Oak Ridge Associated Universities/Oak Ridge National Laboratories Committee on Human Studies Protocols and Related Documents

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REVIEW AND ACTION Committee on I-luman Studies Oak Ridge Associated Universities Identifying No. /Principal Investigator: "Clinical Trial of 'l3Inm as a Kidney and Bone Scanning Agent" After discussion, the proposal was approved after appropriate clearances have been made. Secretary, Committee on Human Studies

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REVIEW AND ACTION Committee on Human Studies Oak Ridge Associated Universities After discussion, the proposal was approved after appropriate clearances have been made. Disapproved: (date) Secretary, Committee on Human Studies

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REVIEW AND ACTION Committee on Human Studies Oak Ridge Associated Universities Project Title: "Immunotherapy of A cute Leukemia This project invoked a great deal of discussion about possible risks to the recipient of irradiated malignant cells. The members of the committee approved the plans for at least a few more studies since the risks are most certainly minimal, but recommended that possible other methods for obtaining specifically sensitized malignant cells be explored. Disapproved: (date) Secretary, Committee on Human Studies

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immunotherapy, and I believe includes a fairly adequate dfscussion of the possible hazards involved. Appended to the paper is a memo from Dr. Helen Vodopick suggeating changes in the protocol. I wonder if this information will be adequate as a basis for discussion at our meeting on September 15. This paper explains what we have been trying to do in clinical

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9 UBJECT PROTOCOL FOR THE I M After our discussion with Dr. Peter Alexander, it was felt that our protocol for the immunotherapy o f acute leukemia should be amended. Enclosed is a revision of the protocol which incorporates some of these changes that were proFoscd. Please feel free t o make any further amendments. If there is any omissions which should be included, please note this We would hope t o have a ''working" protocol ready in expectation for OUT next suitable patient.I would appreciate it if you would forward your comments to m e so that a written final plan can be drawn up. Thank you for your help.

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leultenia untreated - probably child, or solid tumor, incurable but to apparent limited extent. AI30 compatible normal person to receive killed malignant cells and t o donate " sensitized thoracic duct lymphocytes. marrow aspiration(anticoagulant 470 IC2 EDTA) or piece of solid tumor minced and washed with Tc 199. For preservation : autologous serum a ) Freeze by nieans of slow freeze liquid nitrogen (l°C/min) to preserve these cells for future use ; b ) Remove DhGO before irradiation and wash with Hank's buffered salt c) Irradiate with 10,000 R or more just before giving. 3. Route of sensitizing dose - intra lymphatic into normal recipient. Use Sweeney adaptor to remove large particles. 4. Thoracic duct can nul ation of " sensitized " recipient - Time of cannulation: Day 4 - 7 . Check for pyro nino phil ic cells in thoracic duct lymph and i n blood smears (possibly use this to determine when can nul ation should b e done). 5. Before infusion of lymphocytes into recipient - a ) leukemic - patient should bo in full remission. No steroids are given during administration.Stop anti leuk emi c drugs just before commencing After infusions - 7continue anti leuk emi c drugs. b)solid tunor - 7 immunosuppressive agent to patient before sensitized

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d ) do not wash cells (keep lymph t o minimum e ) Collectipons every 3hrs - check sizing (pick up larger pyro nino phil ic cells i ater this way) f ) Keep sufficient number of cells for g) Infuse into patient as soon a s processed. b ) Imuran - when temperature rises, diarrhea,skin rash, not attributable to anything else occurs. a)Clinical remission or regression of tumor b) In vitro testing.

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REVIEW AND ACTION Committee on Human Studies Oak Ridge Associated Universities An on-going study, presented and discussed, 9/15/67 Disapproved: (date) Secretary, Committee on Human Studies

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HUMAN BONE MARROW TRANSPLANTATION ORAU MEDICAL DIVISION Using the procedures outlined in the protocol for therapeutic al loge nic transplantation of human bone marrow as approved by this committee, w e have performed three bone marrow transplants up t o males,51years and 41years old, and one woman, 53years of age. All of these patients had acute gran u loc y tic leukemia.In two of The patients receiving this kind of treatment were two these patients we found a his to compatible donor according to the HL-A typing and the results of the mixed lymphocyte cultures.In the41year old man we did not find an identical donor and the HL-A typing indicated aD match, which means a difference of atleast3 antigens.In this third case there was also as light reactivity in mixed lymphocyte cultures. All of these patients received anti-human thymocyte globulin and total body irradiation with500R as pre - grafting immunosuppress ion. The anti-human thymocyte globulin was generally tolerated well,except for the last patient, who reacted with severe fever spikes following most of the daily injections of the horse globulin. Each of the patients tolerated the radiation very well. Except for slight nausea following the total body irradiation(only the second patient vomited)the only symptom experienced by.the patients was drowsiness which was in part due to the phe not hi azide medication used to suppress nausea - and vomiting. We do not believe the immunosuppression shortened the life of any of these patients.

