The International Registry of Tumor Immunotherapy

Symposium on Immunotherapy in Malignant Disease

The International Registry of Tumor Immunotherapy Dorothy Windhorst, M.D. *

The International Registry of Tumor Immunotherapy was established early in 1973 for the purpose of cataloging protocols of clinical trials in immunotherapy while the trials are actually in process so that a compendium could be prepared and provided to cooperating investigators. A few of the protocols which were in the first compendium issued by the Registry have been completed, many have been modified, and still others have been dropped. This type of change over a brief period illustrates the natural evolution of immunotherapy in its status as a new modality of cancer treatment. From the perspective of the Registry, one of the more noticeable trends in immunotherapy is an increasing sophistication in protocol design. Indeed, the major goal of the Registry is to help investigators develop good clinical studies. Design of the Clinical Protocol The term protocol as used here means "plan," specifically a written plan for a scientific experiment involving human subjects. Although the word is not defined in this way in either standard or medical dictionaries, this usage has clear legitimacy, especially among cancer therapists, and there is some agreement about the necessary components of such a plan.1- 3 The experimental design for a clinical research project fulfills the scientific process in that a question is asked (Is treatment X any good?); a baseline or control is determined (Compared to what?); and every effort is made to assure that the only difference between the test group and control group will be the experimental manipulation. However, the clinical investigator cannot select genetically identical individuals in whom to make comparisons and he cannot control environmental factors as can be done in the animal laboratory. Because clinical research cannot eliminate variability among the experimental subjects, other ways must be found to assure that the ex"Office of the Associate Director for Immunology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Medical Clinics of North America-Va!' 60, No. 3, May 1976

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perimental and control groups do not differ significantly. This usually means ascertaining that the more important variables are equally represented in both groups-the proportion of patients in older versus younger age groups or the ratio of male to female patients for example. It is important that plans be made in advance to handle all known factors which affect the prognosis of the disease being studied, and large segments of clinical protocols are devoted to this problem. Table 1, adapted from Gehan and Schneiderman, lists the major components of a protocol to evaluate the effectiveness of a therapeutic agent. Not all protocols need contain all components listed. For instance, a pilot study to permit an investigator to gain experience in handling a new therapeutic agent might be limited to a specified small number of patients and the written plan would deal simply with a description of eligible patients, the possible toxicities, and the nature of the informed consent. However, a definitive evaluation of the therapeutic worth of the agent requires more detailed planning in order to assure that the results of the study will be interpretable. The Registry contains examples of all varieties of protocols, from simple feasibility studies to elaborate sequential and randomized trials. Table 1. Example of a Format for Clinical Protocols The Protocol Title should name tumor to be studied and agent(s) being tested. It should also indicate any institutional coding system. 1.0 Goal of protocol: Should state question to be answered including the nature of the control against which the experimental result will be evaluated. 1.1 Secondary goals. 1.2 ... 2.0 Definition of population to be considered: Gives the diagnosis, stage of disease, and other criteria used for selection or exclusion of patients, such as age, other diseases, etc. 3.0 Design of study: Gives stratification and randomization steps. Should include prognostic or other features which will be used to balance the randomization. Should be diagrammed. 4.0 Therapeutic agents: Lists all types of therapy, including chemical name or formula, dose, route, modality, schedule, supplier, known toxicity, and dose modifications for toxic reactions. A diagram of the schedule should be given. 5.0 Parameter(s) being measured for efficacy of therapy: Measurements for indication of disease progression, and timing of such measurements. 6.0 Clinical studies to be done, with timing: Should include brief allusion to items in 5.0 and should be diagrammed. 7.0 Special studies: (e.g., Immunologic assays) with timing. 8.0 Criteria for taking patients off-st-uify:- This will include treatment failures, toxicity, and a statement about provisions for continued follow-up and availability of related protocols for patients when they go off-study. 9.0 Statistical considerations: Considers patient accrual estimates based on experience of the institution, gives a schedule for patient accrual and follow-up, and estimates total time to complete the study based on statistical analysis of the known course of the disease and possible effects of the experimental therapy. 10.0 Human subject considerations: Gives information on ethics, committee review, and informed consent. 11.0 Additional related materials: 11.1 Name, address and phone numbers (day and night) of responsible investigators. 11.2 Log book for all patients considered for entry. 11.3 Record forms for patient entry, follow-up evaluation, off study, etc. 11.4 Scientific rationale or justification for the study with literature references.

