Full Text CA-95-009

AIDS-ASSOCIATED MALIGNANCIES CLINICAL TRIALS CONSORTIUM

NIH GUIDE, Volume 24, Number 7, February 24, 1995

RFA:  CA-95-009

P.T. 34

Keywords: 
  AIDS 
  Cancer/Carcinogenesis 
  Clinical Trial 


National Cancer Institute

Letter Of Intent Receipt Date:  April 4, 1995
Application Receipt Date:  May 4, 1995

PURPOSE

The Cancer Therapy Evaluation Program (CTEP) of the Division of
Cancer Treatment (DCT) at the National Cancer Institute (NCI) invites
applications from single institutions or consortia of institutions
for cooperative agreements (U01) to design and develop clinical
trials with novel agents or using innovative approaches in patients
with AIDS-associated malignancies.  The NCI is seeking talented
scientists from academic, non-profit and for-profit research
organizations who will interact with other members of the Consortium,
and with CTEP in a concerted way to conceive, create, and evaluate
new approaches to therapy of AIDS-associated malignancies.  One
consortium, called the AIDS-associated Malignancies Clinical Trials
Consortium, will be developed out of the separate funded awardees.
Scientific approaches taken by the Consortium will be broad and will
reflect the creativity and capabilities of team participants.
Clinical trials using conventional cytotoxic chemotherapy regimens
alone would not be performed within the Consortium.  The potential
exists for expanding to phase III studies should the initial efforts
with this project prove successful, and relevant phase III questions
are appropriate.  The purpose of the proposed awards is to stimulate
cooperative efforts to improve treatment and to develop more
effective therapies for AIDS-associated malignancies.

HEALTHY PEOPLE 2000

The Public Health Service (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 Request
for Applications (RFA), Aids-Associated Malignancies Clinical Trials
Consortium, is related to the priority areas of cancer and AIDS.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001--00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Domestic and Canadian for-profit and non-profit organizations, public
and private, such as universities, colleges, hospitals, laboratories,
units of State and local governments, and eligible agencies of the
Federal government are eligible to apply.  Foreign institutions other
than Canadian are not eligible to apply or be a collaborating
institution.  Canadian institutions are included because many of them
are members of the NCI Clinical Trials Cooperative Groups and the
National Institute of Allergy and Infectious Diseases (NIAID) AIDS
Clinical Treatment Units.  Applications may consist of one
institution or several institutions, which can include, but are not
limited to, the NCI Clinical Trials Cooperative Groups, the NIAID
AIDS Clinical Treatment Units, or a coalition between a Cancer Center
and collaborating institutions.  New and experienced investigators
are encouraged to apply.  Applications with racial/ethnic minority
individuals, women, and persons with disabilities as Principal
Investigators are encouraged.

Eligible institutions may apply for either or both of the following
types of awards:  (1) Clinical Trials Member, (2) Operations,
Statistical and Data Management Center.  A separate application must
be submitted for each type of award.

Each applicant as a Clinical Trials Member must demonstrate the
ability to recruit a minimum of 30 patients per year and the
willingness to accrue patients onto four to six different clinical
trials.  It is anticipated that the AIDS-Associated Malignancies
Clinical Trials Consortium will perform four to six clinical trials
involving approximately 200 patients with different AIDS-associated
malignancies per year.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01), an "assistance" mechanism, in
which substantial NCI scientific and/or programmatic involvement with
the awardee is anticipated during performance of the activity.  Under
the cooperative agreement, the NCI purpose is to support and/or
stimulate the recipient's activity by involvement in and otherwise
working jointly with the award recipient in a partner role, but it is
not to assume direction, prime responsibility, or a dominant role in
the activity.  Details of the responsibilities, relationships, and
governance of the study to be funded under cooperative agreement(s)
are discussed later in this document under the section "Terms and
Conditions of Award."

Awards and level of support depend on receipt of a sufficient number
of applications of high scientific merit.  Because of the variation
in numbers of patients to be accrued and the type of award, it is
anticipated that the size of awards will vary also. It is anticipated
that the award for the Operations, Statistical and Data Management
Center will be approximately $300,000 direct costs per year (of which
$100,000 is reserved for a Discretionary Fund for laboratory studies
and for the collection of patient specimens and clinical data for the
Tissue and Biological Fluids Banks of HIV-Associated Malignancies).
The award for each Clinical Trial Member will be approximately
$125,000 direct costs per year.  The total project period for each
application submitted in response to the RFA may not exceed four
years.  The earliest anticipated award date is September 30, 1995.
Although this program is provided for in the financial plans of the
NCI, awards pursuant to this RFA are contingent upon the availability
of funds for this purpose.

This RFA is a one-time solicitation.  At this time the NCI has not
determined whether or how this solicitation will be continued beyond
the present RFA.  If it is determined that there is a sufficient
continuing program need, the NCI will either invite recipients of
awards under this RFA to submit competitive continuation cooperative
agreement applications for review or re-issue the RFA for re-
competition.  If the NCI does not continue the program, awardees may
submit grant applications through the usual investigator-initiated
grants program.

FUNDS AVAILABLE

Approximately $2,000,000 in total costs per year for four years will
be committed to fund applications submitted in response to this RFA.
It is anticipated that eight to ten new awards for Clinical Trials
Member of the AIDS-Associated Malignancies Clinical Trials Consortium
will be made.  There will be only one Statistical, Operations, and
Data Management Center award.

