/BIOLOGIC

S9431 Biologic IntergroupCoordinating Group: SWOG

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

Intergroup Participants:SWOG, ECOG

Study Coordinators:M Slovak, C Fenoglio-Preiser, R Tuthill, V Sondak,J Sosman, 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 June 30, 2001, 53 patients were registered to thisstudy. One patient with no registration to a SWOG-coordinated treatment trial was ineligible. Fifty-onepatients were from treatment trial S9430 and one wasfrom treatment trial S9350. ECOG joined the study onMarch 24, 2000.

Investigators are strongly encouraged to submit snap-frozen tissue samples in order to study the relationshipbetween gene expressions and clinical outcomes.

A number of samples have arrived in unusable condi-tion because of improper packing. Institutions are re-minded to contact the SWOG Tumor Bank by phone toensure receipt and proper handling. To ensure thatsnap-frozen specimens do not thaw during overnighttransit, the Tumor Bank recommends using a sealedheavy grade styrofoam container at least 1.5 inchesthick filled with five pounds of dry ice. Blood samplesand frozen samples should not be packed together. Ex-plicit packing instructions were included in a Septem-ber 15, 2000 amendment to section 5.3 of the protocol.


S9431/BIOLOGIC



TotalReg

Oregon Hlth Sci Univ 17 Carilion Medical Ctr/Temple University 1Michigan, U of 16 Kansas City CCOP 1City of Hope Med Ctr 4 Montana CCOP 1Wayne State Univ 3 New Mexico, U of 1Salem Hospital/Oregon Hlth Sci Univ 2 Puget Sound 1Utah, U of 2 South Alabama CCOP 1Wichita CCOP 2 Total (14 Institutions) 53Arizona, U of 1


S9804/II

S9804 Phase II

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

Study Coordinator:R Whitehead




Date Closed:8/1/2001

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. Patientsmust 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 StatementThis study permanently closed on August 1, 2001 afterno responses were observed among the patients ac-crued during the first stage. Twenty-four patients wereregistered. Five patients were ineligible for the fol-lowing reasons: evidence of brain metastases (2), prioradjuvant chemotherapy (1), and insufficient baselinedocumentation (2). Institutions are required to submitoutstanding eligibility documentation.

Five eligible patients could not have their exact re-sponse status determined, one who died before re-sponse could be assessed, and four others because ofinadequate follow up assessments. However, none ofthese five patients were responding to treatment. Onepatient remains on treatment with stable disease, butwas deemed unlikely to ever achieve a partial responseafter 15 months of treatment. The one remaining ineli-gible patient who could become eligible if appropriatedocumentation is submitted did not have a response.

Nineteen eligible patients have been evaluated for tox-icity. There was one Grade 5 toxicity (febrile neutrope-nia). Six patients experienced Grade 4 toxicities, in-cluding six cases of neutropenia/granulocytopenia, twocases of leukopenia, and one case each of dyspnea andfatigue.The response rate is 0/19, (95% confidence interval 0%to 18%), while the estimated median progression-freesurvival is 2 months and the estimated median overallsurvival is 5 months. Further investigation in this set-ting is not warranted.


S9804/II

Registration by Institution


TotalReg

Thompson Ca Surv Ctr/San Antonio, U of TX 4 Puget Sound 1Arizona, U of 3 Santa Rosa CCOP 1St Mary Med Ctr/Los Angeles, U of CA 2 Southeast CCC CCOP 1Central IL CCOP 1 St Lukes/Mt States/Utah, U of 1E Idaho Reg Med Ctr/Utah, U of 1 St Mary's Hospital/Colorado, U of 1Kansas City CCOP 1 Utah, U of 1MD Anderson, Florida/Arkansas, U of 1 Washington Reg MC/Arkansas, U of 1Merle West Med Ctr/Davis, U of CA 1 Wichita CCOP 1Montana CCOP 1 Total (18 Institutions) 24Montgomery CC LLC/Tulane University 1

Registration, Eligibility, and EvaluabilityData as of August 8, 2001Navelbine Navelbine