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In Table 1, item 1.0, "Goal," is the scientific question, including a description of the control. Items 4.0, 5.0, 6.0, and 7.0, describe the manipulations and measurements to be undertaken, and item 10.0 deals with special ethical aspects of research involving human subjects. Essentially all the rest of a protocol, incorporated in items 2.0,3.0,8.0, and 9.0, is directed toward assuring that extraneous factors which might affect a patient's course have been anticipated and negated insofar as they might influence the evaluation of the therapeutic responses. They are intended to control variability by assuring that the treatment group does not differ from the control group, and that opportunities for investigator bias in the form of subjective judgment have been eliminated as much as possible. Many clinical investigators feel that the best way to control the problem of unknown variables and to reduce investigator bias is the use of randomization in the research design. Thus, treatment A might be compared to treatment B, which would already have been shown to be better than an older treatment (or to no treatment),and the treatment which a specific patient would receive in the trial would be determined by a random assignment. Clearly, the investigator must regard the existing evidence for the usefulness of treatment A to be that it is probably as good as (and no worse than) treatment B. "Usefulness" in this context implicitly includes a consideration of known hypothetical risks of the agent. Some argue that if the investigator feels that treatment A may be better than treatment B, then it may be unethical to deny any patient the new therapy, making a concurrent randomized control group inappropriate, and requiring that treatment B be compared in sequence with past experience with treatment A-a "historical control." Others hold the strictly scientific view that until a treatment has been shown to be useful by objective criteria, it should be administered only under conditions which will permit the best possible evaluation ofits true worth. Indeed, the capacity for medical enthusiasm to overwhelm scientific judgment is well demonstrated in medical practice. 4 These points illustrate the complex added dimension in human research of considerations relating to ethics, but a detailed discussion of this is beyond the scope of this chapter. The concept of performing sequential studies in which the effects of a new therapy are compared with the results of a past study on a similar group of patients poses even more difficult problems of management of the variability between the experimental and control (historical) groups and it has been suggested that such studies require a particularly clear and rigid protocol design.:J Added factors include the possibility that the nature of the disease may change with time, there may be differences in the kind of ancillary care that is given, and the primary therapy (e.g., surgery, radiation therapy) may have changed as a consequence of the development of newer techniques. One of the arguments in favor of sequential studies is the claim that they can be completed in a shorter period of time than those which require enough patients to be randomized to two or more "arms" of treatment. This consideration arises from still another major difference between clinical research and that in the basic laboratory, namely, that the research subjects can only be accumulated "naturally" in the course of daily

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medical practice. The rate of accrual may be accelerated by enlarging the population from which the patients may be derived, as illustrated by the efforts of clinical cooperative groups, but the fact that it is not possible to initiate all the treatments at once has led to such concepts as a period of patient entry, closure of the study to patient entry, and follow-up of the patients "on study" until all necessary data has been collected. Clearly, this means that very little clinical research of any kind can be accomplished in less than a period of many months, and most require several to many years. In such a period oftime, a given experiment is at risk of becoming out dated by new information developed by other investigators which may require that the study design be altered or even abandoned before it can be completed. Thus, in order to achieve a useful result from a clinical trial, several things are needed: a research goal which will not have lost its meaning during the time it takes to conduct the study; a written plan, which may have to be reworked several times and must be in considerable detail especially if more than one physician is to be entering and following patients; and time-both to write the plan and to do the study. These rather pragmatic needs require that the investigator be informed about protocol design and about protocols which may already be addressing the problem in which he is interested. This takes effort over and above the energy a physician-scientist will already be expending in a primary scientific discipline of, say, the pharmacology of chemotherapeutic agents, or the nature of the immune response. It also requires the availability of a specialized kind of informational resource. The International Registry ofTumor Immunotherapy was initiated in response to such a need. Clinicians involved in early immunotherapeutic trials wished to know what else was being done, and immunologists and oncologists found themselves joining to plan clinical trials and needing to talk to others attempting similar collaborations.

