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DF/HCC TPETT Program: Testing novel therapeutics in phase I and II trials

Pre- and on-treatment biopsies from a patient with Mantle Cell Lymphoma treated with the CDK inhibitor palbociclib. The on-treatment biopsy shows a marked reduction in phospho-retinoblastoma (RB) protein staining, while total RB staining remains intact, confirming inhibition of CDK4/6 by the drug. The reduction in phospho-RB is accompanied by a reduction in the percentage of cells staining for Ki-67, indicating a marked effect on tumor cell proliferation. This trial was critical for demonstrating target engagement by palbociclib and established preliminary activity of the drug in this lymphoma subset. © The American Society of Hematology (full photo credit below).

April 2014 | eNews

As researchers delve ever deeper into the underpinnings of cancer biology, more therapeutic targets emerge; targets that, when attacked, will in theory shut down the growth of cancer cells—ideally while sparing healthy cells. Every new therapy on the market begins with experimental research. Such is the mission of the Translational Pharmacology and Early Therapeutic Trials (TPETT) Program at DF/HCC: to identify and test out novel therapeutics in phase I and II trials by combining the basic science and clinical resources of its member institutions.

“We have been at this for over 20 years now, and we have a very active program,” says Donald Kufe, MD (DFCI), who along with Bruce Chabner, MD (MGH) co-leads the TPETT program. “We have about 70 new agents in clinical trials within the program, and the development of new anticancer agents is really essential to the mission of DF/HCC,” he says.

According to Kufe, the program identifies promising new leads that are first developed in phase I trials and then if successful, are moved into phase II trials in conjunction with the disease-based centers at DF/HCC. “Our program resides at a key point in the pipeline of discovery by providing the expertise and opportunity for basic science investigators to bring new agents through preclinical development into clinical trials,” Kufe says. “The program also serves as an important conduit for the acquisition of agents from the National Cancer Institute (NCI) and industry and their transition to phase II trials in the DF/HCC disease based programs.”

The Birth Place of Crizotinib

A noteworthy example of an agent born in the TPETT program is crizotinib, an oral agent that targets ALK (anaplastic lymphoma kinase) mutated in cancers, as well as other tyrosine kinases. The trial was initiated at DF/HCC by Eunice Kwak, MD, PhD (MGH) and Jeffrey Clark, MD (MGH). Originally, there was interest in the agent as an inhibitor of the c-MET tyrosine kinase. However, in November 2013—seven years after starting out in phase I trials at TPETT—crizotinib received U.S. Food and Drug Administration (FDA) approval for the treatment of metastatic non-small cell lung cancer (NSCLC) harboring ALK rearrangement.

“What is remarkable about the crizotinib story is that a number of factors coalesced all at once,” says Geoffrey Shapiro, MD, PhD (DFCI), who conducts basic and translational research on cyclin-dependent kinase inhibitors and other novel therapeutics within the TPETT program. First, says Shapiro, findings suggesting the presence of an ALK rearrangement in lung cancer were published. Shortly after, John Iafrate, MD, PhD (MGH) and Scott Rodig, MD, PhD (BWH) developed assays to identify patients with those ALK rearrangements. It was then recognized that crizotinib was a potent ALK inhibitor. Investigators at MGH treated one of the first lung cancer patients to be identified with ALK-rearranged disease; at the same time, DFCI was treating a patient with ALK-positive sarcoma. “Both of those patients had notable responses coupled with clinical improvement, so that the trial ‘morphed’ very quickly into a trial for ALK-positive disease,” Shapiro says. He adds that the way this happened “speaks to the adaptable nature of the phase I trials in TPETT, and the ease with which agents can move into further evaluation within the DF/HCC disease programs.”

