Chairman and Director Chief of Lymphoma Director, Clinical and Translational Cancer Research

Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates

John Theurer Cancer Center at Hackensack University Medical Center

We are without a doubt in the midst of an ongoing revolution in cancer care, as I have often previously discussed in this column. It is estimated that over two-thirds of the entire pipeline of medicine is in oncology, and we have a greater understanding than ever before of cancer cell biology (and its incredible diversity), which hopefully will help guide patient management with the end goal of precise medicine.

However, despite these unprecedented and exciting changes, only 3% of patients in the United States are enrolled in clinical trials. Up to 60% of oncology trials, according to Covance, fail to enroll more than a single patient! As per the NCI, up to 40% of oncology trials fail to achieve the minimum patient enrollment and over 60% of phase III trials do not reach planned enrollment. This dismal participation rate has not budged in years, and complicating matters, cancer incidence is predicted to increase by 40% in the next 20 years, due to an aging population, among other factors.

The root causes involved in this complex issue are evidently multifactorial:

		There is a crucial lack of information from patients and caregivers, as well as physicians. Recent surveys suggest that 50% to 80% of patients do not have any information on potential clinical trials for their condition. This might be one of the causes for the well-documented disparities in minority access to clinical trials.

		Patients (and sometimes care providers, as well) often still believe the default “standard of care” is a priori better or at least less risky—though no one would argue that we do not have satisfactory regimens in the relapse/refractory setting in most situations in oncology, particularly in solid tumors. Meanwhile, several of the recently approved drugs or those in development are game changers, such as B-cell receptor inhibitors, checkpoint inhibitor, and CAR T-cell therapies, which have all shown dramatic results, even in chemorefractory patients.

		The complexity of clinical trials has significantly worsened. It is estimated that for an average phase III trial, the number of endpoints and/or eligibility criteria has increased by at least 50% in the last 10 to 15 years.

		Among these inclusion criteria, the number of prior therapies allowed (to find the clinical “unmet” need) is often a limit to enrollment. Meanwhile, most novel agents, such as ibrutinib and lenalidomide, work by mechanisms distinct from chemotherapy, and have been approved and showed efficacy regardless of prior regimens received. Evidently, this issue gets worse as additional drugs get approved, changing the paradigm in a given disease. This can make some trials impossible to enroll as the studies then either require patients to have all received the latest newly approved drug (next clinical benefit benchmark) or on the opposite end, to not have received the latest newly approved treatment (“me-too drug” concept).

		Finally, patients are often selected (ie, excluded) based on comorbidities. In a study from Duke comparing patients treated in the real world (after approval of the drug) with those in the corresponding phase III trial, up to 40% of patients would have failed to qualify to receive the drug on trial that they were receiving in the real world.

		Not surprisingly, issues related to coverage and cost of clinical trials are adding to the complexity and pace of enrollment.

Failed clinical trials come at a huge cost to pharmaceutical sponsors, patients’ lives, and society through impact on innovation. For example, it can cost a sponsor about $50,000 for a site start-up, which is estimated at an almost $2 billion loss between 2005 and 2010 from non-performing sites.

Unfortunately, there is a clear misalignment of all stakeholders involved in clinical research and discovery. Zillions of papers and reports have been written on the subject, with—sadly to say&mdash;no major improvement, so far.

There needs to be a real concerted effort to encourage research, while involving patients, communities and all players together. This will require true changes in design of future trials. When possible “molecularly relevant trials” (biomarkers are available) should be able to lead to approval in refined populations (“find trees in the forest”). Otherwise, trials should at least focus on a defined subset of patients who are as similar as possible (ie, based on clinical and molecular features) to reduce the variance that might dilute the benefit of a tested compound and hypothesis. For example, in the LymphoCare study in follicular lymphoma, the diversity of management (hence of prior therapies at the time of relapse) was at best surprising.

We also need to foster drug development away from the standard randomized trials paradigm as the only alternative that will enroll heterogeneous populations (or the best of the high-risk patients) at the risk of being negative though the phase II data were robust.

Finally, one needs to be able to develop initiatives/ support for investigators as well as simplify the incredibly complex current regulatory environment. The use of technology (ie, mheath [mobile health]) might help bring all the stakeholders together and help solve some of the challenges detailed above and truly embrace—and not hinder&mdash;our fight against cancer.

Articles

Failed clinical trials come at a huge cost to
pharmaceutical sponsors, patients' lives, and society
through impact on innovation.

Clinical Trials: The Elephant in the Room

With a series of recent approvals, the FDA bolstered oncologists’ armamentarium for treating patients with melanoma, soft tissue sarcoma, and pancreatic cancer. These approvals are always tremendous victories for the researchers and pharmaceutical companies whose dedicated work and entrepreneurial spirit produced these novel products. But in the end, the real victors with these regulatory actions are the patients fighting these diseases and their loved ones.

Two of the recent FDA approvals were in melanoma. The first-in-class oncolytic immunotherapy talimogene laherparepvec (T-VEC; Imlygic) is now approved for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. The approval was based on the phase III OPTiM study, in which T-VEC significantly extended durable response rates compared with GM-CSF.

Also in melanoma, the FDA expanded the approval of ipilimumab (Yervoy) in melanoma to include adjuvant treatment of patients with stage III melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection including total lymphadenectomy. The approval is based on results from the phase III EORTC 18071 trial, in which adjuvant ipilimumab at a 10 mg/kg dose reduced the risk of recurrence by 25% versus placebo.