RESEARCH OBJECTIVES

Background

Individuals infected with the human immunodeficiency virus (HIV) have
a marked increase in the appearance of intermediate and high-grade B
cell Non-Hodgkin's Lymphoma (NHL) and Kaposi's sarcoma (KS), and show
trends for an increased incidence for Hodgkin's disease, anogenital
dysplasia, and cancer, as compared to age-matched controls.
Epidemiological studies have shown that the relative risks for KS and
NHL were 40,000 and 100, respectively.  In January 1993, the Centers
for Disease Control added cervical cancer in HIV infected women, to
the list of AIDS defining malignancies.

Conventional treatment for these malignancies has only been modestly
effective at best.  The median survival of HIV-associated NHL is less
than one year, and is only two months for primary central nervous
system lymphoma.  Kaposi's sarcoma is an AIDS defining illness in 20
percent of HIV infected individuals, and has been found at death in
over 50 percent of the patients.  In addition to its disfiguring
complications, it can lead to significant morbidity and mortality due
to gastrointestinal and pulmonary complications in a significant
proportion of patients.  Conventional therapy in KS has been
palliative.  Several studies suggest that anogenital dysplasias and
cancer in the HIV infected population may be more biologically
aggressive and resistant to conventional therapeutic approaches.

Research into the pathogenesis of these HIV-associated tumors has
focused on potential interactions of cytokines, HIV, other viral co-
factors (e.g., human papilloma virus in squamous cell cancer of the
anogenital region, and EBV in the high-grade primary central nervous
system lymphomas), and oncogenes.  Numerous studies have pointed to
dysregulation of cytokines and to angiogenesis as significant in the
pathogenesis of KS.  New clinical research opportunities exist
because of the development of differentiation agents, monoclonal
antibodies, angiogenesis inhibitors, cytokines and growth factor
modulators, and new approaches to gene therapy and immunomodulating
therapy.  Based on the current information on the potential
interactions in the formation of these tumors and the lack of
effective, standard regimens, the NCI is encouraging investigators to
apply novel therapies or innovative approaches in pilot or phase I
and II clinical trials with the ultimate goal of expanding to phase
III clinical trials.

One of the major obstacles in carrying out AIDS-associated
malignancies therapeutic research is patient accrual onto clinical
trials.  The accrual targets for trials in AIDS-associated
malignancies may best be achieved through a multicenter Consortium
through a cooperative agreement award (U01) in which prioritization
of studies is made, and the patient volume is large and accessible.

Objectives and Scope

The purpose of the proposed awards is to stimulate cooperative
efforts to design and develop clinical trials with novel agents or
using innovative approaches in patients with AIDS-associated
malignancies.  The NCI is seeking talented scientists from academic,
non-profit, and for-profit research organizations who will interact
with other members of the Consortium and with CTEP in a concerted way
to conceive, create, and evaluate new approaches to therapy of AIDS-
associated malignancies.  Scientific approaches taken by the
Consortium will be broad and will reflect the creativity and
capabilities of team participants.  Clinical trials using
conventional cytotoxic chemotherapy regimens alone would not be
performed within the Consortium.  In the case of pilot, phase I, or
phase II clinical trials, laboratory studies to monitor patients
(e.g., pharmacokinetics, pharmacodynamics) or to measure a particular
biological response that may provide information relevant to the
interpretation of the success or failure of the therapy administered
are encouraged and will be included in the protocol(s) to be created
by the Consortium.  Tissue specimens or biological fluids will be
collected by the Clinical Trial Members for use in laboratory studies
or donation to the Tissue and Biological Fluids Banks of HIV-
Associated Malignancies.  The potential exists for expanding to phase
III studies should the initial efforts with this project prove
successful, and relevant phase III questions are appropriate.  If the
Consortium decides to perform phase III clinical studies, the NCI
Clinical Trials Cooperative Groups and the NIAID AIDS Clinical
Treatment Units will be asked to participate.

Each application may consist of one or more institutions.  Eligible
institutions may apply for either or both of the following types of
awards:  (1) Clinical Trials Member, (2) Operations, Statistical and
Data Management Center.  A separate application must be submitted for
each type of award.  One consortium, called the AIDS-Associated
Malignancies Clinical Trials Consortium, will be developed from the
separate cooperative agreements.  One Statistical, Operations, and
Data management Center will be funded through a cooperative agreement
to coordinate the statistical, operational, and data management
issues for the Consortium.

It is anticipated that the AIDS-Associated Malignancies Clinical
Trials Consortium will perform four to six clinical trials involving
approximately 200 patients with different AIDS-associated
malignancies per year.  Thus, each applicant to be a Clinical Trials
Member must demonstrate the ability to recruit a minimum of 30
patients per year in one or more variety of AIDS-associated
malignancies and the willingness to accrue patients onto four to six
different clinical trials.  Applicants should describe areas of
clinical and laboratory expertise that would serve as a basis for the
development of clinical protocols in specific malignancies by the
Consortium.

