A Manual for Participants in Clinical Trials of Investigational Agents ...

5.1.3 Combining Agents
We believe that the most rational approach to development of a new cancer agent is
reserving its combination with another agent(s) until it has shown reproducible evidence
of activity in at least two single-agent trials in a disease. Alternatively, or in addition,
investigators may propose combinations when a rationale firmly grounded on laboratory
evidence is relevant to the clinical circumstance.
In the past, oncologists developed many agent combinations intuitively; they combined
two, three, or more putatively active agents in uncontrolled studies of antitumor effect
and adverse effects. To be sure, some very real therapeutic advances were achieved by
this process. However, the lack of a systematic, stepwise approach and the frequent
absence of proper control groups often left the oncology community in the uncertain
position of not knowing whether results with a particular regimen represented progress
or not. A new agent’s overall impact on efficacy and adverse events may remain unclear
without a systematic approach. Ultimately, when available data do not elucidate each
new agent’s specific contribution, the process of NDA or BLA approval is impeded.
Intelligently designed and flexible new agent development programs must provide room
for both approaches. Well-conceived small pilot trials testing new hypotheses will always
have an important place in cancer’s developmental therapy. We shall, however, continue
to pay close attention to the rationale behind all proposed combinations. We will also
continue to ask whether certain proposals for therapeutic research might not be better
approached by a phase 3 design rather than phase 2.
In the past, activity was the most common basis for a single agent’s inclusion in a
combination. CTEP now considers other rationales as well. For example, we consider
radiosensitizers or substantial laboratory evidence of synergy between two cancer
agents. This is particularly compelling if it is consistent with a putative mechanism of
action. Alternatively, an agent inert against cancer might be added because of evidence
that it alters a second (anticancer) agent’s pharmacodynamics or pharmacokinetics.
Agents can also be tested as both chemotherapeutics and radiosensitizers. In such
cases, CTEP will carefully assess the rationale and evidence offered in support of a
proposal.
When investigators submit combination studies to CTEP for review, therefore, it is
particularly important to state the proposal’s goals, background, and rationale clearly.
• If experimental results in the laboratory are the basis for the study, they should
be relevant to the clinical circumstance and cited in adequate detail.
• If preliminary clinical results are the motivation, they should be similarly cited;
unpublished results should be provided as part of the background or in an
attachment to the protocol document.
• If the trial proposes a feasibility pilot, the protocol should state clearly what kinds
of results the investigators would regard as medically significant and where they
would propose to go next if a significant result is obtained.
A detailed plan of a follow-up study or detailed speculations about likely outcomes is not
necessary at this stage of review. Rather, we are seeking an understanding of how the
pilot proposal will fit into a strategy of development of the new therapeutic idea.
Section 5 - Investigator’s Manual 2009 20