Cancer is a major cause of morbidity and mortality worldwide. Many believe that progress in drug development has not been as rapid as one would have predicted based on the significant technological advancements that have led to improved molecular understanding of this disease. There are numerous explanations for the lag in clinical success with new therapeutics. However, work in the past decade has provided support for what has become known as the cancer stem cell hypothesis. This model suggests that there is a class of cells that are the main drivers of tumor growth that are resistant to standard treatments. In one model the cancer stem cells inhabit an anatomical “niche” that prevents drug efficacy. Another view is one in which tumors can achieve resistance by cell fate decisions in which some tumor cells are killed by therapeutics, while other cells avoid this fate by choosing to become cancer stem cells. These stem cells are thought to be capable of both cancer stem cell renewal and repopulation of the tumor.
Our proposal aims to conduct a Phase I clinical trial of a first-in-class mitotic inhibitor. The target is a serine/threonine kinase that was originally selected because blocking this target affects both tumor cell lines and tumor initiating cells (TICs). Our data suggest that the target kinase functions at the intersection of mitotic regulation, DNA damage and repair, and cell fate decisions associated with stem cell renewal. Preclinical work has begun to segregate “sensitive” and “resistant” groups of tumor cell lines and TICs after treatment with the drug candidate as a single agent and in combination with standard-of-care therapeutics. Our data also support the model in which cancer stem cell resistance is likely to arise, at least in some cases, due to stem cell fate decisions that happen in response to therapeutic intervention.
This grant is a natural progression of work partially funded by CIRM that enabled the isolation of Tumor Initiating Cells (TICs)from tumors in different tissue types. This facilitated the development and assessment of drug candidates that target both bulk tumor cells and TICs and has now led to the development of a potential anti-cancer drug which we are now preparing to test in humans. The goal of the Phase I trial is to determine the maximum tolerated dose, the recommended Phase II dose, and any dose-limiting toxicities. We will also characterize safety, pharmacokinetic, and pharmacodynamic profiles along with any antitumor activity. Once the maximum tolerated dose has been identified, a biomarker expansion cohort will be opened in order to determine whether appropriately selected biomarkers are associated with a predictable patient response. This will allow a rational approach to study single agent and combination studies that perturb this network and allow us the opportunity to facilitate a targeted clinical development plan.
It has been estimated, by the California Department of Public Health, that in 2013 about 145,000 Californians will be diagnosed with cancer and more than 55,000 of these will ultimately succumb to their disease. Furthermore, more than 1.3 million Californians are living today with a history of cancer. Therefore, innovative research programs that are able to impact this devastating disease burden are likely to have a large potential benefit to the state of California and its residents.
This grant application proposes a Phase I clinical trial for a first-in-class inhibitor of a target that has never been tested in patients. The aim of this trial is to determine the maximum tolerated dose in humans, the recommended dose for phase II trials, and evaluate any dose-limiting toxicities. The trial will also characterize safety, pharmacokinetics, and pharmacodynamic properties. It will also provide early insight into any antitumor activity.
Our group has developed a comprehensive unbiased platform that facilitates the segregation of sensitive and resistant populations of cancer based on their molecular subtypes. This capability has the promise to improve the success rate and reduce the cost of oncology clinical trials by focusing on the subsets that are most likely to benefit while avoiding unnecessarily treating patients that would otherwise benefit from alternative treatments. Our preliminary pre-clinical work, funded by CIRM in the context of a Disease Team I award, suggests that this approach can be successfully applied to the networks associated with mitotic regulation, DNA repair, and stem-cell fate decisions. Our ongoing research has tested a number of chemical compounds that are able to block pathways that are critical to the growth and proliferation of many cancer models. These compounds have all been tested in multiple in vitro and in vivo systems and have been found to inhibit the ability of the cancer stem cell to repopulate. Now that our pre-clinical enabling studies have been completed, we have submitted an Investigational New Drug (IND) application to the FDA for a first-in-human phase I clinical trial. In the current proposal, we will be able to test our hypotheses in a clinical setting, which if successful will lead to confirmation of safety and the establishment of the appropriate dose with which to test in later stage trials. This trial will set the stage for a new class of agents that has not yet been tested in clinical settings.
We believe that the proposal described herein has the promise to expand the reach of targeted therapies into mechanisms that in most cases have been resistant to innovation. Finally, it is reasonable to expect that our preclinical work and the proposed clinical trials will validate a number of potential biomarkers that will identify susceptible patient subpopulations.
This application proposes to conduct a Phase 1 clinical trial of a first-in-class mitotic inhibitor that targets both tumor cells and cancer stem cells (CSCs) in a variety of solid tumor types. The proposed project is a progression of a previous Disease Team 1 Award. The goal of the Phase 1 trial is to determine the maximum tolerated dose (MTD), the recommended Phase 2 dose, and any dose-limiting toxicities. The applicant will also characterize the safety, pharmacokinetic and pharmacodynamic profiles and potential antitumor activity of the drug candidate. Once the maximum tolerated dose has been identified, a biomarker expansion cohort will be opened in order to determine whether appropriately selected biomarkers are associated with a predictable patient response. In addition, manufacturing activities are proposed, both to support current and future clinical trials and to improve the yield of drug product.
