(VBP) Chemotherapy in the Manag

1- GOG #45

NAVl.954211.002

1.0 OBJECTIVES 1.1 To evaluate the effect of four cycles of combined vinblastine, bleomycin and cis-platinum (VBP) chemotherapy in the management of patients with endodermal sinus tumor, embryonal carcinoma, , immature teratoma (all grades), choriocarcinoma, and malignant mixed germ cell tumors of the ovary with advanced or recurrent disease, incompletely resected. 1.2 To evaluate the role of serum markers, especially alphafeto- protein (AFP) and human chorionic gonadotropin (beta hCG), when these are present, in predicting response and relapse. 1.3 To determine the role of restaging laparotomy in patients in clinical remission, in assessing completeness of response, and in planning further therapy. 1.4 To evaluate and compare the effect of vincristine, dactinomycin and cyclophosphamide (VAC) chemotherapy in patients found to have persistent disease at the time of restaging laparotomy. 2.0 BACKGROUND AND RATIONALE

In an earlier study VAC chemotherapy was found to be effective and reasonably well tolerated in patients with early disease (Stages I-IIA) after resection of all gross tumor, with only seven failures in 23 patients with a median follow-up of 24 months. Fifteen of the tumors in this series contained endodermal sinus elements. On the other hand, of 16 patients with advanced or recurrent disease, 8 failed, with a median follow-up period of 26.5 months. VBP chemotherapy, a combination used effectively in advanced malignant germ cell tumors of the testis’ has been used effectively by Ehrlich3 and by Major4 in patients with advanced and recurrent malignant germ cell tumors of the ovary, and may prolong survival both in patients previously untreated, as well as in VAC fai 1 ures . Alpha-fetoprotein (AFP) is produced in the yolk sac and later in the embryonal liver, disappears from the circulation at birth, to reappear later only in association with tumors of the 1 iver, gastrointestinal tract, and with embryonal tumors of the ovary and testis, and m?! be a useful 2erum marker in following the course of the disease in affected patients. Elevated serum levels of human chorionic gonadotropin have been found in association with a variety of embryonal and non-embryonal tumors. With the development of a sensitive and specific radioimune assay for the beta chain of this polypeptide it is now possible to follow the course of patients with these tumors, and in some cases to predict relapse.6

Rev. 7/23/82

we%) -- - 10 - 3 GOG 845 -DS-,wlq

,4.34 primary tumors should be sampled at a minimum rate of one section per 2 cm. of greatest diameter of tumor. All slides should be received at GOG Head- quarters within six weeks after entry. Form F (Pathology Form) and a copy of the dictated patholo5 report must be submitted with the slides.

5.1 Telephone Entry When a candidate is suitable for entry and has fulfilled t eligibility requirements according to Section 3.0, Fast F2 Sheet data should be gathered. With this data in hand, tt meadquarters in Philadelphia should be called via "WAl line: 1-800-523-2917, Monday-Friday, 9:00 a.m. - 5:OO p.n Eastern Time. Entry will take place on the telephone aft€ consideration of Fast Fact Sheet data (See Appendix 11). A verifying On-Study Form wi 11 be mailed from Headquarter5 after entry and must be filled out by the institution and returned to Headquarters within 2 weeks to assure proper I credit for the entry. (See Section 10) 6.0 TREATMENT PLAN AND DOSE MODIFICATION

1- After adequate recovery from required surgery (see Section 4.1: all patients will receive 3-4 cycles of V8P therapy as outline: in Section 6.1. Previous VAC failures showing evidence of prc; during VBP therapy may be transferred to Protocol 26, if eligi: Patients never having received VAC previously who show evidenc: , progression while on VBP therapy will receive 12 courses of VA( according to Section 6.3. If further progression is noted, el' patients will be candidates for Protocol 26. Patients exhibiting a complete response or a partial response making remaining disease resectable will undergo restaging lapar as outlined in Section 4.12. Patients with persistent disease at the time of restaging laparotomy who have previously received VAC will be candidates for Protocol GOG #26, if eliqiz Patients with persistent disease at restaging laparotomy, and who have not previously received VAC will receiv6 six cycles of VAC at the dose levels in Section 6.3. If further progress is noted at any time, patients will be candidates for Protocol GOG 126, if eligible. Patients who are free of disease with negative markers after six cycles of VAC will receive a "third-look" laparotomy to help plan further therapy.

