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Drug developer Clovis Oncology is planning to report data from a clinical trial later this year that may yield a new treatment option for pancreatic cancer patients who are poor responders to gemcitabine.

Clovis is conducting a study, called LEAP, of 360 chemotherapy-naïve metastatic pancreatic cancer patients who are randomized to receive the current standard of care gemcitabine, or the investigational CO-101, a gemcitabine-lipid conjugate. The study investigators are hypothesizing that unlike gemcitabine, CO-101 won’t depend on the expression levels of the protein cellular transporter hENT1 to enter and destroy tumor cells.

Gemcitabine, currently the first-line standard chemotherapy treatment for metastatic pancreatic cancer patients, requires a transport mechanism to help it enter tumor cells. Previously published data suggest that patients with high hENT1 expression respond well to gemcitabine, while those with low expression — about two-thirds of pancreatic cancer patients — respond poorly to the chemotherapeutic.

LEAP researchers have prospectively collected biopsy samples and have enrolled both high- and low-hENT1 expressers. Study investigators will be blind to the hENT1 expression status of patients until the end of the trial. Clovis is working with Roche subsidiary Ventana Medical Systems to simultaneously develop and validate a companion diagnostic that can gauge low and high hENT1 expression. The primary outcome that study investigators are measuring in LEAP is overall survival in the hENT1-low population.

“The question really is whether the lipid, which facilitates entry into the cell through passive diffusion, is going to be able to deliver gemcitabine as efficiently as when a nucleoside transporter is present,” Clovis CEO Patrick Mahaffy told PGx Reporter. “The answer is we don’t know, but we’ll find out in the study.”

The study may reveal that since CO-101 doesn’t depend on hENT1 to enter tumor cells, all metastatic pancreatic cancer patients, regardless of low or high expression of this protein, derive a level of benefit from the new treatment. Still, Clovis is using a companion test to stratify patients after factoring in reimbursement and cost-effectiveness considerations, which currently are perhaps the biggest barriers to the adoption of personalized treatments.

“Nothing we know suggests that we would be better than gemcitabine … in the hENT1 high population. Given the evolving reimbursement environment and the fact that gemcitabine is generic and is priced as such, pending a successful outcome we anticipate that [CO-101] would be used primarily, if not solely, in the hENT1 low population where we anticipate poor outcomes for gemcitabine,” Mahaffy said. “We anticipate that gemcitabine would continue to be the favored product on price alone even if we were to show equivalence to CO-101 in the hENT1 high population.”

Clovis Oncology will commercialize CO-101 globally. The company is currently setting up commercialization infrastructure in the US for the drug, anticipating a launch as early as next year. Clovis won’t necessarily co-promote CO-101 and the companion test with Ventana. The test developer will be in charge of commercializing the test, and Clovis will market the drug with its sales representatives, who will also be educating oncologists about the need for a companion test.

Ventana will submit its premarket approval application for the hENT1 expression test at the same time that Clovis submits its new drug application for CO-101. The test will be marketed as not just a companion diagnostic to assess whether pancreatic cancer patients have low levels of hENT1 and would therefore respond to CO-101, but Ventana will also be able to market the diagnostic as a tool to determine which high-hENT1 expressing patients should be given gemcitabine.

“The [LEAP] trial will clinically validate the diagnostic both for determining response to both gemcitabine and CO-101,” Mahaffy said.

There are around 120,000 cases of pancreatic cancer each year in the US, EU, and Japan, and around 24 percent of patients survive for one year. Around 80 percent of pancreatic cancer patients receive gemcitabine as monotherapy or in combination with other cytotoxic agents. Based on the low incidence of metastatic pancreatic cancer, Clovis has garnered Orphan Drug status for CO-101 from US and European regulatory authorities.

Although a number of retrospective trials have demonstrated that hENT1 expression levels impact outcomes in pancreatic cancer patients in the metastatic and adjuvant setting, LEAP will be the first prospective validation of this observation. “That’s why this trial is so important to the pancreatic cancer community,” Mahaffy said. “Because not only are we going to learn about CO-101, but we’re going to learn prospectively about the role hENT1 plays in determining the outcome for patients’ treatment with gemcitabine alone.”