Role of Registry in Clinical Studies in Immunotherapy In the winter of 1972, a small group of physicians interested in immunotherapy met briefly to discuss some of these problems. '" In the course of their discussions, it became clear that the most useful thing that could be accomplished would be to compile a complete and relatively detailed list of ongoing trials in immunotherapy, making the list available to interested investigators for use in their planning efforts. This same group also foresaw the exponential growth in research in tumor immunology, not only in the laboratory but also in the form of clinical investigation. They were aware that procedures for acquiring and handling protocol

*Participants were: Drs. Evan Hersh (Houston), Myron Karon (Los Angeles), A. B. Miller (Toronto), Carl Pinsky (N ew York), H. F. Seigler (Durham), Richard Simmons (Minneapolis), and J. W. Thomas (Vancouver, B.C.). In addition, members of N.C.1. involved in this effort have included: Drs. Mary Fink, Ronald Herberman, Brigid Leventhal, Herbert Rapp, Steven Rosenberg, John Schneider, William Terry, Dorothy Windhorst, and John Ziegler.

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information for such a registry would be easier to develop and refine while protocols were still relatively few in number. Thus, the Registry from the beginning has been a service project conceived by, and operated for investigators who wish to be· informed about a specific area of clinical research. It is a basic resource, containing information about clinical studies of investigators doing this type of work all over the world. The major product of the Registry is the Compendium of Immunotherapy Protocols, which lists and gives brief descriptions of clinical projects planned and underway. The compendium is distributed to all investigators who submit protocols to the Registry, and each may obtain additional information about protocols of interest by direct communication with the relevant investigators through addresses and telephone numbers which are incorporated into the compendium. This facilitation ofinformation exchange constitutes a major educational influence of the Registry, and has undoubtedly contributed to the quality of many newer protocols. The compendium has grown from less than 70 protocols registered in the first edition oOune 1973, to 129 protocols listed in the second edition of July 1974, to more than 220 protocols registered in the new version of September 1975. Table 2 gives the protocols currently registered according to the disease and agent being evaluated. All together these protocols are evaluating more than 20 different cancers with 9 different agents or combination of agents. A resource such as the Registry must be current, since its usefulness is entirely dependent upon providing information that has not yet reached the stage that it can be considered for publication in the medical literature. The third edition ofthe compendium issued in September 1975 was totally updated by contacting all investigators and is the first one based on an automation of information about the registered protocols. The automated procedure for handling protocol details will enable the Registry to interact efficiently with investigators through computer printed mailings. By this means the most recent information about the status of protocols will be obtained and projected studies will be registered at an early stage. Thus future issues of the compendium will be based on regular direct contact with investigators and will contain the most current information possible. Automation of protocol information has necessitated the translation of all protocols into a common format similar to that given in Table 1. In the future, this will permit selective searching ofthe Registry for clinical trials of a given design regardless of the number of pro to cols registered. It is expected that this capacity will provide both investigators and funding agencies broader perspectives for long range planning as the number of active protocols continues to grow. In the future it may be that the Registry will develop a capacity for accumulating information about early results of ongoing studies as an added dimension in the coordination of forward planning. This goal will require careful development, since it would be undesirable for the Registry mechanism to be used to prematurely publicize unconfirmed experiments. Since 1972, the Registry has mailed four information letters to practicing physicians who have expressed an interest in tumor im-

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Table 2. Clinical Trials Listed with the International Registry of Tumor Immunotherapy, 1975

TUMORS

NO. OF TRIALS

IMMUNOTHERAPEUTIC AGENTS Cells, etc.

BCG

MER

Levamisole, 2 Transfer factor, 2 Transfer factor with BCG, 2

2

4

Levamisole, 1 Levamisole with BCG, 1 Levamisole with C. parvum, 1 Poly I. C, 1 Transfer factor, 1

1

2

Levamisole, 1 Vitamin A, 1

3

Coenzyme Q-lO, 1 Levamisole, 1 Poly A. Poly U, 1

59

15 (10 moM.)