- Rev 1/9/81 I- -11- GOG #45 /’ 3

6.0 TREATMENT PLAN AND DOSE MODIFICATION (continued) 6.1 VBP Chemotherapy 6.11 Children age 13 and under will receive: 6.111 Vinblastine 12 mg/m2 I.V. push on day 1 every three weeks. for twelve weeks, for a total of four doses. The initial dose of vinblastine will be 9 mq/m2 for patients with a history of prior pelvic rad i othera py . 6.112 Bleomycin, 10 units/m2 I.V. weekly for seven weeks starting on day 1. .,he8th course will be given on week 10. If possible bleomycin will be given six hours after vinblastine when bleomycin and vinblastine are given the same week. 6.113 Cis-platinum 20 mg/m2 in 50 cc sterile water over 15 minutes, I.V. daily times five, every three weeks for three courses. A fourth course may be given if clinical remission does not appear to be complete with three and no significant nephrotoxicity is observed (BUN less than 50 and creatinine less than 3.0 mg/dl). 6.1131 The first dose of each cis-platinum course will be given together with bleomycin, six hours after vinblastine. 6.1132 Vigorous saline hydration should be given with each course of cis-platinum. All patients should receive 100 ml/hour normal saline I.V. hydration for 12 hours before institution of chemotherapy and for the entire five day course of ci s-pl ati num. 6.1133 Diuretics may be necessary to prevent fluid overload in older patients. 6.12 Women 14 and over will receive 20 units/m2 I.V. (maximum dose 30 units) of bleomycin weekly for seven weeks. The eighth course will be given on week ten. The total bleomycin dose shall not exceed 360 units. Doses of vinblastine and cis- platinum will remain as above.

Rev. 1/9/81 7/23/82 GOG #45 8'349 3 I -- %diffcations for VBP

bj! I 1.21 Hematologic Toxicity (See Ap pendix I1 tcI*;:F= p 6.211 During VBP therapy there wi 11 be no rnodificati on of vtnbl asti ne dosage regard1 e ss of the degree \ of myelosuppression, except fo rPatients with an c Jllness characterized by fever gr eater than 101" .. associated with an ab solute gr anu locyte count le than 7,000. Subsequent doses of vinblastine w il be reduced 25% in SUCh patientsw ithout delay in therapy, even if they continue to have a fever

6.22 Gastro-Intestinal Toxicity ( See Appen dix 111) ..%..- 6.221 Most patients will de velop sev ere nausea and vomiting during thera py with c is- platinum; however, antiemet i cs should be used liberally and every attempt sho uld be nla de to complete the entire course of ci s-plati num therapy.

. 6.222 Constipation (witb vi nblastine 1should be prevented by the use of laxatives and stool soft- I eners. 1 6.23 Genitourinary Toxicity (See Appendix 111 ) 6.231 Since bleomycin is excreted primarily by the kidneys, the dose will be cut 50% if the serum creatinine is over 2.0 mg/dl. 6.232 If the serum creatinine rises above 3.0 mg/dl subsequent courses of cis-platinum will be held until the creatinine level drops below 3.0 mg/dl and subsequent doses of cis-platinum will be cut 25%. 6.233 An effort should be made to avoid the concurrent use of aminoglycoside antibiotics (gentamicin, tobramycin, amikacin) which may potentiate the nephrotoxicity of cis-platinum.w 6.24 Hepatic Toxicity (See Appendix 111)

6.241 The dose of vfnblastine will be reduced 50% if the total serum bilirubin is over 2.0 mg/dl, but will be increased to 100% normal when the bilirubin level returns to normal.