Testing for hENT1 expression status is not widely conducted by doctors in the care of pancreatic patients. “In fact, it’s not even widely known in the broader community setting,” noted Mahaffy, adding that academic oncologists are increasingly aware of the association between hENT1 expression and gemcitabine efficacy. After LEAP concludes and if the trial is successful, Clovis plans to initiate discussions with treatment guideline-setting bodies.

In addition to looking at CO-101 as a first-line metastatic pancreatic cancer treatment in hENT1-low patients, Clovis is also studying the drug-conjugate as a second-line treatment in metastatic pancreatic cancer (Phase II), as well as in non-small cell lung cancer (Phase I).

Personalized NSCLC Drug

In addition to CO-101, Clovis has a number of investigational agents in its pipeline that it is developing in molecularly defined patient subsets. For example, CO-1686 is a selective covalent inhibitor of EGFR mutations that the firm is exploring in patients with NSCLC. Currently Clovis is conducting a dose-finding Phase I/II trial involving CO-1686 in NSCLC patients with T790M mutations. Patients with these “gatekeeper” mutations become resistant to treatment to widely prescribed EGFR-inhibiting NSCLC drugs, Roche/Genentech’s Tarceva and AstraZeneca’s Iressa.

CO-1686 “is a very potent inhibitor of T790M … [mutations in] which occur in 50 percent of lung cancer patients, after treatment with Tarceva,” Mahaffy said. After the dose-finding portion of the Phase I/II trial, Clovis plans to initiate an expansion cohort looking at T790M mutation-positive patients who are resistant to Tarceva. “If we see the kind of results we hope to in that expansion cohort, we would initiate a registration study beginning in 2014 in Tarceva-failed patients with T790M mutations,” he said.

While CO-1686 is an inhibitor of T790M mutations and other activating mutations of EGFR, the drug doesn’t inhibit wild-type EGFR like Tarceva and Iressa do, which can make NSCLC patients prone to serious side effects. “What is interesting about [CO-1686] is it is a very potent inhibitor of activating mutations of EGFR, the same targets that Tarceva or Iressa address, but unlike those drugs, [CO-1686] does not inhibit wild-type EGFR,” Mahaffy said. With CO-1686, “we should see very limited rash and diarrhea side effects associated with Tarceva and Iressa.”

First, Clovis will study CO-1686 as a second-line treatment in NSCLC patients with T790M mutations. Eventually, Clovis plans to study the drug head-to-head against Tarceva in the first-line setting. “Given the activity of our drug in animal models so far, we think we may have the ability to demonstrate superiority in terms of efficacy and from the side effects of Tarceva,” Mahaffy said. “We would hope to demonstrate in addition to a cleaner safety profile, a longer duration of benefit, because we would prevent that primary resistance mechanism in T790M from emerging.”

Roche Molecular Systems has partnered with Clovis to develop a companion diagnostic for CO-1686.

Meanwhile, last year, the European Commission approved the use of Roche/Genentech’s Tarceva as a first-line treatment for NSCLC in patients with EGFR mutations (PGx Reporter 9/7/2012). Last month, UK’s National Institute for Health and Clinical Excellence issued a draft guidance recommending that the country’s National Health Service pay for Tarceva as an option for this patient population. The company is in discussions with the US Food and Drug Administration about launching Tarceva in this population (PGx Reporter 06/08/2011).

Additionally, Boehringer Ingelheim is developing afatinib, a drug intended for advanced NSCLC patients with EGFR mutation-positive tumors (PGx Reporter 6/6/2012). Boehringer is working with Qiagen to advance a companion test for its drug.

An NGS-Based Companion Dx?

Another drug in Clovis’ pipeline is an inhibitor of PARP 1 and PARP 2, called rucaparib, which the company licensed from Pfizer. Rucaparib is currently undergoing Phase I/II trials in breast and ovarian cancer. The company is investigating the efficacy and safety of the drug in patients who lack the ability to repair damaged DNA that cancer cells need to thrive.

