Sandra Hanner

&ldquo;The investigators are finding very interesting, prolonged responses in some patients,&rdquo; said Nathan Bahary, MD, of the University of Pittsburgh Medical Center, in Pennsylvania, who presented the findings. &ldquo;While we know to be cautiousas plenty of phase 1 data has been upended on phase 2&mdash;there appears to be a signal.&rdquo;

IDO is a tryptophan-catabolizing enzyme that plays a key role in the normal regulation of peripheral immune tolerance. Tumors also employ this mechanism to induce a state of immunosuppression. In cancer, IDO mediates an acquired immune tolerance towards tumors.

In other words, IDO allows tumors &ldquo;to thwart the host immune response,&rdquo; the investigators explained in their poster.

Indoximod is an orally available, small molecule, broad IDO pathway inhibitor that potentially interferes with multiple targets within the IDO pathway. Pre-clinical models have demonstrated synergy between indoximod and chemotherapy.

This phase 1b/2 study is evaluating the effect of adding indoximob to the standard-of-care regimen of gemcitabine and nab-paclitaxel (gem/nab). Researchers presented the phase 1b portion of the study at the Symposium.

Indoximod was escalated (600mg/1000mg/1200mg PO twice daily continuous dosing) in combination with gemcitabine (1000 mg/m2) and nab-paclitaxel (125mg/m

) weekly in the first-line metastatic setting, until disease progression. The primary endpoints were safety, toxicity, and determination of a Phase 2 dose.

Fifteen patients were required to successfully dose escalate the Phase 1 study to 1200 mg twice daily. Two patients were replaced in the lowest dose cohort after rapid deterioration due to underlying disease during the regimen limiting toxicity (RLT) window.

The objective response rate was 42% (including one complete response), which is higher than observed in the MPACT trial of patients treated with gemcitabine/nab-paclitaxel (23%), the researchers noted.

The one patient with a complete response achieved this in Cycle 8. A delayed response pattern was seen in a number of patients, which is suggestive of an immune-mediated mechanism of action, Dr. Bahary said.

&ldquo;We are seeing reductions in tumor size of 50% to 70%, and we have some phase 2 patients with ongoing responses now out to 6 months,&rdquo; he said. &ldquo;This is in something that has otherwise been difficult to see with immune therapies.&rdquo;

&ldquo;The overall response rate, observance of a complete response, and delayed and durable response patterns are promising for this combination regimen in metastatic pancreatic cancer,&rdquo; the researchers noted on their poster.

The triplet was well tolerated, investigators noted. Only one dose-limiting toxicity was observed during the study (ascites Grade 3) at the highest dose cohort. The most common adverse events (all Grade 1 or 2), regardless of attribution, were nausea, fatigue, peripheral edema, peripheral neuropathy, alopecia.

The Phase 2 dose was set at 1200 mg twice daily and Phase 2 enrollment (target 80 patients) is ongoing.

Articles

Novel therapy with indoximod, an indoleamine 2,3-dioxygenase (IDO) pathway inhibitor, in combination with standard chemotherapy, yielded a response rate of 42% as first-line therapy for metastatic pancreatic adenocarcinoma

Novel IDO Inhibitor Yields Durable Responses in Metastatic Pancreatic Cancer

Overall survival (OS) was comparable with, or somewhat better, than that seen with other late-line regimens. &ldquo;But the toxicity profile is what stands out,&rdquo; said Richard D. Kim, MD, of Moffitt Cancer Center and Research Institute in Tampa, Florida. &ldquo;These patients are much sicker than patients receiving first-line treatment, and toxicity profile does matter with them,&rdquo; Kim said in an interview with

Ensituximab is an analog of the MUC5AC-related tumorassociated antigen, but it does not react with MUC5AC antigen in nonmalignant tissue. It targets an MUC5AC variant with specificity to CRC, attacking the tumors through antibodydependent cellular cytotoxicity. The compound was developed from a colon cancer vaccine that was in development in the 1980s, explained Philip M. Arlen, MD, CEO of Precision Biologics, Inc, Rockville, Maryland, the manufacturer.