NUMBER REGISTERED 24 RESPONSE ASSESSMENT 19

INELIGIBLE 5 Determinable 14Insufficient Documentation 2 Not Determinable 5

Irreversible 1Reversible 1 TOXICITY ASSESSMENT

ELIGIBLE 19 Evaluable 19

Patient CharacteristicsData as of August 8, 2001

Navelbine(n=19)

Navelbine(n=19)

AGE PRIOR BIOLOGIC OR IMMUNOTHERAPYMedian 58.0 none 1 5%Minimum 28 for adjuvant disease only 3 16%Maximum 76 for advanced disease only 9 47%

for both adj. and adv. disease 6 32%SEX

Male 13 68% PRIOR HORMONAL THERAPYFemale 6 32% no 16 84%

yes 3 16%RACE

White (Non-Hispanic) 19 100% PRIOR RADIATION THERAPYno 13 68%

PERFORMANCE STATUS yes 6 32%0 6 32%1 12 63% PRIOR SURGERY2 1 5% no 1 5%

yes 18 95%

METASTATIC ORGAN INVOLVMENTbone 1 5%liver 8 42%lymph node, skin, soft tissue 9 47%lung / pleura 13 68%other 4 21%


S9804/II

Treatment SummaryData as of August 8, 2001

Navelbine NUMBER ON PROTOCOL TREATMENT 1

NUMBER OFF PROTOCOL TREATMENT 18 REASON OFF TREATMENT

Toxicity or side effects 1 Refusal unrelated to toxicity 0 Progression/relapse 12 Death 3 Other - not protocol specified 2

MAJOR PROTOCOL DEVIATIONS 0

Number of Patients with a Given Type and Degree of ToxicityData as of August 8, 2001

Navelbine Navelbine(n=19) (n=19)

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

Abdominal pain/cramping 0 18 0 0 1 0 0

Local injection site reaction 0 16 2 1 0 0 0

Alkaline phosphatase increase 0 16 2 0 1 0 0 Lymphopenia 0 11 1 3 4 0 0Alopecia 0 16 2 1 0 0 0 Myalgia 0 17 2 0 0 0 0Anemia 0 8 1 8 2 0 0 Nausea 2 11 6 0 0 0 0Anorexia 1 11 5 1 1 0 0 Neuropathic pain 0 17 0 2 0 0 0Anxiety/agitation 0 18 0 1 0 0 0 Neutropenia/granulocytopenia 0 1 0 5 7 6 0Arthralgia 0 17 2 0 0 0 0 Pain-other 0 16 2 0 1 0 0Bilirubin increase 0 18 0 1 0 0 0 Phlebitis 0 17 0 2 0 0 0Bone pain 0 18 1 0 0 0 0 Platelet transfusion 0 18 0 0 1 0 0Cataract 0 18 0 0 1 0 0 Rash/desquamation 0 17 2 0 0 0 0Chest pain,not cardio or pleur 0 18 1 0 0 0 0 Rectal bleeding/hematochezia 0 18 1 0 0 0 0Constipation/bowel obstruction 0 16 2 1 0 0 0 Rigors/chills 0 18 1 0 0 0 0Cough 0 18 1 0 0 0 0 Sensory neuropathy 0 13 3 2 1 0 0Diarrhea without colostomy 0 16 2 1 0 0 0 Sinus tachycardia 0 18 0 1 0 0 0Dizziness/light headedness 0 18 1 0 0 0 0 Skin-other 0 18 1 0 0 0 0Dyspepsia/heartburn 0 18 0 0 1 0 0 Stomatitis/pharyngitis 0 18 1 0 0 0 0Dyspnea 0 17 0 1 0 1 0 Sweating 0 18 0 1 0 0 0Edema 1 17 0 1 0 0 0 Taste disturbance 0 18 1 0 0 0 0Fatigue/malaise/lethargy 2 5 2 6 3 1 0 Tearing 0 18 0 1 0 0 0Febrile neutropenia 0 17 0 0 1 0 1 Thrombocytopenia 0 16 3 0 0 0 0Fever without neutropenia 0 18 1 0 0 0 0 Tumor pain 0 18 0 1 0 0 0Flu-like symptoms-other 0 18 1 0 0 0 0 Urinary retention 0 17 1 0 1 0 0GU-other 0 18 1 0 0 0 0 Vertigo 0 18 1 0 0 0 0Headache 0 18 0 1 0 0 0 Vomiting 2 14 3 0 0 0 0Hiccoughs 0 18 1 0 0 0 0 Weight gain 0 18 0 1 0 0 0Hypertension 0 18 0 0 1 0 0 Weight loss 0 16 3 0 0 0 0Hypotension 0 18 1 0 0 0 0 pRBC transfusion 0 17 0 0 2 0 0Immuno-other 0 18 1 0 0 0 0Infection with 3-4 neutropenia 0 18 0 0 1 0 0 MAXIMUM GRADEInsomnia 0 16 2 0 1 0 0 ANY TOXICITYLeukopenia 0 5 0 6 6 2 0 Number 0 0 1 2 9 6 1