**c I Rev 9/21/79 i Rev 10/17/79 '. I I Rev 1/9/81 / - 13 - GOG #45 g3-OS-lSrj 7-of

6.25 Pulmonary Toxicity (See Appendix 111) ’ 6.251 Bleomycin will be discontinued if there is any clinical evidence of pulmonary fibrosis. 6.26 Neurologic Toxicity (See Appendix 111) 6.261 Neurologic toxicity will be monitored but vinblastine and cis-platinum will not be withheld unless there are seizures, motor weakness, or severe paralytic i leus. 6.262 Neurologic toxicity, including ileus, may be more common and more severe following vinblastine in patients who have previously received vincristine. Secondary Treatment with VAC (For VBP failures who have not received VAC previously). 6.31 Dactinomycin, 350 micrograms/M2 body surface area, ‘ I.V. daily for five days every four weeks. 6.32 Cyclophosphamide, 150 rng/M2 body surface area I.V. daily for five days every four weeks. 6.33 Vincristine, 1.5 mg/M2 body surface area (single dose not to exceed 2.0 mg) I.V. every two weeks for twenty-four weeks. 6.4 Dose Modifications for VAC 6.41 Hematologic Toxicity (See Appendix 111) 6.411 Subsequent courses of dactinomycin and cyclophosphamide will not begin until the granulocyte count is greater than 2000/mm3 and the platelet count greater than lOO,OOO/mm’ If these levels are not present, weekly counts should be done and treatment delayed until these criteria are met. A delay of more than four weeks will be cause for notification of the study chairman. 6.412 A blood count will be obtained before the fifth dose of dactinomycin and cyclophosphamide and if the granulocyte count is less than 1000/mm3 or the platelet count less than 50,000/mm3 the fifth dose will not be given. ti& #45 -- ', 3 -14- -3 53-08-18 E;7-Oyy 6.413 Similarly, if the weekly nadir granulocyte count drops below 1000/mm3 or the nadir platelet count drops below 50,000/m3; the Study Chairman will be notified and subsequent courses will be shortened to four days.

6.42 Gastrointestinal Toxicity (See Appendix 111) 6.421 Antiemetics should be given liberally and every attempt made to complete a course of dactinomycin and cyclophosphamide. However, subsequent doses of dactinomycin and cyclophosphamide will be withheld for severe and uncon- trolled (Grade 111) nausea and vomiting and, when resumed, doses will be cut 20% or treatment shortened to four days. 6.422 If severe (Grade 111) diarrhea or mucositis occur, subsequent doses of dacti nomyci n and cyclophosphamide should be withheld and, when resumed, doses will be cut 20%.

6.423 Constipation (from vincristine) should be prevented by use of laxatives and stool softeners. 6.43 Neurotoxicity (See Appendix 111)

6.431 Vincristine should be withheld in the event of severe or disabling paresthesia, muscle weakness or paralytic ileus and, when resumed, the dose will be cut 50%. 6.432 Neurologic toxicity including ileus may be more comnon and more severe in patients peviously treated with vi nbl as tine. 6.44 Genito-Urinary Toxicity (See Appendix 111) 6.441 Cyclophosphamide whould be withheld for four weeks if cystitis occurs during a course of treatment. Every effort should be made to insure adequate hydration on the day of drug injection. When resumed the dose should be cut 50%. Hemorrhagic cystitis which requires blood transfusion or the intravesical instillation of formal in solution should be reported to the Study Chairman. 6.45 Hepatic Toxicity (See Appendix 111) 6.451 The dose of dactinomycin will be reduced 50% in the presence of a total bilirubin level over 3.0 mg/dl or an SGOT level over 150 IU/L.

Rev. 1/16/82