Mahaffy highlighted that Clovis is currently continuing a dose-finding Phase I study initiated by Pfizer combining rucaparib with carboplatin, and is conducting a Phase I trial investigating the drug as a monotherapy. This latter study will include an extension cohort of ovarian cancer patients with germline BRCA mutations.

Clovis is among a handful of drug developers, including Abbott and AstraZeneca, that are advancing PARP inhibitors with a personalized medicine strategy, betting that patients with BRCA 1/2 mutations will respond better to this class of drugs than those without these mutations. Previous studies have demonstrated that the PARP 1 enzyme and the BRCA gene work in concert to repair DNA damage, enabling survival of cancer tumors. Patients with BRCA mutations can’t repair DNA damage in this way, so then PARP inhibitors can be more effective in stopping cancer growth.

Abbott and AstraZeneca are using a companion test developed by Myriad Genetics to study their PARP inhibitors in BRCA-mutated patients with these diseases. Myriad markets BRACAnalysis, a test that gauges germline BRCA mutations associated with hereditary breast and ovarian cancer. However, gene alternations other than germline BRCA 1/2 mutations are linked to faulty DNA repair and PARP inhibitor response. For example, Clovis estimates that around 15 percent of women with ovarian cancer harbor germline BRCA 1/2 mutations, but another 8 percent of patients have somatic mutations in BRCA. Meanwhile, germline BRCA 1/2 mutations comprise only 5 percent of breast cancers.

When Pfizer was developing rucaparib, it was working with MDxHealth to explore methylation-specific markers associated with DNA damage repair and response to PARP inhibiters (PGx Reporter 2/2/2011). According to MDxHealth both methylation and mutation testing can characterize BRCA gene activity. The company previously estimated that BRCA methylation appears in about 40 percent to 50 percent of triple-negative breast cancer patients, and in about 10 percent to 30 percent in sporadic breast cancers.

Clovis has an open contract with MDxHealth looking at methylation profiles in breast and ovarian cancer, and will continue to explore this approach, specifically for methylated BRCA in triple-negative breast cancer. Additionally, Clovis is “considering the opportunity to look at both germline and somatic mutations of BRCA, based on a tissue-based assay,” Mahaffy said.

Beyond this, in August, Clovis and Foundation Medicine announced they are working together to investigate other genetic defects related to DNA repair deficiency.

“We went with Foundation Medicine … because it will allow us to reach a broader population,” Mahaffy said. For example, in ovarian cancer, Foundation Medicine’s next-generation sequencing platform could identify other mechanisms of DNA repair deficiencies that could potentially increase the intent-to-treat population for rucaparib from 15 percent of ovarian cancer patients with germline BRCA mutations to as much as 50 percent of the population that has somatic mutations in 28 additional genes that have been described as conferring “BRCA-ness” or as having a BRCA-like effect on DNA repair.

Clovis plans to develop a companion test for rucaparib on Foundation Medicine’s Foundation One targeted NGS platform. However, one challenge for Clovis is that the FDA hasn’t yet elucidated how it plans to regulate NGS-based tests. “Clearly, there is a seismic shift underway, and we may be one of the first to have plans to go forward on a premarket approval path with next-gen sequencing,” Mahaffy said. “But clearly the FDA and everyone else knows this tidal wave is coming.”

Clovis hopes to initiate a registration trial in the second half of next year looking at rucaparib as a maintenance therapy in ovarian cancer patients sensitive to platinum-based chemotherapy who have alterations in BRCA and deficiencies in other DNA repair genes. Foundation Medicine and Clovis have separately initiated discussions with the FDA about getting taking NGS-based tests through regulatory approval, Mahaffy said.

Turna Ray is the editor of GenomeWeb’s Pharmacogenomics Reporter. She covers pharmacogenomics, personalized medicine, and companion diagnostics. E-mail her here or follow her GenomeWeb Twitter account at @PGxReporter.