kristoff@GENBANK.BIO.NET (Dave Kristofferson) (05/29/91)
$$XID RFA CA9116 CA-91-16 ********************************************** REQUEST FOR APPLICATIONS RFA: CA-91-16 NEW THERAPEUTIC APPROACHES TO THE TREATMENT OF PROSTATE CANCER P.T. 34; K.W. 0715035, 0705075, 0745070, 0755015, 0760020, 0760025 National Cancer Institute Letter of Intent Receipt Date: July 22, 1991 Application Receipt Date: October 15, 1991 I. PURPOSE The Division of Cancer Treatment (DCT) of the National Cancer Institute (NCI) invites research grant applications (R01) from interested investigators to perform clinical studies in prostate cancer to improve treatment results and clinical outcome. Investigators are encouraged to utilize laboratory advances in understanding tumor growth and hormonal control in prostate cancer to develop an integrated research program of laboratory experimentation and concurrent clinical studies. New and experienced investigators in relevant fields and disciplines may apply for funds to support therapeutic clinical studies. The present Request for Applications (RFA) announcement is for a single competition with a specified application deadline of October 15, 1991. The NCI anticipates making three to four awards for project periods of up to three years. A total of $750,000 has been set aside for funding these activities in the initial year. The PHS is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, New Therapeutic Approaches to the Treatment of Prostate Cancer, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, D.C. 20402-9325 (telephone 202-783-3238). Applications must be prepared and submitted in accordance with the aims and requirements described in the following sections. II. BACKGROUND INFORMATION The incidence of prostate cancer continues to increase each year and has now surpassed lung cancer to become the most common carcinoma in males. It is estimated that approximately 122,000 new cases will be diagnosed in 1991 accounting for 19 percent of all male cancers. Black men in the United States have the highest rate of prostate cancer in the world. At the time of clinical presentation, more than 50 percent of newly diagnosed patients will have either locally advanced or metastatic disease. Prostate cancer is the second leading cause of death from neoplasia among American men causing more than 32,000 deaths in 1990. It is an important cause of morbidity and mortality in the elderly. These upward trends are expected to continue as the male population ages. If prostate cancer is diagnosed early while still confined to the prostate, the disease is curable with radical prostatectomy or radiation therapy. For patients with more advanced stages, initial treatment is based on presumed hormonal dependence of prostatic cancer cell growth and includes surgical and diethylstilbestrol castration. In recent years, new methods of hormone treatment utilize pharmacologic agents capable of reducing or blocking the action of testosterone, the major circulating androgenic hormone, by interrupting the complex interactions among the hypothalamus, pituitary, testis, and adrenal glands. Leuprolide and goserelin (Zoladex) are two LH-RH analogs recently approved for clinical use that produce a medical castration. Flutamide is a synthetic nonsteroidal antiandrogen that has also shown promise in clinical trials. However, these new therapeutic agents do not prevent the emergence of hormone-resistant cells. Advanced prostate cancers ultimately fail to respond to androgen deprivation. The mechanisms involved in the loss of androgen dependence are not understood. There is no alternative therapy that can be offered at present to these patients that consistently results in reduction in tumor mass or palliation of symptoms. In recent years, basic researchers have made promising new advances in understanding the mechanisms of growth control in the human prostate cell. The growth and differentiation of benign and malignant prostatic epithelial cells are regulated by androgens that in turn are modulated by growth factors and other hormones. A production of growth factor activities like Transforming Growth Factor beta, Transforming Growth Factor alpha, and Epithelial Growth Factor have been demonstrated in prostate cancer cell lines. Clinical trials utilizing suramin, which interferes with heparin-binding growth factors, have recently shown responses in advanced prostate cancer. The mechanism of action of suramin is still not completely understood and ancillary laboratory studies are needed. In addition, biological response modifiers in combination with chemotherapy have achieved promising results in other tumor models but have not been adequately explored in prostate cancer. Recent advances in understanding the molecular and cellular mechanisms operative in resistance to chemotherapy have led to the design of new therapeutic strategies to overcome drug resistance in other tumors. Many opportunities exist to develop new treatment strategies in prostate cancer utilizing laboratory advances in understanding tumor growth and hormonal control. III. RESEARCH GOALS AND SCOPE The major goal of this RFA is to foster interactions between basic science laboratories and clinicians performing clinical trials for patients with prostate cancer. Investigators are encouraged to propose pilot therapeutic clinical studies or new clinical trials (Phase I, II, or III) designed to improve therapy in prostate cancer patients. The application