Today, the approximately 70 clinical trials led by the TPETT program are evaluating a plethora of experimental agents. The array of agents can be loosely classified into four distinct groups. One group is the kinase inhibitors of signal transduction, targeting such proteins as PI3 kinase, MEK, and BRAF, which are involved in cancer cell proliferation and survival. Another class consists of antiangiogenic agents that target the blood supply of growing tumors; one example is cediranib (NSC 732208), which acts as an orally available multitargeted kinase inhibitor of the vascular endothelial growth factor (VEGF) receptor family. A third group of agents is the cell cycle inhibitors, which may provide therapeutic benefit by disrupting the growth of cancer cells. These agents include the cyclin-dependent kinase inhibitors palbociclib, LY2835219, and dinaciclib. Work conducted in TPETT demonstrated target engagement by the cyclin-dependent kinase inhibitors and pre-dated the eventual FDA breakthrough designation of palbociclib for breast cancer treatment. A fourth group of agents include compounds that modulate the DNA damage response, including poly ADP ribose polymerase (PARP) inhibitors, such as olaparib (AZD-2281) and veliparib (ABT-888), as well as inhibitors of checkpoint kinases.

The program is also evaluating other miscellaneous classes of agents, including inhibitors of anti-apoptotic proteins; multiple antibody-drug conjugates, which deliver a potent cytotoxic compound to cancer cells expressing specific antigens; as well as epigenetic modulators, such as the bromodomain inhibitors (see breakout piece).

Under One Umbrella

A recent success that will help spur these current efforts is the renewal of the prestigious and highly competitive UM1 grant from the NCI. The grant was initially awarded in 1993 and requires renewal every five years. The current award started in March of 2014. According to Kufe, the program at DF/HCC received an exceptional score in what is an extremely competitive grant review process. Shapiro adds that the NCI has reduced the number of sites that receives this funding to only 12. These elite sites function as part of the NCI’s Cancer Therapy Evaluation Program (CTEP) and form what is called the Early Therapeutics-Clinical Trials Network, or ET-CTN. “This designation is really a ‘feather in our cap,’” says Shapiro. In the context of this program, TPETT investigators will form project teams that will partner with the NCI to construct the development plan of specific agents in the CTEP portfolio and to lead investigator-initiated trials.

PARP Inhibitors

DF/HCC leadership within the CTEP ET-CTN is evident in the development of PARP inhibitors, which are being evaluated in a variety of solid tumors, says Shapiro. PARP is an enzyme involved in DNA repair. Inhibition of PARP causes double strand DNA breaks to accumulate; these strand breaks require a complex process known as homologous recombination, involving the BRCA proteins, for their repair. PARP inhibitors have therefore been lethal to BRCA-deficient cancer cells. However, BRCA deficiency occurs only in the minority of human tumors, often resulting from an inherited mutation. Therefore, several initiatives within the TPETT program are seeking to disrupt BRCA function within cancer cells and sensitize them to PARP inhibitors. Shapiro has shown that this can be accomplished by inhibition of cyclin-dependent kinases. He is the lead investigator of a phase I trial of the PARP inhibitor veliparib and the CDK inhibitor SCH727965 (dinaciclib) in patients with advanced solid tumors. The study will evaluate the safety and tolerability of veliparib taken twice daily continuously through each 28-day treatment cycle along with a 2-hour infusion of dinaciclib on days 8.

Another study facilitated by the DF/HCC UM1 grant is a phase I/II trial that is currently underway with the PARP inhibitor olaparib in combination with the antiangiogenic agent cediranib for the treatment of recurrent papillary-serous ovarian, fallopian tube, peritoneal, and recurrent triple-negative breast cancers. The trial is led by Joyce Liu, MD, MPH (DFCI) and Ursula Matulonis, MD (DFCI). Initial results from this study were recently reported. The data indicated acceptable tolerability with expected class-associated toxicities and promising evidence of antitumor activity, especially in ovarian cancer. Among 18 patients with ovarian cancer who could be evaluated by RECIST, 44% responded, and 61% demonstrated clinical benefit of either a response or stable disease lasting more than 24 weeks. The trial has gone on to directly compare the efficacy of olaparib to the olaparib/cediranib combination.

Overall, the work on PARP inhibitors is part of a larger program of agents that will examine DNA damage modulators. The program has input from DF/HCC investigators with international stature in the field, including Alan D’Andrea, MD (DFCI), who has established a new Center for DNA Damage and Repair. “We understand how cells respond to DNA damage from chemotherapy or radiation, how they try to adapt to that, and how they will repair themselves,” Shapiro says, “so we are working on novel compounds that affect the ability of cancer cells to repair DNA damage.”