In the period immediately following the award of funds, NCI will
sponsor a meeting at which the Principal Investigators of each
awarded U01 and NCI staff will meet to discuss the operational
features of the Consortium.  The ideas for clinical trials provided
in the cooperative agreement applications as well as ideas generated
de novo after the formation of the Consortium will be presented,
discussed and prioritized.  Protocols will then be created, reviewed
by the Steering Committee and submitted to the NCI for review and
approval to ensure they are within the scope of peer review and for
safety considerations, as required by Federal regulations.  The NCI
will consult with NIAID on issues involving anti-retroviral therapy
and infectious diseases as is the current practice.  Such high
priority clinical trials will begin after receiving final NCI
approval.

The Consortium will be formed for the purpose of:  (1) sharing
expertise of researchers in several disciplines; (2) conducting joint
exploratory, phase I and phase II clinical trials of novel agents or
innovative approaches to provide adequate patient populations and
timely completion with the potential of expanding to phase III
clinical trials; and (3) providing tumor tissue and relevant
biological fluids to the recently funded Tissue and Biological Fluids
Banks of HIV-Associated Malignancies.

SPECIAL REQUIREMENTS

Definitions

AWARDEE - The organization to which a cooperative agreement is
awarded and which is responsible and accountable to NCI for the use
of funds provided and for performance of the cooperative agreement-
supported project.

PRINCIPAL INVESTIGATOR (PI) - The single individual designated by the
awardee institution who is responsible for the scientific and
technical direction of the project.

NCI PROGRAM DIRECTOR - The CTEP extramural grants Program Director,
who will coordinate DCT's interactions and administer and provide
guidance for the overall program within the NCI.  He/she is available
for consultation during preparation of applications as well as the
duration of research conducted through this cooperative agreement.
He/she serves in a back-up role for the NCI Coordinator.

NCI COORDINATOR - The Senior Investigator, Medicine Section, Clinical
Investigations Branch, CTEP, DCT, who interacts scientifically with
the Applicant/Awardee Institutions.

AIDS-ASSOCIATED MALIGNANCIES CLINICAL TRIALS CONSORTIUM - The
consortium of Clinical Trials Members and the Operations, Statistics
and Data Management Center who have been awarded separate cooperative
agreement (U01s).

CLINICAL TRIALS MEMBER -  The institution or group of institutions
who submit an individual cooperative agreement application for
conducting clinical trials as part of the AIDS-Associated
Malignancies Clinical Trials Consortium.

OPERATIONS, STATISTICS AND DATA MANAGEMENT CENTER -  The
administrative unit that coordinates all the Consortium activities.
Responsibilities include administrative management, coordination of
protocol development and submission, study conduct, quality control
and protocol performance monitoring, statistical analyses, adherence
to requirements regarding NCI drug accountability and FDA, OPRR, and
HHS regulations, and protocol and institutional performance
reporting.  Statistical responsibilities include experimental design,
participation in study planning and coordination, collection and
analysis of patient and laboratory data, data management and
analysis, data monitoring, and reporting of data.  The Center may be
separate from the sites for the Clinical Trials Members, or may be
located at the same site.

STEERING COMMITTEE - A committee composed of the PIs, the NCI Program
Director and NCI Coordinator that will be the main oversight body of
the AIDS-Associated Malignancies Clinical Trials Consortium.

STEERING COMMITTEE CHAIRPERSON - A member of the Steering Committee
(cannot be the NCI Program Director or the NCI Coordinator) elected
by the Steering Committee who will coordinate the activities of the
Consortium with the Operations, Statistics, and Data Management
Center, and chair the biannual meetings of the Consortium (after the
first meeting, which will be convened by the NCI) to be held at the
NCI.  The chairperson shall prepare and distribute the agendas for
each meeting.

PROTOCOL CHAIRPERSON - The person who is responsible for the
development, coordination and monitoring of a specific clinical
protocol.

DISCRETIONARY FUND - A fixed amount of money ($100,000) given to the
Operations, Statistics and Data Management Center to hold, manage and
allocate according to the instructions of the Steering Committee.
Appropriate uses may include funding for laboratory studies, shipment
of samples and providing clinical data to the Tissue and Biological
Fluids Banks of HIV-Associated Malignancies and supplementing
existing budgets for patient accrual and auditing for clinical
trials.

CTEP PROTOCOL REVIEW COMMITTEE - A committee composed of the
professional staff of the CTEP, additional consultants from other NCI
divisions, and chaired by the Associate Director, CTEP, that reviews
and approves every protocol involving DCT investigational drugs or
studies that have any NCI support (funding) and use an
investigational agent.

Terms and Conditions of Award

The following terms and conditions will be incorporated into the
award statement and provided to the institutional official at the
time of award.  These special Terms of Award are in addition to and
not in lieu of otherwise applicable OMB administrative guidelines,
HHS grant administration regulations in 45 CFR part 74 and 92, and
other HHS, PHS and NIH grant administration policy statements. Under
the cooperative agreement, the NCI purpose is to support and/or
stimulate the recipient's activity by involvement in and otherwise
working jointly with the award recipient in a partner role, but it is
not to assume direction, prime responsibility, or a dominant role in
the activity.  Consistent with the above concept, the dominant role
and prime responsibility for the activity reside with the awardee(s)
for the project as a whole, although specific tasks and activities in
carrying out the studies will be shared among the awardees and the
NCI Program Director and NCI Coordinator.  The NCI Program Director
will coordinate DCT's interactions and administer and provide
guidance for the overall program within the NCI.  He is available for
consultation during preparation of the applications as well as the
duration of research conducted through this cooperative agreement.
He will serve in a back-up role for the NCI Coordinator
scientifically.  The NCI Coordinator will interact scientifically
with the awardee institutions.