may include ancillary laboratory studies linked to the clinical trial. Applications must be focused on integrating clinical goals with laboratory research areas. This RFA envisions funding therapeutic clinical studies that test and exploit basic findings concerning cellular targets of treatment or response to drug or hormone therapies. Clinical studies should involve human subjects and be designed to improve cancer treatment. Examples of clinical studies include: (1) growth factor or hormone therapies utilizing new agents; (2) treatment therapies for overcoming hormone, drug, or radiation resistance; (3) treatment therapies based on novel mechanisms of action; (4) biologics in combination with drug or radiation regimens; (5) new therapies combining endocrine manipulations with chemotherapeutic agents; and (6) radiation modifiers to enhance cell kill or protect normal tissue. Laboratory research studies that are relevant to the therapeutic clinical studies may be included. Investigators already participating in relevant clinical trials are encouraged to develop related complementary laboratory studies. Laboratory experimentation may be designed to examine mechanism of action, mechanism of resistance, or conduct pharmacological analysis of the antitumor agents utilized in the patient studies. Laboratory studies designed to improve diagnosis or studies examining benign prostate disease are not applicable. Examples of therapeutic correlates that would be measured in patients or tumors include: (1) hormone or growth factor receptor alterations that correlate with the development of hormone resistance; (2) studies of phenotypic or genotypic alterations correlated with drug or radiation resistance; (3) correlation of tumor growth factors or oncogenes with response to growth factor targeted therapies; (4) pharmacokinetic and pharmacodynamic studies; and (5) biochemical pharmacologic analysis. Investigators are not limited to the above areas of potential studies. Analysis of potential racial differences in clinical and laboratory parameters must be considered. IV. MECHANISM OF SUPPORT Support of the program will be through the National Institutes of Health (NIH) grant-in-aid (R01). Applicants will be responsible for the planning, direction, and execution of the proposed project. Except as otherwise stated in this RFA, awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1, 1990. This RFA is a one-time solicitation. Most likely continuation applications will compete with all investigator-initiated applications and be reviewed by the Division of Research Grants (DRG). However, if the NCI determines that there is a sufficient continuing program need, a request for competitive continuation applications will be announced. Only recipients of awards under this RFA will be eligible to apply. Approximately $750,000 in total costs per year for three years will be committed to fund applications submitted in response to this RFA. It is anticipated that three to four awards will be made. Applications with requested budgets greatly exceeding these general parameters may be at a disadvantage with respect to final funding decisions. This funding level is dependent on the receipt of a sufficient number of applications of high scientific merit. The total project period for applications submitted in response to the present RFA must not exceed three years. The earliest feasible start date for the initial award will be July 1, 1992. Although this program is provided for in the financial plans of the NCI, the award of grants pursuant to this RFA is also contingent upon the continuing availability of funds for this purpose. V. ELIGIBILITY REQUIREMENTS Non-profit organizations and institutions, governments and their agencies, and individuals are eligible to apply. For-profit organizations are also eligible unless specifically excluded by legislation. Both domestic and foreign applicants may apply. Applications may be submitted from a single institution or may include arrangements with multiple institutions (e.g., consortia and Clinical Trials Cooperative Group) if appropriate. VI. REVIEW PROCEDURES AND CRITERIA A. REVIEW PROCEDURE Upon receipt, applications will be reviewed by the DRG for completeness. Incomplete applications will be returned to the applicant without further consideration. Evaluation for responsiveness to the RFA is an NCI program staff function. Applications will be judged to determine how well they meet the goals and objectives of the program as described in the RFA. Applications that are judged non-responsive will be returned to the applicant but may be submitted as investigator-initiated research grants at the next receipt date. Questions concerning the relevance of proposed research to the RFA should be directed to program staff as described in the INQUIRIES section. In cases where the number of applications is large compared to the number of awards to be made, the NCI will conduct a preliminary scientific peer review to eliminate those that are clearly not competitive. The NCI will withdraw from further competition those applications judged to be noncompetitive for award and notify the applicant and institutional business official. Those applications judged to be both competitive and responsive will be further evaluated, using the review criteria stated below, for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NCI. The second level of review by the National Cancer Advisory Board considers the special needs of the Institute and the priorities of the National Cancer Program. B. REVIEW CRITERIA The factors considered in evaluating the scientific merit of each response to this RFA will be: 1. Significance and originality of the research from a scientific and technical viewpoint. 