Significance and Impact
- Based on the preclinical studies, the drug candidate could have a very significant impact on standard of care management and could offer significant advantages over current standard of care either alone or in combination with other chemotherapeutic agents.
- The potential for significant clinical benefit and competitiveness rests on the candidate’s unique mechanism of action. If the mechanism of action hypothesis is correct, this could have a significant impact on cancer therapy as there are no other therapies with a similar mechanism of action currently available.
- If this trial leads to successful development of a cancer therapeutic, it will be an important accomplishment.
- The TPP is not well- written and should be reconsidered. The TPP is focused on the Phase 1 trial and lead candidate criteria rather than on the aspirational product characteristics for the proposed indication.
- -Reviewers pointed out that the candidate therapeutic is not specifically targeted to cancer stem cells (CSC), but kills bulk tumor cells as well. However, although not specific for CSC, reviewers agreed that the evidence provided suggests that CSC are indeed targeted. Reviewers recommended that the applicant continue to strengthen the evidence that CSC are being targeted and that the CSC feature is likely to be an important component of the potential therapeutic benefit.
- Overall, this is a very promising project.
Scientific Rationale and Risk/Benefit
- The scientific rationale is strong. The preclinical data presented are extensive and consistent and there is a reasonable expectation that the candidate will have clinical benefit.
- Scientific strengths of the proposal are: i. the drug candidate targets a novel target and ii. it inhibits cancer stem cells (CSCs) in several tumor types.
- The drug candidate has good pharmaceutical properties.
- The risk/benefit is a potential issue; based on the preclinical and toxicology data presented, it appears that the therapeutic index could be narrow. Reviewers recommended that the applicant attempt to elucidate the cause of the toxicities.
- The toxicities are not more significant than other anti-cancer agents and potential toxicities are monitorable.
Therapeutic Development Readiness
- All of the therapeutic development readiness criteria have clearly and convincingly been met; this is a great strength of this application.
- Regulatory approval to conduct the Phase 1 trial in a non-USA location has been secured and is close to being secured in the USA.
- There are more than sufficient data to show that this drug is ready for a human trial.
- The development strategy appears straightforward and the clinical trial design is conventional for the type of candidate proposed.
- The clear thinking about the regulatory pathway and the interactions with the regulatory agency are a strength of this application.
Design and Feasibility
- The project plan is well thought out and clearly feasible and the proposed clinical trial can likely be completed within the project period.
- The Phase 1 protocol is very well written and the secondary objectives are especially good. A well respected CRO has been engaged and feasibility seems high.
-A potential weakness is the lack of a Go/No Go criterion based on the maximum tolerated dose (MTD) identified in the Phase 1 trial.
- Milestones and progress criteria are not always explicit; these need to be specified in more detail.
- Reviewers strongly recommended that the applicants initiate conversations with potential partners who own approved drugs that they are considering for combination therapy as soon as it is clear that they are going to consider this route.
Principal Investigator (PI), Development Team and Leadership Plan
- The investigators and team are world renowned experts in the field and there is no doubt about their level of expertise to complete the project. The PI, team and CRO all have an excellent track record and are highly experienced in Phase 1 trials of anti-cancer agents
- There are no concerns regarding the experience of the PI or development team to execute the studies proposed. This is a very qualified and skilled team with good organization and leadership.
- The proposed clinical sites are highly experienced in Phase 1 trials of anticancer agents and have all the support systems to carry out comprehensive studies of this type.
- The budget is high but is fairly well justified.
- For the work proposed the budget seems reasonable
- The applicant is proposing to conduct process improvements and scale up manufacturing primarily to support future clinical trials. This activity might be considered premature, but will depend on whether there is a sufficient supply of drug to complete the Phase 1 trial.
Collaborations, Assets, Resources and Environment
- The proposed CMO, CRO and consultants are appropriate. The fact that medical monitoring, data management and safety analyses are outsourced to a highly reputable CRO is a strength.
- Oversight of the CRO managing the trial, including steps to be taken to measure quality, should be included in a plan before the start of the trial. A more detailed operational plan, including key aspects of trial deliverables such as patient enrollment, patient visits, sample collection, data handling and adverse event reporting should be provided, and also detail how these activities will be accomplished against plans, what risks are possible and what mitigation strategies will be deployed. The aim of these efforts are to make the execution of the trial more reliable for cost, quality and timeline considerations.
- Institutional infrastructures and experience with early stage oncology trials are excellent.
The applicants have secured leveraged funding with resources external to CIRM, and are in conversations with commercial entities.
- Raj Chopra