Under the cooperative agreement, a relationship will exist between
the recipient of these awards and the NCI, in which the performers of
the activities are responsible for the requirements and conditions
described below, and agree to accept program assistance from the NCI
Program Director and/or the NCI Coordinator in achieving project
objectives.  Failure of an awardee to meet the performance
requirements, including these special terms and conditions of award,
or significant changes in the level of performance, may result in a
reduction of budget, withholding of support, suspension and/or
termination of the award.

A.  Awardee Rights and Responsibilities.

The Operations, Statistics, and Data Management Center Awardee is
responsible for:

1.  Coordinating protocol development, protocol submission, study
conduct, quality control and study monitoring, drug ordering, data
management, statistical analysis, protocol amendments/status changes,
adherence to requirements regarding investigational drug management
and federally mandated regulations and protocol and performance
reportings.  All the operations, statistical and data management
decisions related to the Consortium-funded activities and made by the
Clinical Trials Members awardees in collaboration with the NCI, will
be coordinated by the PI of the Operations, Statistics, and Data
Management Center.

2.  Letters of Intent (LOIs) and Protocol submissions to the CTEP
Protocol and Information Office in a timely fashion for review and
approval by NCI.  LOIs must be submitted to the NCI for all trials
that include a NCI investigational agent (see "Investigator's
Handbook" p.32-35, for further discussion; contact Dr. Roy S. Wu for
a copy, see INQUIRIES).  After obtaining approval from the Steering
Committee, all protocols and proposed LOIs will be submitted by the
Protocol Chairperson to the Operations, Statistics and Data
Management Center for processing and submission to NCI.  The PI of
the Operations, Statistics, and Data Management Center, with the
assistance of the Awardee staff, will communicate the results of the
NCI review of LOIs and protocols to the participating Clinical Trials
Members.

3.  Establishing mechanisms for quality control of therapeutic and
diagnostic modalities employed in the clinical trials.

4.  Establishing mechanisms for study monitoring of clinical trials.
The awardee is responsible for assuring accurate and timely knowledge
of the progress of each study through:

a) tracking and reporting of patient accrual and adherence to defined
accrual goals;

b) ongoing assessment of case eligibility and availability;

c) timely medical review and assessment of patient data;

d) rapid reporting of treatment-related morbidity and measures to
ensure communication of this information to all parties;

e) interim evaluation and consideration of measures of outcome as
consistent with patient safety and good clinical trials practice. If
the Consortium wishes to close accrual to a study prior to meeting
the initially established accrual goal, the interim results and other
documentation should be made available to NCI staff for review and
concurrence prior to closure.  It is recommended that statistical
guidelines for early closure be presented as explicitly as possible
in the protocol in order to facilitate these decisions;

f) timely communication of results of studies;

g) an on-site monitoring program which assures that a sampling of
records at each Consortium institution participating in the clinical
trials is audited at least once per year.  The on-site audit will
address issues of data verification, protocol compliance, compliance
with regulatory requirements for the protection of human subjects and
investigational agent accountability.  Any serious problems with data
verification or compliance with Federal regulations must be reported
to the NCI Program Director immediately.  Otherwise, written reports
must be submitted within four weeks of each audit.  Audit schedules
are to be provided to the NCI Program Director on a quarterly bases;

h) For specific phase I/II trials that require monitoring three times
per year by the Clinical Trials Monitoring Service (CTMS), a NCI
contractor, patient information must be provided via electronic
transfer to the CTMS at two week intervals and includes: registration
of each patient entered onto a phase I/II protocol within the
previous two week period, and all data obtained on each registered
patient within the previous two weeks as specified by the NCI/DCT
Standard Case Report Form and the clinical research protocol.

5.  Establishing mechanisms for data management and analysis that
ensure that the data collection and management procedures are:  (a)
adequate for quality control and analysis; (b) as simple as
appropriate in order to encourage maximum participation of physicians
entering patients and to avoid unnecessary expense; and (c)
sufficiently uniform across the institutions participating in the
Consortium.

6.  Establishing an independent Data and Safety Monitoring Committee
(DSMC) if phase III trials are to be conducted.  The DSMC must be
independent of trial investigators, free of conflicts of interest,
and have formally documented policies and procedures which are
approved by NCI.

7.  Establishing mechanisms to meet Food and Drug Administration
(FDA) regulatory requirements for studies involving DCT-sponsored
investigational agents (see Investigators Handbook).

8.  Establishing mechanisms to meet the Office for Protection from
Research Risks (OPRR) requirements for the protection of human
subjects.  These include methods for assuring that each institution
at which investigators are conducting Consortium trials has a
current, approved assurance on file with the OPRR; that each protocol
is reviewed by the responsible Institutional Review Board (IRB) prior
to patient entry; and that each protocol is reviewed annually by the
IRB so long as the protocol is active.

9.  Maintaining and managing the Discretionary Fund including
dispensing the funds for Steering Committee and NCI approved
laboratory studies accompanying clinical protocols.

10.  Managing and coordinating the acquisition and shipping of tumor
specimens, biological fluids and relevant clinical data to the Tissue
and Biological Fluids Banks of HIV-Associated Malignancies.

11.  Establishing policies and procedures, in collaboration with the
Steering Committee and the NCI program staff, for conducting periodic
review of the performance of the Consortium.