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The transfusion of the bone marrow cells went without any complications,especially there were no indications of embolism. The total number of bone marrow cells infused into these three patients ranged between 15xlo9to18xlo9cells. patients received post - transplant immunosuppression with inter - mitten t doses of methotrexate as outlined in the protocol. The dose of the methotrexate was varied according to the clinical course of the patients. mg of methotrexate up tothe117th day post - transplant. The second patient received a total dose of 140 mg the last which was given on day 21. No further methotrexate was considered for the second patient because of abnormal liver function studies. of methotrexate given to the third patient was 195 mg. Our first patient received a total of440 The total dose The two patients who received HL-A identical bone marrow grafts showed well-documented evidence for a successful take of the bone marrow graft.This evidence was derived from red cell markers and white cell markers.In the third patient we had no evidence for a successful graft,and had to conclude that the bone marrow graft was not accepted.In none of the patients did we see any signs or labor at dry evidence for graft - versus - host disease. With regard to the third patient.this would also indicate that we did not obtain a successful graft. The survival time of these patients was 122 days respectively,92days for the patients with the HL-A identical days following the transplant. All three of the patients died with pneumonia or septicemia,although the first patient ' s death was more likely the result of pulmonary embolism and renal failure and The patient with the mismatched bone marrow lived for60 the last2patients died with their leukemia in relapse.

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With regard to the stage of leukemia we observed that in the first patient there was no recurrence of leukemia. causes unrelated to his leukemia, and on autopsy there was no evidence of leukemia. The second patient (female) showed initial absence of leukemia cells from the blood o r bone marrow. However, approximately101 / 2 weeks after the transplants he developed a sudden blast cell crisis,subsequently to which she died from septicemia.In the third patient we never saw evidence for a successful take of the graft and we never observed a complete disappearance of leuk emi c cells from the peripheral blood and / o r He died from

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No. 5 Use of Radioiodine in Surgical Removal of Ca of Thyroid Between 1950 and 1974, 150 patients with cancer of the thyroid were admitted to the ORINS/ORAU Medical Division. Of these 117 received at least one dose of therapeutic iodine-131 as part of their therapy in addition to surgery. A s of our last information 87 of the patients are still living. A s of October 1974 this investigation has been terminated and we are now in the process of compiling the data and evaluating the clinical course of these

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Re: Proposal No. 5 (Old, 1967, or preceding.. .) Title: U s e of Radioactive Iodine in Surgical Removal of This project was started before the formation of the Committee on Human Studies. No formal project proposal is in the Committee filrd. At the December. 3.3'73 meeting D r . Edwards reported that work is continuing. "We a r e to talk about this project in about six months. (2 2 9 /'J*y

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REVIEW AND ACTION Committee on Human Studies Oak Ridge Associated Universities Principal Investigator: Identifying No. 5 Project Title: "Use of Radioiodine in Surgical Removal of Thyroid Cancers" A n ongoing study, presented and discussed. Disapproved: (date) Secretary, Committee on Human Studies

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REVIEW AND ACTION Committee on Human Studies Oak Ridge Associated Universities Principal Investigator: Lintifying No. 6 A n ongoing study presented and discussed 9/15/67 Disapproved: (date) Secretary, Committee on Human Studies

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TO: Committee on Human Studies Oak Ridge Associated Universities APPLICATION FOR THE USE OF HUMANS AS EXPERIMENTAL SUBJECTS (Three copies required. Use reverse side of these forms if additional space is needed.) Title of Project: A Study of Infections in Cancer Patients. II. Objectives of Experiment: ( U s e additional blank pages if needed.) The study will be directed toward the infections that complicate, and often prematurely terminate,intensive chemotherapy and radiotherapy of cancer. The objectives will be to determine the causes of these infections and better ways of preventing them with the following specific aims: (1) To develop procedures for the care and management of these patients during therapy in a sterile(ultra clean) environment using a new laminar - air - flow clean-room facility, and to test the facility for its use in reducing the incidence of infection during this vulnerable period. reducing flora of skin and mucous membranes. Further,to assess the value of these procedures in the ultra clean facility. infections,their portal of entry and response to therapy. (2) To test regimens for bowel sterilization with antibiotics and (3) To identify,in these patients,the microorganisms involved in