MAPing out Melanoma

A target of intense investigation within the kinase inhibitor group is the mitogen activated protein (MAP) kinase pathway, which plays a central role in normal cell growth as well as the etiology of many tumors. MAP kinase is especially important in melanoma. Although melanoma accounts for less than 2% of skin cancer cases—with approximately 76,000 new cases of melanoma expected in 2014—melanoma is responsible for the majority of skin cancer deaths. Five-year survival rates for metastatic melanoma remain low, at about 16%. Keith Flaherty, MD (MGH) has been working on understanding and targeting the pathways involved in melanoma.

According to Flaherty, about 50% of patients have BRAF mutations, 25% have NRAS mutations, and the most recently discovered subset, described about a year ago by researchers at DF/HCC and collaborators, is the group of patients with an inactivating NF1 mutation, which is present in 10% of melanomas. “All three of these mutations are involved in the MAP kinase pathway, which, when you add them up, makes this a disease that is heavily driven by this pathway,” Flaherty says.

Flaherty’s group documented the success of single-agent BRAF inhibitor therapy in patients with the BRAF mutation leading to FDA approval of that approach in 2011. Prior to that, in 2010, they began investigating the first BRAF inhibitor based 2-drug combination within TPETT—a MEK inhibitor trametinib with a BRAF inhibitor dabrafenib, “building on evidence that we, and others, published showing that MAP kinase pathway reactivation was the common theme around BRAF inhibitor resistance in patients,” Flaherty says. In 2012, the group published a paper in the New England Journal of Medicine documenting, in a phase I/II study, compelling efficacy for the 2-drug combination above and beyond single agent BRAF inhibitor therapy. The FDA approved dabrafenib/trametinib on the basis of that trial. The results of a phase III trial evaluating that combination just became mature within the past few weeks.

Flaherty also points out that while melanoma is clearly a paradigm for targeting MAP kinase pathway activation, “we hope and believe that the work we are doing in melanoma is going to have impact in a number of other cancers or subsets of other cancers that are also MAP-kinase pathway dependent.”

Future research is likely to focus on three areas that “co-target” the MAP kinase pathway: the PI3 kinase pathway, the CDK4 pathway, and the MDM2 antagonists. According to Flaherty, MDM2 is a negative regulator of p53, and when MDM2 is blocked, p53 can function. This increases antitumor activity in most cancers, although this approach is feasible only when p53 is intact and not mutated. “It turns out in almost all cases of melanoma, p53 is not mutated, so this is an extremely appealing therapy to explore in melanoma, not as a monotherapy but in combination with other agents.”

Selecting the Right Patients

In addition to the efficacy of a novel therapeutic agent, it is also important to consider whether a patient is likely to respond to that agent. Molecular profiling allows tumors to be more effectively targeted and enables better patient selection.

According to Kufe, the phase I trials previously conducted by the TPETT program were designed mostly to identify a toxic dose for phase II studies based on dose escalation to toxicity. However, this approach has recently changed so that even in the earliest phase trials, the selection of patients is based on molecular profiling.

All patients now undergo molecular profiling, before, during, and after treatment. “Developing strategies and tools that will allow the matching of patients to trials through molecular characterization of tumors has thus become a priority of the TPETT Program,” Kufe says. An accomplishment that he says has largely been made possible through integration with the NCI and the UM1 grant.

Additionally, in trials where patients with refractory disease demonstrate a striking response to an experimental agent and the ability to tolerate that agent, approval could conceivably take place earlier, at the end of an expanded phase I trial. This flexibility of the TPETT program therefore allows new agents to reach the patients who need it faster—potentially extending their lives—which is, after all, the overarching goal of the program. 

— Emma Nichols


Photo credit: 
This research was originally published in Blood. Leonard, JP, Lacasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, Yu JQ, Vallabhajosula S, Schoder H, English P, Neuberg DS, Martin P, Millenson MM, Ely SA, Courtney R, Shaik N, Wilner KD, Randolph S, Van den Abbeele AD, Chen-Kiang SY, Yap JT, Shapiro GI. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 2012; 119: 4597-4607. © the American Society of Hematology.