12.  Submitting biannual reports to the NCI that will include at a
minimum summary data on protocol performance by each Consortium
member and other relevant data.

13.  Working with the Steering Committee Chairperson to develop and
distribute agendas for the biannual meetings of the Consortium, as
well as preparing summaries after each meeting to the Consortium and
NCI program staff.

14.  Serving as the liaison between the NCI program staff and the
Clinical Trials Members.

Each Clinical Trials Member Awardee is responsible for:

1.  Participating in the AIDS-Associated Malignancies Clinical Trials
Consortium as evidenced by participating in research design and
protocol development, including definition of objectives and
approaches, by optimal patient accrual to studies, and by following
and implementing the operating procedures of the Consortium.

2.  Participant recruitment and follow-up, data collection, quality
control, interim data and safety monitoring, final data analysis and
interpretation, and publication of results.

3.  Serving as Protocol Chairs.  For each specific clinical protocol,
a single Protocol Chairperson (if the P.I. does not assume this role)
shall function as the scientific coordinator for that protocol.
He/she will assume responsibility for the development of the protocol
and monitoring the protocol during the review process as well as
during the actual performance of the clinical trial.  It is the
responsibility of the Protocol Chairperson to obtain approval from
the Steering Committee prior to submitting any proposed letters of
intent, concepts, protocols and modifications to the Operations,
Statistics and Data Management Center for processing.

4.  Implementing the core data collection method and strategy
collectively decided upon by the Steering Committee.  It is the
responsibility of each awardee/site to ensure that data will be
submitted in a timely way to the central Operations, Statistics, and
Data Management Center.

5.  Implementing the procedures established by the Operations,
Statistics, and Data Management Center to meet Federal regulatory
requirements especially in the area of NCI-sponsored investigational
agents.

6.  Performing laboratory studies that are specified in the NCI
approved protocols and collecting tumor tissue and biological fluids
for the Tissue and Biological Fluids Banks of HIV-Associated
Malignancies.

7.  Cooperating in the reporting of the study findings.  The NCI will
have access to and may periodically review all data generated under
an award.  Where warranted by appropriate participation, plans for
joint publication with NCI of pooled data and conclusions are to be
developed by the Steering Committee, as applicable.  NIH policies
governing possible co-authorship of publications with NCI staff will
apply in all cases.  In general, to warrant co-authorship, NCI staff
must have contributed to the following areas:  (a) design of the
concepts or experiments being tested; (b) performance of significant
portions of the activity; and (c) preparation and authorship of
pertinent manuscripts.  The awardee(s) will retain custody of and
have primary rights to the data developed under these awards, subject
to Government rights of access consistent with current HHS, PHS and
NIH policies.

B.  NCI Staff Responsibilities

It is expected that the dominant role and prime responsibility for
the activity will reside with the awardee(s) for the project as a
whole, although specific tasks and activities in carrying out the
studies will be shared among the awardees and the NCI Program
Director and NCI Coordinator.  The Program Director and the NCI
Coordinator will be the contact points for all facets of scientific
interaction with the awardee(s).  Two NCI staff are required for the
coordination of activities and to expedite progress, to provide
advice to the awardee on specific scientific and/or analytic issues
in addition to programmatic issues.

NCI Program Staff Responsibilities will include:

1.  Interacting with the PI(s) on a regular basis to monitor study
progress.  Monitoring may include:  regular communications with the
PI and staff, periodic site visits for discussions with awardee
research teams, observation of field data collection and management
techniques, quality control, fiscal review, and other relevant
matters; as well as attendance at Steering Committee, Data and Safety
Monitoring Committee, and related meetings.  The NCI retains, as an
option, periodic external review of progress.

2.  Convening the first meeting of and subsequent participation in
the Steering Committee that oversees the AIDS-Associated Malignancies
Clinical Trials Consortium.  The NCI Program Director and NCI
Coordinator will be full participants and voting members of the
Steering Committee and, if applicable, subcommittee.

3.  Serving as a resource with respect to other ongoing NCI
activities that may be relevant to the protocol to facilitate
compatibility and avoid unnecessary duplication of effort.

4.  Substantial involvement by assisting in the design and
coordination of research activities for awardees as elaborated below:

a.  Assisting by providing advice in the management and technical
performance of the investigations;

b.  Coordinating clearances for investigational agents held by NCI.
The NCI may reserve the right to crossfile or independently file an
Investigational New Drug Application form with the FDA;

c.  Coordinating activities among awardees by assisting in the
design, development, and coordination of a common research or
clinical protocol and statistical evaluations of data; in the
preparation of questionnaires and other data recording forms; and in
the publication of results.  Assistance in protocol development at
the minimum will include providing information regarding: (1) the
existence and nature of concurrent clinical trials in the area of
research, pointing out possible duplication of effort, (2)
pharmacodynamic data concerning investigational agents, (3)
availability of investigational agents, and (4) therapy for
underlying HIV infection and other infectious diseases (NIAID will be
NCI's consultant);

d.  Reviewing and approving protocols to ensure they are within the
scope of peer review and for safety considerations, as required by
Federal regulations.  Final drafts of protocols approved by the
Steering Committee will be reviewed by the CTEP Protocol Review
Committee (PRC) which will meet weekly.  The PRC will be chaired by
the Associate Director, CTEP or his/her designee and is composed of
the professional staff of the CTEP, and additional consultants from
other NCI divisions.  The NCI Coordinator will provide the Protocol
Chairperson via the Operations, Statistics and Data Management Center
with a consensus review that describes recommended modifications and
other suggestions as appropriate.  The major considerations relevant
to protocol review include: (1) the strength of the scientific
rationale supporting the study, (2) the medical importance of the
question being posed, (3) the avoidance of undesirable duplication
with other ongoing studies, (4) the appropriateness of study design,
(5) a satisfactory projected accrual rate and follow-up period, (6)
patient safety, (7) compliance with federal regulatory requirements,
(8) adequacy of data management, (9) appropriateness of patient
selection, evaluation, assessment of toxicity, response to therapy
and follow-up.