Patients with soft tissue sarcoma also received positive news from the FDA. Trabectedin (Yondelis) was approved for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have previously received chemotherapy that included an anthracycline. The approval was based on results from the phase III ET743-SAR-3007 trial, in which trabectedin reduced the risk of disease progression by 45% versus dacarbazine in patients with advanced soft tissue sarcoma.

Another agent, MM-398 (irinotecan liposome injection; Onivyde), was approved for use in combination with 5-fluorouracil (5-FU) and leucovorin as a treatment for patients with metastatic pancreatic cancer following prior administration of a gemcitabine-based regimen. The approval was based on data from the phase III NAPOLI-1 trial, in which the addition of MM-398 to 5-FU and leucovorin reduced the risk of death by 43%, with a median overall survival of 6.1 months for the MM-398 regimen compared with 4.2 months with 5-FU and leucovorin alone. There are several other oncology treatments currently under FDA review with action dates scheduled before the end of the year. Let’s hope that as the holiday season kicks into high gear, the FDA continues to deliver positive news to patients in need.

With a series of recent approvals, the FDA bolstered oncologistsâ€™
armamentarium for treating patients with melanoma, soft tissue
sarcoma, and pancreatic cancer.

Series of FDA Approvals Delivers New Hope to Patients

	Hilary Koprowski Professor and Chair of Cancer Biology

	Professor of Urology, Radiation Oncology, and Medical Oncology

Finding a way to halt or prevent cancer metastasis has proven elusive. We discovered that a molecule called DNA-PKcs could give us a means of knocking out major pathways that control metastasis before it begins.

, we have shown that one molecule appears to be central to many of the processes required for a cancer to spread. That molecule is a DNA repair kinase called DNA-PKcs. The kinase rejoins broken or mutated DNA strands in a cancer cell, acting as a glue to the many broken pieces of DNA and keeping alive a cell that should normally self-destruct. In fact, previous studies had shown that DNA-PKcs was linked to treatment resistance in prostate cancer, in part because it would repair the usually lethal damage to tumors caused by radiation therapy and other treatments.

We demonstrated that that DNA-PKcs has other, far-reaching roles in cancer. DNA-PKcs also appears to act as a master regulator of signaling networks that turn on the entire program of metastatic processes. Specifically, the DNA-PKcs modulates the Rho/Rac enzyme, which allows many cancer cell types to become mobile, as well as a number of other gene networks involved in other steps in the metastatic cascade, such as cell migration and invasion. In addition to experiments in prostate cancer cell lines, we also showed that in mice carrying human models of prostate cancer, we could block the development of metastases by using agents that suppress DNA-PKcs production or function. And in mice with aggressive human tumors, an inhibitor of DNA-PKcs reduced overall tumor burden in metastatic sites.

In a final analysis that demonstrated the importance of DNA-PKcs in human disease, we analyzed 232 samples from prostate cancer patients for the amount of DNA-PKcs those cells contained and compared those levels to the patients’ medical records. We saw that a spike in the kinase levels was a strong predictor of developing metastases and poor outcomes in prostate cancer. They also showed that DNA-PKcs was much more active in human samples of castrate-resistant prostate cancer, an aggressive and treatment- resistant form of the disease.

These results strongly suggest that DNAPKcs is a master regulator of the pathways and signals that lead to the development of metastases in prostate cancer, and that high levels of DNA-PKcs could predict which early stage tumors may go on to metastasize.

The finding that DNA-PKcs is a likely driver of lethal disease states was unexpected and the discovery was made possible by key collaborations across academia and industry.

Additional key collaborators on the study included the laboratories of Felix Feng (University of Michigan), Scott Tomlins (University of Michigan), Owen Witte (UCLA), Cory Abate- Shen (Columbia University), Nima Sharifi (Cleveland Clinic) and Jeffrey Karnes (Mayo Clinic), and contributions from GenomeDx. Although not all molecules are easily turned into drugs, at least one pharma company has already developed a drug that inhibits DNA-PKcs, and is currently testing it in a phase I study (NCT01353625).

We are enthusiastic about the next step of clinical assessment for testing DNA-PKcs inhibitors in the clinic. A new trial will commence shortly using the Celgene CC-115 DNA-PKcs inhibitor. This new trial will be for patients advancing on standard of care therapies, and will be available at multiple centers connected through the Prostate Cancer Clinical Trials Consortium, of which we are a member.

Although the pathway to drug approval can take many years, this new trial will provide some insight into the effect of DNAP-PKcs inhibitors as anti-tumor agents. In parallel, using this kinase as a marker of severe disease may also help identify patients whose tumors will develop into aggressive metastatic disease, so that we can treat them with more aggressive therapy earlier. Given the role of DNA-PKcs in DNA repair as well as control of tumor metastasis, there will be challenges in clinical implementation, but this discovery unveils new opportunities for preventing or treating advanced disease.

	Goodwin JF, Kothari V, Drake JM et al. DNA-PKcs-mediated transcriptional regulation drives prostate cancer progression and metastasis. 

A single molecule called DNA-PKcs may drive metastatic processes that
turn cancer from a slowly growing, relatively benign disease to a killer.

November 2015 | Oncology & Biotech News

Clinical Trials: The Elephant in the Room

Series of FDA Approvals Delivers New Hope to Patients

Lynchpin Molecule for Cancer Metastasis Found