S9804/II

ResponseData as of August 8, 2001

Navelbine Complete Response 0 0%Partial Response 0 0%PR Non-measurable Disease 0 0%Unconfirmed Complete Response 0 0%Unconfirmed Partial Response 0 0%Unconfirmed PR NM Disease 0 0%Stable/No Response 4 21%Increasing Disease 10 53%Early Death 1 5%Assessment Inadequate 4 21% Total 19 100%

Progression-Free Survival by Treatment ArmEligible Patients with Follow-up

Data as of August 9, 2001

0%

20%

40%

60%

80%

100%

0 3 6 9 12 15Months After Registration

NavelbineAt Risk

19Failed

18

Medianin Months

2


S9804/II

Overall Survival by Treatment ArmEligible Patients with Follow-up

Data as of August 8, 2001

0%

20%

40%

60%

80%

100%

0 3 6 9 12 15 18Months After Registration

NavelbineAt Risk

19Deaths

14

Medianin Months

5


S9903/II

S9903 Phase II

A Phase II Pilot Study of Stereotactic Radiosurgery for Limited MalignantMelanoma Brain Metastases

Study Coordinators:J Thompson, K Stelzer, J Douglas

Statistician:C Rankin

Data Coordinators:L Kingsbury


Date Closed:6/15/2001

ObjectivesTo estimate the 6-month intracranial progression rateand 6-month overall survival rate in patients with lim-ited brain metastases from malignant melanoma usingwhole brain radiotherapy (WBRT) followed by stereo-tactic radiosurgery boost (STRS).To evaluate qualitative and quantitative toxicities asso-ciated with this regimen in this patient population.

To assess the feasibility of accruing patients with lim-ited brain metastases from malignant melanoma usingWBRT followed by STRS boost in the cooperativegroup setting.

Patient PopulationPatients must have prior confirmation of malignantmelanoma, either at the primary site or any metastaticsite. Patients must have no more than three brain me-tastases as determined by MRI, with and withoutGadolinium, with no greater than one centimeter sepa-ration between images. Patients must have bidimen-sionally measurable disease. Patients with any brainlesion greater than four centimeters in maximum di-mension, leptomeningeal spread, brain stem lesions, orlesions within five millimeters of the optic chiasm arenot eligible.

Patients must not have received previous radiation,stereotactic or conventional radiotherapy to any fieldencompassing the brain. Patients may have receivedprior systemic chemotherapy, however, systemic ther-apy is not allowed during the course of whole brainirradiation. Systemic therapy is permitted after WBRT,including prior to and during radiosurgery. Patientswho have had surgical resection of a brain metastasismust have one or two other brain metastases and/orhave measurable residual enhancing disease at the sur-gical site.Patients must have a SWOG performance status of 0 -2. At the time of entry on this study, the process offinding a SWOG approved STRS facility must be initi-ated if the patient is at a site not approved to do STRSby the Southwest Oncology Group.

