ACTNOW Opens the Gate for Timely, Novel Research

Dr. John E. Niederhuber

The 2009 American Recovery and Reinvestment Act (ARRA) provides a tremendous opportunity to significantly increase our support of cancer research by raising the payline, launching new multidisciplinary and collaborative programs, and accelerating clinical trials that will get treatments to patients more rapidly. The success of NCI’s ARRA investments will, in my opinion, be measured not only in terms of economic recovery, but also in our ability to report scientific advancements and what we have done to help patients.

To the latter goal, I am very pleased to announce a new program that distributes a portion of our ARRA funds to ACTNOW (Accelerating Clinical Trials of Novel Oncologic Pathways), a program that is uniquely poised to advance targeted, personalized cancer treatment in an accelerated timeframe, so that the results benefit patients and the research community as quickly as possible.

The ACTNOW program funds 37 early phase clinical trials of new treatment regimens that we hope will soon expand our ability to provide targeted, personalized medicine. The program has dedicated $31 million for phase I and II trials, plus $5 million for support contracts, including those to assist the investigators with data monitoring and statistical analysis. This is money that will pay compound dividends in health care and jobs for physician scientists, oncology nurses, clinical research coordinators, statisticians, medical assistants, and other staff members who will help administer ACTNOW trials at institutions all over the country.

Members of NCI’s funded clinical trial networks nominated the studies, which were chosen by a peer-review panel composed of NCI and non-NCI clinicians. The review criteria stressed the scientific evidence for the clinical research and selected strong early phase trials that were stalled by lack of available funding. In other words, these trials would not have been started without ARRA.

One of these clinical trials will test a compound called ABT-888, which inhibits the function of certain nuclear proteins that sense and repair DNA damage. The idea is that combining the compound with DNA-damaging treatments, such as chemotherapies and radiation, will make them more effective at killing cancer cells by blocking the cells’ ability to repair damaged DNA. Without the ability to repair, the therapy-induced, DNA-damaged cell cannot survive.

Previous studies with ABT-888, including results from a phase 0 trial published just a few months ago, have shown promising results. Now a phase I trial funded through ACTNOW will test the safety of ABT-888 as a potentiator of carboplatin and paclitaxel for patients with BRCA gene mutations who have inoperable breast cancer, as well as other solid tumors. Although BRCA-deficient tumors are more likely to be sensitive to ABT-888, patients with BRCA-deficiency, who lack normal DNA repair machinery, could be at higher risk for toxicity when exposed to the combination regimen of carboplatin, paclitaxel, and ABT-888; therefore, the safety of this drug combination needs to be tested first. If it proves safe and increases tumor shrinkage, then definitive trials to determine its ultimate role in improving survival will be undertaken.

Another trial will explore the use of two experimental agents, an oral gamma-secretase inhibitor (which alters the function of certain protein machinery in cells) and GDC-0499 (an inhibitor of the hedgehog signaling pathway that has been implicated in numerous cancers), to treat women with invasive breast cancer.

Still another trial will test the use of temsirolimus, the drug recently approved for renal cell carcinoma, along with an antibody that targets the IGF-1 receptor for people who have metastatic soft tissue and bone cancers.

These trials are ideal uses of ARRA dollars and will now be moving forward at universities, cancer centers, and private research organizations across the country.

Importantly, all of the ACTNOW studies are designed to integrate the latest imaging technologies and correlative laboratory research studies to help us understand the underlying biological mechanisms of action. Examples include comparing a positron emission tomography (PET) probe that tracks DNA replication and cell proliferation with standard computed tomography (CT) in assessing treatment response in early stage, resectable, non-small cell lung cancer. Another trial involving patients with late-stage Hodgkin lymphoma will use response-adapted therapy using early interim PET with a probe that measures glucose metabolism. To ensure reproducibility and reliability of the data, the assays will be CLIA (Clinical Laboratory Improvement Amendments) certified.

ACTNOW awards are also contingent on a very strict, accelerated timeline. Study investigators will be required to finalize institutional review board approval and begin enrolling patients within 90 days, and enrollment must be completed within 2 years. Investigators will submit metrics related to the economic impact of their project quarterly throughout the funding period.

Most of the ACTNOW studies are being funded as grants, but NCI was able to use contracting agreements to fund a portion of these clinical trials. Contracts are particularly useful for implementing ARRA-funded programs and projects because they have targeted deliverables and built-in reporting requirements that align with the accountability that is integral to ARRA spending.

As we approach the end of this fiscal year, ACTNOW is an excellent example of how NCI and researchers in the extramural community are working together expeditiously toward the goals that the leaders of our country laid out with ARRA last February: to stimulate the economy through scientific research; to initiate new programs that would require new jobs; to make health care more cost-effective by developing personalized, targeted treatments; and to do these things with the highest standards for transparency and accountability to benefit the people of our country.

We look forward to watching the effects of these awards begin to unfold this autumn and throughout the course of the coming 2 years. Look for periodic updates on their outcomes at http://www.cancer.gov/recovery.

Dr. John E. Niederhuber
Director, National Cancer Institute