If a proposed protocol is disapproved, the specific reasons for lack
of approval will be communicated to the Protocol Chairperson and the
Steering Committee as a consensus review within 30 days of protocol
receipt by the NCI.  NCI will not provide investigational drugs or
permit expenditure of NCI funds for a protocol that PRC has not
approved.  The NCI Coordinator will be available to assist the
Protocol Chairperson and the Steering Committee in developing a
mutually acceptable protocol, consistent with the research interests,
abilities and strategic plans of the Consortium and of the NCI;

e.  Monitoring protocol progress and involvement in protocol closure.
The NCI Program Director and NCI Coordinator will monitor protocol
progress, and may request that a protocol study be closed to accrual
for reasons including:  (a) accrual rate insufficient to complete
study in a timely fashion; (b) accrual goals met early; (c) poor
protocol performance; (d) patient safety and regulatory concerns; (e)
study results that are already conclusive; and (f) emergence of new
information that diminishes the scientific importance of the study
question.  The NCI will not permit further expenditures of NCI funds
for a study after requesting closure (except for patients already on-
study);

f.  Reviewing and providing advice regarding the establishment of
mechanisms for quality control and study monitoring.  For specific
phase I/II trials with NCI-sponsored agents, the NCI will arrange for
the CTMS to document regulatory compliance, to maintain a
computerized data base and to produce periodic routine reports of the
results and special reports as necessary.  For phase II trials with
NCI-sponsored investigational agents not requiring the above
described monitoring, NCI will delegate to the Operations, Statistics
and Data Management Center awardee the task of providing an
independent audit of each research study.  The CTMS shall be used to
conduct these audits.  Random audits by NCI staff will be performed
to assure that the awardee is performing the delegated audit duties.

5.  Making recommendations to the Steering Committee on the
allocation of monies from the Discretionary Fund.

C.  Collaborative Responsibilities

In addition to the interactions defined above, NCI Staff and Awardees
shall share responsibility for the following activities:

1.  Service on the Steering Committee;

The Steering Committee has primary responsibility to design research
activities, establish priorities, develop and provide preliminary
approval of protocols (prior to submission to NCI and final NCI
approval), develop manuals, questionnaires and other data recording
forms, establish and maintain quality control among awardees, review
progress, monitor patient accrual, coordinate and standardize data
management, and cooperate on the publication of results.  Major
scientific decisions regarding the core data will be determined by
the Steering Committee.  The Steering Committee will also authorize
spending of money from the Discretionary Fund and allocate the funds
to Clinical Trial Members based on scientific and administrative
needs and priorities.  Appropriate uses may include funding for
laboratory studies, shipment of samples and providing clinical data
to the Tissue and Biological Fluids Banks of HIV-Associated
Malignancies and supplementing existing budgets for patient accrual
and for auditing of clinical trials.  The PI of the Operations,
Statistical and Data Coordinating Center with the help of the
Steering Committee Chairperson will document actions taken and
progress in written reports to the NCI Program Director, and will
provide periodic supplementary reports to designated NCI staff upon
request.

The Steering Committee will be composed of all PI(s), (including the
PI of the Operations, Statistical, and Data Coordinating Center), and
the NCI Program Director and NCI Coordinator.  An initial meeting of
the Steering Committee will be convened early after award by the NCI
Program Director and NCI Coordinator.  The final structure of the
Steering Committee will be established at the first meeting.  The NCI
will have one vote on the Steering Committee or any of its
subcommittees despite the fact that two NCI staff members (Program
Director and NCI Coordinator) may serve on such committees.  Such a
committee usually will meet twice yearly.

A Steering Committee Chairperson, other than the NCI representatives,
will be selected by a vote of the members during the initial meeting
of the AIDS-Associated Malignancies Clinical Trial Consortium.  The
Chairperson shall function as a liaison between the NCI program staff
and the Consortium, as well as a liaison between the Clinical Trial
Members and the Operations, Statistics, and Data Management Center.
He/she is responsible for coordinating the Committee activities, for
preparing meeting agendas, and for scheduling and chairing meetings.

2.  Service on Data and Safety Monitoring Committee and Ad Hoc
Monitoring Committees.  The major emphasis of the Consortium is on
exploratory, phase I and phase II trials.  However, the potential
exists for expansion to phase III trials should the initial results
with the early phase trials prove promising, and appropriate phase
III questions exist.  If phase III trials are undertaken, an
independent Data and Safety Monitoring Committee must be established
by the Steering Committee.  The Data and Safety Monitoring Committee
will review interim results periodically and report to the Steering
Committee and the NCI.  In all other studies, exploratory, phase I
and phase II trials, where warranted, the NCI Program Director and
NCI Coordinator will facilitate and the awardee shall allow for
interim data and safety monitoring through ad hoc committees
established by the Operations, Statistics, and Data Management
Center.

