Peregrine Pharmaceuticals Inc. turned out the lights on its lead candidate, bavituximab (bavi), in the lead program in non-small-cell lung cancer (NSCLC). The company said it is halting the phase III SUNRISE trial evaluating bavi plus docetaxel in patients with previously treated locally advanced or metastatic nonsquamous NSCLC compared to docetaxel alone after the study's independent data monitoring committee concluded the bavi group showed insufficient improvement in overall survival (OS) to warrant continuation of SUNRISE.

The pre-specified interim analysis was conducted after 33 percent of targeted events (patient deaths) in the study were reached.

The interim analysis showed that OS in the bavi combination group matched trial expectations but the docetaxel group dramatically outperformed OS expectations, both in terms of trial assumptions and in comparison to published studies. The company said there were no significant differences in enrollment criteria or patient segmentation between the phase II and phase III studies.

"We've never seen these [docetaxel] numbers before," Steve King, Peregrine's president and CEO, said on a call with analysts. "This is quite perplexing. We'll see as the study matures, but certainly at this point the performance of the docetaxel arm was, for us, completely out of left field."

King offered no details on the OS or other data, with the explanation that Peregrine was taking "a deliberate and detailed approach to reviewing and verifying all available data from the trial in order to understand what subgroups or other patient characteristics may have impacted the performance of the study."

Until that analysis is completed, he said, the company is putting other combo studies of bavi with chemotherapy on hold. Those include a planned phase II trial of paclitaxel and bavi in early stage triple-negative breast cancer and a phase II/III trial of taxane with or without bavi in HER2-negative metastatic breast cancer.

Placing the chemo combo studies on hold will allow the company to "unwind" the SUNRISE data and will conserve cash, reported at $67.5 million as of Jan. 31.

Peregrine's shares (NASDAQ:PPHM) responded to the news by plunging 65 percent Friday, to a one-year low of 37 cents, before closing at 41 cents, for a drop of 66 cents. Volume was approximately 16 million shares, or more than 15 times the stock's three-month moving average.

SUNRISE opened in December 2013, fully enrolling with approximately 580 patients, according to Cortellis Clinical Trials Intelligence. All patients received up to six 21-day cycles of docetaxel (75 mg/m2) and were randomized to additional weekly infusions of bavi (3 mg/kg or 24 mg/ml iv) or placebo, until progression or toxicity.

In addition to OS as the primary outcome measure, the study was assessing progression-free survival (PFS) and overall response rate (ORR) along with safety, exploratory immunological studies and pharmacokinetics, according to Cortellis.

COMPANY MOVING FORWARD WITH I-O COMBINATION

Although King characterized the bavi chemo combo setback as "unexpected and disappointing," it wasn't the first for the chimeric monoclonal antibody, which targets phosphatidylserine, or PS.

Bavi showed early signs of success in NSCLC, where a phase II study showed 50 percent improvement in ORR. (See BioWorld Today, Dec. 7, 2011.)

The ORR findings were apparently confirmed in a phase IIb study that also showed improvements in a secondary endpoint of PFS in two bavi-containing arms. Median OS in the phase IIb was less than six months in the control arm and was not reached in either bavi treatment arm. (See BioWorld Today, May 22, 2012.)

Six months later, however, the phase IIb findings garnered controversy when the company reported what it called "major discrepancies" between some patient sample test results and treatment code assignments. The inconsistencies were discovered while the company was preparing for an end-of-phase II meeting with the FDA. (See BioWorld Today, Sept. 25, 2012.)

After an internal review, Peregrine concluded the errors were isolated to placebo and the 1-mg/kg treatment arms, leaving the 3-mg/kg treatment arm – identified as the proposed phase III dosage – unaffected. At the time, the Tustin, Calif.-based company said findings continued to show favorable tumor response rates, PFS and OS compared to the control arm. (See BioWorld Today, Jan. 8, 2013.)

But later in 2013, Peregrine reported that bavi, when combined with carboplatin and paclitaxel, failed to improve OS for patients with stage IIIb and stage IV NSCLC in a phase II trial, compared with carboplatin and paclitaxel without the add-on. Nevertheless, the company vowed to press on with the phase III for second-line NSCLC after reaching agreement with the FDA on trial design. (See BioWorld Today, June 28, 2013, and Dec. 31, 2013.)

Last year, Peregrine inked a nonexclusive agreement with Astrazeneca plc, of London, to evaluate the combination of bavi and the anti-programmed death-ligand 1 (PD-L1) candidate durvalumab, plus chemotherapy, as a potential immuno-oncology (I-O) combo treatment in various solid tumors. The collaboration was subsequently expanded to include a phase II combination trial in NSCLC.

"We have not seen anything in these trial results that in any way diminish our enthusiasm for advancing our immuno-oncology combination clinical studies," King emphasized on the conference call. "The I-O combination studies are based on different mechanistic synergies that are clearly separate from the chemotherapy combination being evaluated in the SUNRISE study. One of these studies is nearing initiation, and we plan to continue moving forward with the overall I-O combination clinical program."

Bavi's role in an I-O combination is completely different from the chemo combination studies, King explained. In I-O, "we're effectively trying to give an immune response," he said. "Bavituximab's target, PS, is involved in inhibiting immune responses. So, in those patients who aren't having immune responses, we have a great opportunity to get it started and then to combine with a PD-1/PD-L1 inhibitor to keep it going. Mechanistically, it's still rock solid."

Peregrine also continues to generate cash from its wholly owned contract manufacturing subsidiary, Avid Bioservices, which had a revenue backlog in excess of $58 million as of Feb. 1, according to King.

Still, Roth Capital Partners analyst Joseph Pantginis called SUNRISE a "kick in the gut for bavi," downgrading the stock to neutral and lowering the price target to 50 cents, from $3.

"Until we receive more information as to the level or extent of confounding data, the trial is viewed as a complete failure," he wrote.

"We are stepping to the sidelines," Pantginis added, at least until data from the Astrazeneca collaboration begin to emerge. Although positive signals from the I-O combo could nudge the pharma toward a partnership, he cautioned that the negative impact from SUNRISE could have a dampening effect on Peregrine's business development activities.