26 (2 w/C. parvum) (1 wIDNCB) (1 w/MER)

4

Hematologic neoplasms

33

14 (6 modif.)

14 (1 w/C. parvum)

4

Multiple

26

9 (2 modif.)

Lung

23

9 (4 modif.)

Breast

20

Gastrointestinal

17

Genitourinary

11

Sarcomas

10

Head and neck

9

Miscellaneous (esophagus,l; skin, 2; neuroblastoma, 1)

4

1

212

60

TOTAL

3

Cl modif.) 2 (1 modif.)

9 (1 w/C. parvum) 9 (1 w/C. parvum) 8

Other

8

Melanoma

6

C. parvum

Levamisole with C. parvum, 1

5

6

4

5 (3 modif.)

1

2

Transfer factor, 2

1 (modif.)

3

2

Levamisole, 1 Transfer factor with BCG, 1 PPD,1

1

83

19

27

22

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munotherapy, even though they may not be participating in a research protocol. This mechanism has been used to announce the compendium issues, report toxicity of various immunotherapeutic agents, and provide brief information of current developments in the field including literature references. The mailing list for newsletters has grown from less than 500 to more than 2000 names. In the future the active protocols in the Registry will be listed by title in the newsletter in order to provide this selected audience of oncologists a resource ofinformation about protocols and for use in referral of patients.

International Efforts Both immunology and oncology in general and immunotherapy in particular have attracted a large, vigorous, and sophisticated research effort throughout the world. From the beginning, the Registry has made every effort to be internationally comprehensive. As can be seen from Table 3, 27 protocols in the current issue of the compendium come from Europe; 3 come from Asia and Australia; 2 from Africa; and 9 come from North and South America other than the United States. While many of these protocols were submitted directly to the Registry by the responsible investigators, others were located through the cooperation of Dr. R. Flamant, editor of the listing of controlled therapeutic trials published by the International Union against cancer.!

Future of the Registry The Registry was established early in the course ofthe recent expansion of interest in Immunotherapy trials, and an early commitment was made to develop automated systems to handle information in the Registry. Thus, the Registry is in a position to act as a primary informational resource about an important field of cancerresearch, because bulletins on toxicology, updated versions of the compendium, and other materials can Table 3. Distribution of Registry Participation, 1975 COUNTRY

Argentina Australia Austria Belgium Bulgaria Canada China England France Israel Italy Japan Netherlands Switzerland United States TOTAL

NO. OF TRIALS

1

6 1

4 8 1

8 5 2 2 1 1 1 170 212

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DOROTHY WINDHORST

be distributed on short notice to the most relevant audience. In addition, selective searching of the registry computer "files" will allow new projects to be developed on firm rational grounds. Since the automated system will also permit the Registry to expand easily as this area of research continues to develop, it should be possible to maintain the data base in a comprehensive manner. Thus, the International Registry of Tumor Immunotherapy will continue to be capable of providing current, relevant and complete information about clinical trials in this field as long as investigators express a need by their own cooperation in the Registry's work. ACKNOWLEDGMENT

The tables were prepared by Molly Wolfe and Mary Jane Ruhl oflnformatics, Inc. Their help is gratefully acknowledged.

REFERENCES 1. Armitage, P., Flamant, R, and Gehan, K A.: The Methodology of Controlled Therapeutic Trials in Cancer in "Controlled Therapeutic Trials in Cancer" UICC Technical Report Series, Volume 14, International Union Against Cancer, Geneva 1974. 2. Burdette, W. J., and Gehan, K A.: Planning and Analysis of Clinical Studies. Springfield, Illinois, Charles C Thomas, 1970. 3. Gehan, K A., and Schneiderman, M. A.: In Holland, J. F., and Frei, K, Ill, eds.: Cancer Medicine. Philadelphia, Lea and Febiger, 1973. 4. Hiatt, H. H.: Protecting the medical commons: Who is responsible? New Eng. J. Med., 293 :235, 1975. Office of the Associate Director for Immunology National Cancer Institute Bldg. 10, Rm 4B17 National Institutes of Health Bethesda, Maryland 20014