Once there is a strong rationale that supports clinical testing, two key parameters have to be considered for success.
First is to select the most appropriate drugs for clinical testing, considering the pharmacology of each drug, routes of delivery, and potential drug–drug interactions ().
The interaction between two given drugs could be a result of pharmacodynamic interaction or pharmacokinetics (via inhibition or induction of metabolic enzymes or transporters). The latter occur when one drug influences the absorption, distribution, metabolism, and/or excretion of another. Today, it is common practice and FDA mandatory [56
] to test preclinically for potential drug interactions of novel combinations. Several in vitro methods assess drug interaction issues pertaining to transportation and enzyme inhibition and/or induction. The major paradigm shift in the field is associated with the use of modern human tissue preparations such as human liver slices, freshly isolated human liver cells, human hepatocyte primary cultures, subcellular fractions such as microsomes, cytosol, and S9 fractions, recombinant human enzymes (cytochrome P-450 and UDP-glucuronosyltransferase), transgenic cell lines, and cell-based reporter assays (reviewed in [57
Still, the prediction of in vivo drug interactions from in vitro metabolic data remains highly controversial because the in vitro data do not necessarily translate directly into relative extents of inhibition in vivo. The mentioned assays, therefore, are more likely to be useful to halt the further development of potentially problematic drug combinations if alternative ones are available.
Information regarding the interaction of drugs with monoclonal antibodies is scarce, and a formal assessment of this type of relationship is inherently complicated. Still, one may expect these interactions to be not clinically significant (reviewed in [60
Obtaining the desired drug(s) for the trial can be problematic () because there are limited options surrounding approved targeted therapies. For one, in order for a drug to be approved in the first place, significant activity has to be demonstrated, requiring time, and also it may be difficult to prove the activity of single agents. For combining investigational agents, the Cancer Therapy Evaluation Program of the National Cancer Institute has access to some of these experimental drugs and it has championed clinical trials combining targeted therapies [61
Potential sources of targeted drugs
Trial design is another important consideration. The design of the clinical trial may be key for proof of concept (“hitting the target”) or may eliminate, early in development, combinations that will eventually fail.
Since the realization that molecularly targeted therapies likely behave differently from classical cytotoxic chemotherapeutic agents, many proposals have advocated changing how early clinical trials are conducted when targeted therapies are being tested [62
]. Some of these proposals have been incorporated into the design of phase I and phase II trials and have been proven to be successful. Still, the way that we perform combination trials has rarely changed, and few guidelines or proposals of novel designs for testing combinations have been discussed. In our organization, some of these proposals, with variations, are being considered for clinical trials ().
Proposal of novel trial design. Some of these designs are nicknamed “octopus trials” (A1, A2, C2) because they can assess several options in a single study.
Broad Trial Indication Designated Finder with Multiple Cancers in One Study
This is a proposal for a phase I/II clinical trial in which drug activity in many different tumors is quickly assessed. Once the recommended doses of drugs are determined, multiple expansion cohorts, one for each indication, are opened, each of them analogous to the first part of a Simon two-stage design (A1). This can be performed with either single agents or combination therapy.
Multiple Agents Compared in a Single Study
This is also designated “complete phase I” and uses the same approach as above. Here, an array of different combinations is assessed. In this trial design, one drug could remain the same in each arm with the second drug being variable (A2).
Multiple Permissible Maximum-Tolerated Doses
This clinical trial design explores various possible combinations of dose levels. The model of Plimack and Berry (B1) is a two-dimensional escalation model that allows several cohorts to be opened at the same time if only one drug is escalated (high doses of drug A and low doses of drug B or low doses of drug A and high doses of drug B or intermediate doses of both drugs). Rodon's model (B2) is a three-dimensional extension of Plimack's schema, combining three drugs (e.g., bevacizumab, sorafenib, and temsirolimus) with rules based on mechanism-related toxicities required to stop escalation in one of the directions.
Here, the treatment leads in with drug A, and after assessment drug B is added (C1). Assessments at different time points (biomarker, efficacy, toxicity) are used to determine molecular synergy. If several drug candidates are to be evaluated, an arm for each combination is developed and patients are allocated by adaptive randomization based on such assessments (C2). For example, an EGFR inhibitor plus dasatinib versus an EGFR inhibitor plus a MET inhibitor, with the endpoint being overcoming resistance to EGFR inhibitors. A similar objective could be achieved with a phase 0 trial combining targeted therapies for biomarker testing (for this, the doses of both drugs of the combination must be well known, there must be no expectation of interaction between the drugs, and the biomarker must already have been validated) [63
This is when a phase I trial leads to an embedded phase II trial that ultimately adds a control arm and becomes a phase III trial (E). Intermediate assessments of feasibility are incorporated at each stage (safety or biomarker based in the phase I stage and Simon's stopping rules in the phase II stage) [65
Histology-Independent Clinical Trial
Patients are selected on the basis of the presence of a molecular marker, regardless of the anatomic origin of the tumor. This approach is based on the concept that tumors with a similar genetic background (and oncogene addiction) may respond similarly, and specific targeted therapies may be active for specific genetic backgrounds, for example, mutation or amplifications of PI3K-
α (mutations are frequent in breast and bowel cancers, whereas amplifications are present in >50% of ovarian, cervical, and lung cancers) [66
]. This approach is applicable to the study of single targeted agents as well as combination regimens.
Early clinical trials are becoming an arena for hypothesis testing, and ideas such as mechanism(s) of action and proof of concept, optimal biologic dose, and the incorporation of pharmacodynamic endpoints will need to be incorporated into their design. Whether these concepts change how we test drug combinations has yet to be determined.