Accrual GoalsSixty eligible patients will be registered to this study.

Summary StatementThis study closed on June 15, 2001 due to poor accrual.Two patients were registered (Montana CCOP andPuget Sound).


S0008/III

S0008 Phase III IntergroupCoordinating 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, CALGB, ECOG

Study Coordinators:L Flaherty, J Thompson, V Sondak, R Tuthill, J Vetto,J Kirkwood (ECOG), F Haluska (CALGB)




Schema

RANDOMIZE CDDP, VLB, DTIC + IL-2 and IFN Alpha - 2b

1 year High Dose IFN Alpha - 2b

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: an ulcerated primary melanoma with one ormore regional lymph node metastases; OR a non-ulcerated melanoma with two or more regional lymphnode metastases or one clinically apparent overt,macro-, regional lymph node metastasis (including asingle matted nodal mass); OR, any satellite/in-transitmetastasis with or without regional lymph node invol-vment; OR, histologically confirmed: regional nodalrecurrence,recurrent disease in the basin of a previouscomplete lymphadenectomy, or satellite/in-transit re-currence. Patients are eligible for this trial either at

initial presentation of their melanoma or at the time ofthe first clinically detected recurrent disease. Patientswith multiple regional nodal basin involvement arepermitted as long as they are the appropriate anatomicdrainage basins for the primary site. Gross or micro-scopic extracapsular nodal extension is permitted. Pa-tients with distant metastases are not eligible.

Patients at initial presentation of melanoma must haveadequate wide excision of the primary lesion, if pres-ent. Patients with recurrent disease must have all dis-ease completely resected. A full lymphadenectomy isrequired for all patients. Patients with recurrent diseasewho have previously undergone a complete lymphade-nectomy fulfill this requirement. Patients must be reg-istered within 56 days of either lymphadenectomy ORsurgery to remove all recurrent disease if completelymphadenectomy has previously been performed. Pa-tients must not have had prior radiotherapy, chemo-therapy (including infusion or perfusion therapy), orany immunotherapy with interferon and/or interleukinsfor any type of cancer.


S0008/III

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 pulmonaryfunction. 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: newly diagnosed versus re-current disease.

Newly diagnosed patients are further stratified by thefollowing factors: (1) number of involved nodes: 1-3 vs4 or more or any matted nodal mass(es) vs satellite/in-transit metastases with no lymph node involvement; (2)type of lymph node involvement: micrometastases only

(including satellite/in-transit metastases) vs any mac-rometastases; (3) ulceration of the primary: yes vs novs unknown primary.

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.

Summary StatementAs of June 30, 2001, 19 patients have been registered.CALGB joined the study on July 1, 2001.

Among the eight patients evaluated for toxicity, therehave been three Grade 4 toxicities on the CVD+IFN/IL-2 arm, (leukopenia and granulocytopenia in onepatient, and delusions in another), and one Grade 3toxicity (elevated SGPT) in the High Dose IFN Alpha-2b arm.


InstitutionsTotalReg

ECOG 8Wayne State Univ 4Arizona, U of 1Arkansas, U of 1City of Hope Med Ctr 1Community Onc Grp/Cleveland Clinic OH 1Grand Rapids CCOP 1Michigan, U of 1U of Illinois MBCCOP 1Total (9 Institutions) 19

Registration, Eligibility, and EvaluabilityRegistrations ending June 30, 2001; Data as of August 8, 2001

TOTALHigh Dose

IFN Alpha-2bCVD

+ IFN/IL-2 NUMBER REGISTERED 19 10 9

ELIG./ PEND. ELIG. 19 10 9Analyzable, Pend. Elig. 19 10 9

TOXICITY ASSESSMENTEvaluable 8 4 4Too Early 11 6 5


S0008/III

Patient CharacteristicsRegistrations ending June 30, 2001; Data as of August 8, 2001

High Dose IFN Alpha-2b(n=10)

CVD + IFN/IL-2(n=9)