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Page 1 A - Objectives of Experiment: (4) To characterize the microflora (mouth, nasopharynx, gastrointestinal tract, respiratory tract) of cancer patients in order to determine whether or not shifts in the microflora occur coincident with therapy and whether or not such shifts in the microflora are related to infectious complications. Thus the relative roles played by microorganisms from the endogenous flora and those microorganisms not considered as part of the normal flora can be more critically evaluated. (5) To determine whether cancer therapy is responsible for the development of a more antibiotic-resistant bacterial flora. (6) To detect alterations in host defense mechanlsms that may be induced by immunosuppressive cancer therapy.

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Application for use of humans as experimental subjects Page 2 m. Methods of Procedure: Brief description of methods, all medications including name and dose range, number and types of subjects anticipated, time for single session, total number of sessions, total duration of study, methods used to screen subjects, etc. (Use additional blank pages if needed.) (1) Patients in O M U hospital with malignant disorders of the hemopoietic system receiving intensive chemotherapy or radiotherapy. a. Randomization of patients after criteria have been met of: (1) Type of disease - acute leukemia; chronic leukemias; stage I11 and IV lymphoma and Hodgkin's disease; other disseminated malignant neoplasms. ( 2 ) Mode of therapy - radiation or suppressive chemotherapy that can be expected to cause granulopenia below l,000/mm3. ( 3 ) Informed consent - patients judged psychologically able to tolerate this closed environment for extended periodsfor a minimum of two weeks; possibly up to 6 months in certain patients, and willing to accept randomization and the prescribed antibiotic regimen. Continued on Page 2 A 1V. Possible hazards and their evaluation: We anticipate no unusual hazards to be associated with operation of the laminar-flow patient facilities. The use of oxygen tents will not be feasible, and patients requiring oxygen will be administered oxygen through a nasal mask. The use of oxygen at 5 liters per hour (0.15 cubic feet per hour) is well below the fresh air intake of 200-300 cubic feet per minute and will prevent any hazardous concentration of oxygen in the room. through-the-wall oxygen system is available to preclude the use of oxygen tanks in the patient room.

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Application for use of humans as experimental subjects Page 2 A 111. Methods of Procedure (Continued): b . The patient will be placed in the unit for2to3days,or where possible longer,before beginning therapy to obtain regimen such as ny statin, 1,000,000 o r more units q 4-6 h: gent a mic in, 200 mg q4h ; ox a cill in, 0.5 g q 4-6 h on a pHisoHex o r Betadine. Daily Betadine douche and vaginal ny statin suppositories for females. Sprays of neomycin, bac it rac in, and ox a cill in into nose and mouth, q.i.d. (3)If Pseudomonas is cultured, polymyxin B will be added by appropriate routes. (4) With persistence of resistant organisms, other appropriate antibiotics will be given on the basis of in vitro sensitivity (5) Clinical infections will be treated with specific agents. (6) Newer, more effective agents or regimens will be adopted as they become available. (7) "Controls" will be housed identically in the "clean" rooms and will receive the same isolation procedures. Infections will be treated with specific agents. Gut - after giving patient an enema and cathartics : a Skin and mucosal surfaces - shampoo and bathe daily with (2) To compare the relative importance of endogenous and exogenous microorganisms in infections of immunologically repressed patients,we will study patients receiving similar therapy in standard hospital rooms and also in Ultra clean Laminar Flow rooms using sterile techniques to prevent contact contamination of patients. The air in the laminar-flow facilities will be essentially free of microorganisms. The air, randomly selected sections of the walls and floors, and the fixtures will be monitored routinely for organisms. We will also monitor the micro flora of personnel who have access tothe rooms. The patient will be given a sterile diet and drinking water. Routine entry from the preparation room to the clean patient rooms will be limited to authorized,trained personnel. Gas o r steam sterilization procedures will be used on all linens,utensils,or any other items introduced into the room. Until our microbiological sampling indicates otherwise,all personnel will be required to wear sterile gloves,hair covers, masks, gowns, and shoe covers. However, i t may be possible later to eliminate some of the sterile clothing,since industrial laminar-flow facilities have been operating with simpler protective coverings and have no increased contamination problems. Experience and the training of all personnel to avoid contact contamination may justify similar moves on our part. The use of the room's toilet facilities is still controversial at this time. Our accumulated experience will also determine whether it will be necessary to resort to portable …