Cerulean Pharma Inc.'s top-line phase II blowup with lead candidate CRLX101 in advanced renal cell carcinoma (RCC) put the kibosh on the idea that targeting hypoxia inducible factor (HIF) in combination with a vascular endothelial growth factor inhibitor might work, so the company is narrowing its focus to topoisomerase-1-sensitive tumors.

Meanwhile, shares of the Waltham, Mass.-based firm (NASDAQ:CERU) plummeted 56.2 percent, or $1.54, to close Thursday at $1.20. CRLX101, a nanoparticle-drug conjugate designed to concentrate in tumors and slowly release camptothecin inside the cells, was paired with Avastin (bevacizumab, Roche AG) in RCC, which overexpresses HIF, vs. standard of care (SOC).

Adrian Senderowicz, chief medical officer (CMO), said the company believes that SOC "is slightly better than we expected, because we have a significant number of patients who received axitinib [Inlyta, Pfizer Inc.]," and a subgroup analysis suggested Inlyta "did much better" than other SOC therapies chosen by physicians from among seven. But, he added, "the problem with this study was not that the control arm overachieved."

Cerulean is "convinced that CRLX101 is an active drug, and let me tell you why," Senderowicz said. "[The compound] has clear objective responses as monotherapy in different topoisomerase-1-sensitive tumors such as ovarian cancer and different gastrointestinal tumors such as pancreas and colorectal," and data will roll out at the European Society for Medical Oncology meeting in October in Copenhagen, Denmark. "Moreover, in addition to the monotherapy, there is clear synergistic antitumor activity as measured by durable objective responses in platinum-resistant ovarian cancer in combination with paclitaxel. We have two private studies, the non-small-cell lung cancer [study] and now the RCC, that did not show clinical benefit." But neither of those tumor types (unlike, for example, ovarian cancer) is topoisomerase-1-sensitive, which is the type where Cerulean will put all of its energy now.

Researchers found no statistically significant difference in median progression-free survival (PFS, the primary endpoint) or objective response rate in the trial at 43 sites in the U.S. and South Korea that enrolled 115 RCC patients who had progressed through two or three lines of therapy already. Specifically, the primary endpoint was PFS in the clear-cell tumor population (n=102) assessed by independent radiological review. Secondary endpoints included overall response rate, duration of response and overall survival.

Median PFS turned up 3.7 months for the CRLX101 combination compared with a median PFS of 3.9 months for SOC (hazard ratio: 1.25, p=0.822). The 95 percent confidence interval for PFS for the CRLX101 combination was two months to 4.3 months and for SOC was 2.2 months to 5.4 months. Objective response rate by independent radiological review for patients who received the CRLX101 combination was 5 percent (2/42) compared to 14 percent (6/43) for SOC (p=0.836). The CRLX101 plus Avastin combo appeared safe and well-tolerated, consistent with earlier studies, the company said.

STILL 'ATTRACTIVE OPPORTUNITY'

CEO Chris Guiffre said during a conference call with investors that Cerulean was surprised the PFS wasn't higher, given the rather long follow-up time. "We needed 70 events to trigger the readout" but didn't have them at the end of the second quarter as expected. Only lately did the contract research organization conducting the trial deliver the results. "We have been rushing through [them] in the last few days and we put [the data] out as promptly as we could," he said. "We are disappointed with this result but we won't dwell on this outcome," choosing instead to "abandon the HIF hypothesis and leave it to others to find a way to harness the power of HIF."

In the work ahead, Cerulean will "focus on CRLX101's best-in-class potential as a topo-1 inhibitor" and concentrate on "three other pillars of our combination strategy: chemotherapy, DNA damage repair and immunotherapy, all of which involve topo inhibition," Guiffre said, pointing out that the drug's payload camptothecin is a more potent topoisomerase-1 inhibitor than irinotecan and topotecan. "We envision CRLX101 replacing irinotecan and topotecan as monotherapy, and also enabling combinations with other cancer treatments that cannot be combined" with those two, he said. Trials are ongoing that combine CRLX101 with weekly paclitaxel and Lynparza (olaparib), the poly ADP-ribose polymerase inhibitor from London-based Astrazeneca plc.

In ovarian cancer, CRLX101 has shown activity as a monotherapy and in combo experiments, including with paclitaxel, Guiffre said. "In fact, based on data from just nine patients enrolled in the phase Ib portion of the ongoing trial combining CRLX101 with weekly paclitaxel, the FDA recently gave us fast-track designation in platinum-resistant ovarian cancer. We are moving forward with the development of this combination, and have scheduled an end-of-phase II meeting with FDA this fall to discuss the design for a pivotal study." He pointed out that "many companies in our industry go through setbacks like this, and many of them ultimately emerge to create significant value for shareholders while they create important medicines for patients. That is exactly what we intend to do."

Also in the works is CRLX301, with a docetaxel payload. In June, Cerulean dosed the first patient in the phase IIa stage of the ongoing phase I/IIa trial of CRLX301 in patients with advanced solid tumors.

The expansion includes two stages. The first will enroll up to eight patients in each dosing schedule. That stage of the study is designed to further establish the safety and tolerability of each dosing schedule and to provide more data on pharmacokinetics, pharmacodynamics and antitumor activity. Stage two will enroll up to 36 more patients with specific tumor types using the optimal dosing schedule.

Roth Capital Partners analyst Joseph Pantginis kept the faith in Cerulean along with his buy rating, though he lowered the price target to $2.50 from $9. "With a platform technology providing long-term pipeline fill and what we perceive to be significant improvements in tumor targeting, we believe [the company] remains an attractive opportunity despite the failure in late-stage RCC," he wrote in a report.