D.  Arbitration

Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between award recipients and the NCI
may be brought to arbitration.  An arbitration panel will be composed
of three members -- one selected by the awardee, a second member
selected by NCI, and the third member elected by the two prior
selected members.  These special arbitration procedures in no way
affect the awardee's right to appeal an adverse action that is
otherwise appealable in accordance with PHS regulations at 42 CFR
Part 50, Subpart D, and HHS regulations at 45 CFR part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.

Investigators proposing research involving human subjects should read
the "NIH Guidelines For Inclusion of Women and Minorities as Subjects
in Clinical Research," which was reprinted in the Federal Register of
March 28, 1994 (59 FR 14508-14513) to correct typesetting errors in
the earlier publication, and reprinted in the NIH Guide for Grants
and Contracts, Volume 23, Number 11, March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by April 4, 1995, a
letter of intent that includes a descriptive title of the proposed
research, name, address, and telephone number of the Principal
Investigator, identities of other key personnel and participating
institutions, and number and title of the RFA in response to which
the application may be submitted.  Although a letter of intent is not
required, is not binding, and does not enter into the review of
subsequent applications, the information allows the National Cancer
Institute staff to estimate the potential review workload and to
avoid conflict of interest in the review.

The letter of intent is to be sent to Dr. Roy S. Wu at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev 9/91) is to be used
in applying for these awards.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/584-7248; and from the NIH program
administrator listed under INQUIRIES.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or Principal Investigator must be included with
the application.

It is critical that applicants clearly describe plans to accommodate
stated criteria and staff involvement as listed in the Terms and
Conditions of Award, and in the Review Criteria section.

Investigators applying to be a Clinical Trials member should provide
documentation of all of the following:

o  ability to meet the minimum requirement of accruing 30 patients
with AIDS associated malignancies per year by documenting the number
of HIV-infected patients seen at their institutions, the number of
patients for each AIDS-Associated Malignancy available for accrual,
the number of AIDS patients with malignancies who actually enrolled
on clinical trials, and the plans for outreach to women/minority
populations;

o  the commitment to accrue patients to clinical trials being
performed through the Consortium and acknowledge that those clinical
trials have the highest priority, and detailing other competing
studies (e.g., pharmaceutical sponsored) in a similar patient
population;

o  ability and history of conducting and monitoring phase I and phase
II trials with specific documentation of such trials;

o  expertise in specific therapeutic modalities, specific laboratory
methodologies, and data management;

o  availability of appropriate facilities and equipment including
clinical, computer and data management, laboratory facilities and
facilities for handling and storing patient specimens;

o  clinical expertise in disease specific issues in the AIDS-
malignancies they wish to study, which may include, but are not
limited to, AIDS-associated NHL, KS, and the anogenital dysplasias
and cancer;

o  clinical expertise in infectious disease(s) for patient care;

o  willingness to provide clinical data and tumor tissue and relevant
biological fluids to the Tissue and Biological Fluids Banks of HIV
Malignancies;

o  willingness to collaborate with other Clinical Trials Members of
the Consortium and with CTEP, and to prioritize and to participate in
the clinical trials that will be run by the Consortium;

o  provide a discussion of the types of clinical studies/trials, for
which the investigators have expertise, that could be run through the
Consortium.  The investigators would have the option to describe the
laboratory monitoring of patients, and whether or not their
institution has the expertise to perform such laboratory monitoring;

o  state the applicant's area of scientific expertise in AIDS-
associated malignancies, discuss and document the expertise (funded
grants, publications, etc.), and describe how the applicant would
bring this expertise into the Consortium;

o  describe the unique contributions that could be made by the
applicant to the Consortium.

The applicants for Clinical Trials Member must request a budget of
approximately $125,000 direct costs per year for the clinical
studies, including monies for the efforts expended in the performance
of the clinical trials necessary to accrue a minimum of 30
patients/year; monies for quality control of data and travel for two
meetings per year at the NCI.

Investigators applying to be the Operations, Statistics, and Data
Management Center should provide documentation of all of the
following:

o  plans for coordinating protocol development and submission in a
timely manner;

o  procedures to ensure that data collection and management are
adequate for quality control and analysis;

o  plans for coordination of data collection that would encourage
maximum participation of physicians entering patients and avoid
unnecessary expense, and function for all of the participating
institutions;

o  plans for providing relevant clinical data to the Tissue and
Biological Fluids Bank of HIV-Associated Malignancies in
coordination with the provision of tumor tissue and biological fluids
by the Clinical Trials Members;

o  ability to perform statistical analysis of clinical trials and
laboratory studies;

o  ability for fiscal management of Discretionary Fund;

o  ability to do on-site audits;

o  ability to electronically transfer data to the CTMS where
appropriate.

The applicants for the Operations, Statistics, and Data Management
Center should include in their budgets monies for (1) data
collection, retrieval, and management, (2) quality control and
auditing (in years 2 and 4, $10,000 is to be requested and reserved
for auditing by the CTMS), (3) statistical support and analysis, (4)
travel for two meetings per year at the NCI, and (5) a $100,000
(direct costs) set-aside for the Discretionary Fund.  All budgets
should be based on accruing 200 patients of different AIDS-associated
malignancies to four to six different clinical trials/yr.  The direct
costs per year for all these activities should be approximately
$300,000 per year.