2. Feasibility of proposed research. 3. Adequacy and appropriateness of the methodology and protocol design. 4. Clinical and diagnostic pathological experience, training, time availability, and research competence of the investigators involved. 5. Adequacy of available resources and environment (facilities, equipment, statistical collaboration, patient population, specimens, and others). 6. Provision for the adequate protection of human subjects. 7. Documentation of support from collaborators and consultants through letters of commitment. The review group will critically examine the submitted budget and will recommend an appropriate budget and period of support for each approved application. If the clinical trial is funded through another source and the investigator is only asking for support for laboratory investigations, this should be clearly outlined. C. SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS The following is a statement of NIH and ADAMHA policies concerning inclusion of women and minorities in clinical research study populations. The inclusion of women is standard terminology for all grants and contracts; however, due to the specific subject of this RFA (prostate cancer), it is not applicable under this RFA. NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Section 2, A-D of the Research Plan AND summarized in Section 2, E, Human Subjects. Appli-cants/offerors are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority popula-tions (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. VII. METHOD OF APPLYING The research grant application form PHS 398 (revised 10/88) must be used in applying for these grants. These forms are available at most institutional business offices; from the Office of Grant Inquiries, Division of Research Grants, National Institutes of Health, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD 20892; and from the NCI Program Director named below. The RFA label available in the 10/88 revision of application form PHS 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA number and title must be typed on line 2 of the face page of the application form. Submit a signed, typewritten original of the application, including the Checklist, and four signed, exact photocopies, in one package to the Division of Research Grants at the address below. The photocopies must be clear and single sided. Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to: Referral Officer Division of Extramural Activities National Cancer Institute Westwood Building, Room 848 5333 Westbard Avenue Bethesda, MD 20892 Applications must be received by October 15, 1991. If an application is received after that date, it will be returned. If the application submitted in response to this RFA is substantially similar to a research grant application already submitted to the NIH for review, but has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application cannot be submitted in response to this RFA that is essentially identical to one that has already been reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. VIII. LETTER OF INTENT Prospective applicants are asked to submit by July 22, 1991, a letter of intent that includes a descriptive title of the proposed research, the name and address of the Principal Investigator, the names of other key personnel, the participating institutions, the number and title of the RFA in response to which the application is being submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, it is requested in order to provide an indication of the number and scope of applications to be reviewed. The letter of intent is be sent to: BY US POSTAL Ms. Diane Bronzert Program Director Cancer Therapy Evaluation Program Division of Cancer Treatment National Cancer Institute Executive Plaza North, Room 734 Bethesda, MD 20892 Telephone: (301) 496-8866 FAX: (301) 480-4663 BY DIRECT DELIVERY Ms. Diane Bronzert Program Director Cancer Therapy Evaluation Program Division of Cancer Treatment National Cancer Institute Executive Plaza North, Room 734 6130 Executive Blvd. Rockville, MD 20852 IX. INQUIRIES Written and telephone inquiries concerning the objectives and scope of this RFA or inquiries about whether or not specific proposed research would be responsive are encouraged and should be directed to Ms. Diane Bronzert at the above address. The program director welcomes the opportunity to clarify any issues or questions from potential applicants. Written and telephone inquires of a budgetary, administrative, and/or policy nature should be directed to: Ms. Carolyn Mason Grants Management Specialist Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 6120 Executive Blvd. Bethesda, MD 20892 Telephone: (301) 496-7800, extension 59 FAX: (301) 496-8601 This program is described in the Catalog of Federal Domestic Assistance No 93.395, Cancer Treatment Research. Awards are made under the authorization of the Public Health Service Act, Title IV Sections 301, 410, and 411, Part A (Public Law 78-410, 42 USC 241 as amended, Public Law 99-158, 42 USC 285a) and administered under PHS grant policies and Federal Regulations at 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review.