AGE

Median 52 .5 50.0Minimum 27 21Maximum 60 65

SEX

Male 10 100% 8 89%Female 0 0% 1 11%

RACE

White (Non-Hispanic) 6 60% 6 67%Hispanic 1 10% 2 22%Other 3 30% 1 11%

DISEASE STATUS

new 5 50% 4 44%recurrent 5 50% 5 56%

FOR NEWLY DIAGNOSED DISEASE (n=5) (n=4) NUMBER OF NODES

1-3 3 60% 2 50% ≥ 4 2 40% 2 50% satellite/in-transit metastases 0 0% 0 0%

NODAL INVOLVEMENT TYPE

micro or satellite/in-transit metastases 3 60% 2 50% macrometastases 2 40% 2 50%

ULCERATION

no 0 0% 2 50% yes 3 60% 1 25% unknown primary 2 40% 1 25%


S0026/II

S0026 Phase II

Evaluation of Interferon Alpha-2b and Thalidomide in Patients withDisseminated Malignant Melanoma, Phase II

Study Coordinators:L Hutchins, J Clark



ObjectivesTo evaluate the six-month progression-free survivalrate of patients with disseminated malignant melanomawhen treated with interferon alpha-2b and thalidomide.

To evaluate the confirmed and unconfirmed completeand partial response rate in those patients with measur-able disease.

To evaluate the qualitative and quantitative toxicities ofinterferon alpha-2b and thalidomide administered in aPhase II study.

Patient PopulationPatients must have histologically proven, surgicallyincurable Stage IV malignant melanoma. Patients mayhave measurable or non-measurable disease. Patientswith a history of brain metastases are eligible only if

they have been resected completely free of disease inthe brain and then had whole brain radiation therapy.

All patients must have received one prior systemictherapy for Stage IV disease. If all known sites of dis-ease have been previously radiated, there must be ob-jective evidence of progression for the patient to beeligible.

Patients must have adequate renal and liver function,and a Zubrod performance status of 0-2. Patients withknown AIDS or HIV-1 associated complex, or knownto be HIV antibody seropositive are ineligible. Femalepatients must not be pregnant or nursing.

Accrual GoalsThirty-five eligible patients will be accrued.


S0116/II

S0116 Phase II

A Phase II Trial of a D1/3-MAGE3-HIS Fusion Protein with Adjuvant SB-AS02B for Patients with Stage IV, M1a or M1b Metastatic Melanoma

Study Coordinators:J Weber, V Sondak, M Disis



ObjectivesTo assess confirmed clinical response rate, estimate thesix-month progression-free survival rate, assess quali-tative and quantitative toxicities, and measure immuneresponses in patients with Stage IV, M1a or M1b meta-static melanoma receiving Protein D1/3-MAGE3-Hisplus adjuvant SB-AS02B.

Patient PopulationPatients must have histologically documented StageIV, M1a or M1b, metastatic melanoma that is consid-ered incurable by surgery, radiotherapy, or limb perfu-sion. Patients must have measurable disease. Patientswith metastatic mucosal melanoma are eligible. Pa-tients with a uveal or choroidal primary, or with a his-tory of brain metastases are not eligible.

Patients may have had prior adjuvant therapy. Prioradjuvant isolated limb perfusion is allowed if there ismeasurable disease outside the field of the prior limbperfusion. Patients must not have received a previousMAGE-3 peptide or protein vaccine preparation, or anyprior radiation therapy, chemotherapy, biologic ther-apy, or any other prior treatment for Stage IV disease.

Patients must be class I HLA haplotyped prior to reg-istration. Patients must have a Zubrod performancestatus of 0-2. Patients with AIDS, HIV-1 associatedcomplex, or known to be HIV seropositive, positive forHepatitis BsAg, or Hepatitis C are not eligible.

Accrual GoalsTwenty-five eligible patients will be enrolled initially.If one or more responses are observed, an additional 20eligible patients will be accrued.

melanoma committee 2001/melanoma.pdf · nant melanoma. publication status. dr. whitehead s9622...

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