The RFA label available in the PHS 398 must be affixed to the bottom
of the face page of the application.  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
title and number must be typed on line 2a of the face page of the
application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including
the Checklist and three signed, photocopies, in one package to:

Division of Research Grants
National Institutes of Health
6701 Rockledge Drive, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express mail)

At the time of submission, send two additional copies of the
application directly to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard
Bethesda, MD  20892 (for express mail)

Applications must be received by May 4, 1995.  If an application is
received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The DRG will not accept
any application that is essentially the same as one already 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.

REVIEW CONSIDERATIONS

All applications will be judged on the basis of the documented
ability of the investigators to meet the RESEARCH OBJECTIVES of the
RFA as listed under Review Criteria.

Review Method

Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NCI.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NCI staff will return the
application to the applicant.  Applications that are complete and
responsive to the RFA will be evaluated for scientific and technical
merit by an appropriate peer review group convened by the NCI in
accordance with the review criteria stated below.  As part of the
initial merit review, all applications will receive a written
critique and may undergo a process in which only those applications
deemed to have the highest scientific merit will be discussed,
assigned a priority score, and receive a second level of review by
the National Cancer Advisory Board.

Review Criteria

Applications for Clinical Trials Member will be reviewed on the basis
of the following criteria:

o  extent to which the application address the goals and objectives
of the RFA;

o  adequacy of applicant's plans for addressing the special
scientific and technical program requirements presented in the RFA;

o  extent of potential contributions to the Consortium in scientific
and clinical approach;

o  demonstration of the numbers of patients with HIV-associated
malignancies accessible to the investigators for clinical studies and
specimen collection;

o  ability to design, conduct, monitor and analyze phase I and II
clinical trials;

o  ability to perform laboratory studies to monitor patients that
would be relevant to AIDS-associated malignancies as documented by
publications or previous funding;

o  qualifications and experience of the Principal Investigator and
staff;

o  merit of the proposed activities and organizational plans for
implementing the proposed AIDS-Associated Malignancies Clinical
Trials Consortium;

o  adequacy of existing physical facilities and resources of the
organization;

o  adequacy of plans for effective cooperation and coordination among
participating awardees, the NCI Program Director and the NCI
Coordinator, as per Special Requirements of the RFA;

o  adequacy of plans to provide tumor tissue, biological fluids and
relevant clinical data to the Tissue and Biological Fluids Banks of
HIV-Associated Malignancies;

o  evidence that appropriate steps have been taken to ensure the
protection of human subjects;

o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.

Applications for the Operations, Statistics and Data Management
Center will be reviewed on the basis of the following criteria:

o  qualifications and research experience of the PI and the key
personnel including, but not limited to, previous experience with
design and administration and analysis of multi-institutional
clinical trials and relevant laboratory studies;

o  adequacy of plans for the development, implementation, and
analysis of multi-institutional clinical trials;

o  adequacy of statistical approach for correlating laboratory
studies with treatment outcomes in clinical trials;

o  adequacy of plans for providing relevant clinical data to the
Tissue and Biological Fluids Banks of HIV-Associated Malignancies in
coordination with the provision of tumor tissue and biological fluids
by the Clinical Trials Members;

o  evidence of competence with regard to fiscal administration and
management of the Discretionary Fund.

o  adequacy of plans for effective communication and coordination
between the Clinical Trials Members and the Operations, Statistics
and Data Management Office and with the NCI;

o  adequacy of the available facilities and data management resources
and personnel;

o  evidence of competence with regard to the mechanisms for
administration, experimental design, quality control, study
monitoring, data management and reporting, statistical analysis, and
compliance with regulatory requirements;

AWARD CRITERIA

Applications recommended by the National Cancer Advisory Board will
be considered for award based upon (a) technical merit of the
application as reflected in the priority score, (b) availability of
resources, and study population and (c) availability of funds.
Furthermore, the applicant organization must indicate a commitment to
accept provisions outlined under the SPECIAL REQUIREMENTS section,
Terms and Conditions of Award.  The earliest anticipated date of
award is September 30, 1995.

Letter of Intent Receipt Date:    April 4, 1995
Application Receipt Date:         May 4, 1995
Review by NCI Advisory Council:   September 1995
Earliest Anticipated Award Date:  September 30, 1995

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding scientific issues to:

Ellen Feigal, M.D.
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Suite 741
6130 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-2522
FAX:  (301) 402-0557
Email:  FEIGALE@DCT.NCI.NIH.GOV

For Programmatic Information:

Roy S. Wu, Ph.D.
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 734
6130 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663
Email:  WUR@DCT.NCI.NIH.GOV

Direct inquiries regarding fiscal information to:

Ms. Kelli Newball
Grants Management Branch
National Cancer Institute
Executive Plaza South, Room 242
6120 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 261
FAX:  (301) 496-8601
Email:  NEWBALLK@GAB.NCI.NIH.GOV

AUTHORITY AND REGULATIONS

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,
Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC
241 and 285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52, 45 CFR Part 74 and 45 CFR Part 92.  This
program is not subject to the intergovernmental review requirements
of Executive Order 12372 or Health Systems agency review.

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products.  This
is consistent with the PHS mission to protect and advance the
physical and mental health of the American people.

.

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