[Components of a competitive Letter of Intent (LOI)]{.underline}

As with any application for support, a great idea can be poorly
communicated or well communicated. The review criteria for LOI are:

1\) Strong scientific hypothesis

2\) Supporting preliminary data and/or a strong rationale

3\) Adequate patient accrual

4\) Innovative and well-justified correlative studies

5\) Ability to meet regulatory requirements

6\) Not duplicative

7\) Agent availability

8)  Industry sponsor concurrence

LOIs with great ideas (or even good ideas), which **do not** provide
specific information about the rationale/ hypothesis, supportive data,
trial design, patient population, treatment plan and statistical
evaluation generally are assigned worse scores by CTEP than they would
receive if that information had been provided. Competitive LOIs most
effectively assure CTEP that the question being asked is important and
that the methodology applied to the question will be sound. While all
components of LOIs are reviewed, the sections discussed below are
critical to the CTEP review process.

1.  Rationale/Hypothesis section:

    a.  The rationale for performing the specific clinical trial should
        be explicitly stated. There is no need to reproduce data from
        either the solicitation for the LOI or general medical
        literature on the disease. However, a specific reason to test an
        agent should be offered. Reasons might include compelling *in
        vitro* or *in vivo* experiments, molecular biological rationales
        (drug "hits" target protein, and this protein is selectively
        over-expressed in the tumor type to be studied in the LOI.), or
        prior clinical data such as a significant number of tumor
        responses in prior studies using the agent or similar agents.

    b.  The hypothesis should be succinctly stated as a question to be
        asked as the primary endpoint of the study, and the design of
        the study should permit an unequivocal answer to the question.

A poorly stated rationale and hypothesis: "Cancer X has a poor prognosis
and there is no approved effective therapy. It is possible that agent Y
will demonstrate activity against cancer X in humans."

> A well-stated rationale and hypothesis: "Cancer X is known to over
> express the Q receptor in 75% of cancer X specimens sampled from
> patients who have a recurrence after definitive regional therapy. Drug
> Y binds to and inactivates the growth stimulating effects of receptor
> Q, and in multiple animal tumor models of cancer X, drug Y has been
> shown to have twice the tumor shrinkage rate as commercially available
> drugs, and cures 30% of all mice treated. We hypothesize that drug Y
> will demonstrate an overall response rate of at least 30% by RECIST
> criteria when administered to chemotherapy naïve patients with cancer
> X, whose cancers have recurred following regional therapy, compared to
> 15% who historically respond when treated with commercially available
> drugs.

c.  Supportive data: If you have used this agent in your laboratory or
    in a clinical trial at your site, and have unpublished data that is
    relevant, include a summary of that data, with figures, pre-prints
    or a summary from a grant progress report or grant application, if
    available, for the reviewers. It is helpful to receive data such as:
    "of 8 patients with prostate cancer in the phase I trial, who had
    disease progression after prior therapy with docetaxel, 4 receiving
    docetaxel with agent Y had PR sustained from 3-9 months", compared
    to: "we saw some activity in our (unpublished) phase I trial that we
    want to pursue in this phase II trial"

2\. Endpoints/Statistical Considerations: The primary endpoint must be
explicitly stated, and the statistics supporting the endpoint and trial
design must be provided.

> A poorly-stated endpoint: We will assess progression free survival
> (PFS), toxicity, serum protein X levels and QOL. We will declare a PFS
> of 35% to be interesting.
>
> A well- stated endpoint: The primary end point will be 6 month
> progression free survival (PFS). Secondary exploratory evaluations of
> toxicity and QOL, and serum protein X will be made. Based on our
> institutions prior 5 trials including 200 patients, the proportion of
> patients alive without progression following standard therapy is 15%
> (95% c.i. 10-19%). Therefore, the null hypothesis is that 15% will
> remain alive without progression at 6 months, and our hypothesis is
> that use of drug Y will increase the PFS to 35%. A two-stage design
> will be used. If at least 4/20 patients achieve a PFS of 6 months, a
> total of 44 patients will be accrued, assuming a 10% ineligibility
> rate. If 11/40 evaluable patients achieve a PFS of 6 months, we will
> conclude agent Y should be further explored in this setting.

3\. Laboratory correlates: A discussion concerning the rationale,
hypothesis, and methods for laboratory correlates should be succinct,
yet specific enough for CTEP to evaluate the relative merits of the
correlates. The choice of targets to be evaluated and the choice of
assays that will be used to assess them should be explicitly justified,
and reasons for not looking at other targets/using other assays should
be included.

A poorly stated correlatives section: We will look at Q, R, S, T, U, and
V receptor levels and circulating t\*, u\* and v\* from whole blood, and
correlate these levels with outcome.

> A well-stated correlatives section: As noted above, drug Y binds to
> and inactivates the growth stimulating effects of receptor Q. This
> presence of the activated target (expected in 75% of patients with X
> cancer) can be evaluated with immunohistochemistry methods (ref). We
> will measure Q receptor levels on paraffin embedded tumor samples from
> biopsies taken within 2 months prior to enrollment on this trial.
> Commercial "Q-assay" kits will be used or, pending funding, the assay
> method of Block and Cube \[citation\] utilizing standard reagents will
> be used. There is no standard cutoff between normal and abnormal Q
> receptor levels. We will use the median Q receptor levels defined in
> this population to separate low versus high expressors, and using the
> statistical technique of Sphere and Globe \[citation\] we will look
> for an association between baseline tumor Q receptor expression and
> response rate. Although there has been some suggestion that T and V,
> downstream of Q, might be related to Q inhibition by Y, it has not
> been possible to measure phosphoT or phosphoV reliably in specimens
> from murine tumors, and there is no reason to think that modulation of
> Q will alter the total T and total V in cells.

4\. Patient population: In the LOI, you have the opportunity to note
prior studies in this patient population and your accrual rate. If you
project some very different and improved accrual rate, state why: e.g.
Although our last trial in AML accrued only 5 patients in 3 years from
1998-2001, we have since recruited Drs. X, Y, and Z, who together have
seen 200 potentially eligible new patients in the last 12 months, and
were responsible for consenting 45, 62, and 93 patients per year for
clinical trials before they left St. Elsewhere. Thus, we anticipate
being able to accrue 4 patients/month to this trial, despite our
pathetic prior track record.

5\. Competing studies: Please note when you expect competing trials to
be completed, so that we can discount the problem of competing studies.
Having 3 open competing studies in the same patient population doesn't
give reviewers great confidence that this trial will receive priority
and have adequate accrual.

We cannot stress the value of clarity and brevity enough. Most accepted
LOIs are in the 4-6 page range. Exceedingly long LOIs distract the
reviewers from the essence of the proposal. Fully written protocols
submitted as LOIs are unlikely to earn a score higher than what would
have been assigned to a much shorter well-written LOI.