&ldquo;This unique antibody was not developed in a lab with recombinant proteins. It was a biologically functional process,&rdquo; he said.

Approximately 60% of patients with CRC express the MUC5AC variant. This could serve as a biomarker to select patients for the treatment, Kim noted. An earlier phase I study established the maximum tolerated dose of ensituximab at 3 mg/kg IV every 2 weeks. Using this dose, investigators conducted the single-arm, open-label, multicenter phase II trial of adults with mCRC who progressed after at least 2 lines of standard chemotherapy. An immunohistochemistry- based companion diagnostic assay was used to select eligible patients whose tumors express the target in >20% of tumor cells.

The study enrolled 53 patients, with 48 patients evaluable for the primary endpoint, OS. Patients were heavily pretreated, and had failed an average of 5 prior lines of therapy, including chemotherapy, cetuximab, panitumumab, regorafenib, and aflibercept, and a number of investigational agents.

Median OS for patients who received at least 2 doses of ensituximab at 3 mg/kg was 6.8 months. &ldquo;We assumed an OS of about 7 months, and we almost got there. We basically hit our goal,&rdquo; Kim said.

Of the 48 subjects evaluable for response, 15 (31%) remained alive as of December 31, 2015. Response (measured by Response Evaluation Criteria In Solid Tumors [RECIST]) was evaluated in 37 patients, 13 of whom received more than 4 doses. Despite advanced disease in this population, 18 subjects (48.6%) exhibited stable disease in target lesions at the end of the first course (day 57), the researchers reported.

The only grade 3/4 adverse event (AE) seen in more than 1% of patients was anemia, which occurred in 3 patients (1.3%). Hyperbilirubinemia and fatigue were seen in 2 patients each, and nausea, vomiting, diarrhea, headache, and hypoxia were observed in 1 patient each. The most common grade 1/2 AEs were fatigue (10.6%), anemia (10.2%), and nausea (4.9%). &ldquo;The main point is that the drug was very well tolerated,&rdquo; Kim emphasized. &ldquo;Grade 3/4 toxicity was very rare.&rdquo;

The investigators hope to conduct a larger phase III trial of the drug in various combinations and are evaluating the immune correlates of response in the current study.

&ldquo;If we could come up with a combination in the refractory setting, with a low toxicity profile, that could really move the needle in this field,&rdquo; Arlan commented.

Kim RD, Azad NS, Morse M, et al. A phase II therapeutic, open-label, multicenter clinical trial of NPC-1C, a chimeric monoclonal antibody (mAb), in adults with chemotherapy refractory metastatic colorectal cancer (mCRC), initial results. J Clin Oncol. 2016;34(suppl 4S): Abstract 500.

Treatment with ensituximab (NPC-1C), a chimeric IgG1 monoclonal antibody, induced stable disease in nearly half of patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) without contributing significant toxicity.

Ensituximab Proves Promising in Refractory mCRC

In patients with chemotherapy-refractory metastatic colorectal cancer (mCRC), ensituximab (NPC-1C), a chimeric immunoglobulin IgG1 monoclonal antibody, produced stable disease in almost half the patients in a phase II study, without contributing toxicity, investigators reported at the 2016 Gastrointestinal Cancers Symposium.

Overall survival (OS) was comparable with, or maybe somewhat better than, that seen with other late-line regimens, "But the toxicity profile is what stands out," said Richard D. Kim, MD, of Moffitt Cancer Center and Research Institute in Tampa, Florida.

"These patients are much sicker than patients receiving first-line treatment, and toxicity profile does matter with them," Kim said in an interview with

Ensituximab is an analogue of the MUC5AC-related tumor-associated antigen, but it does not react with MUC5AC antigen in nonmalignant tissue. It targets an MUC5AC variant with specificity to CRC, attacking the tumors through antibody-dependent cellular cytotoxicity. The compound was developed from a colon cancer vaccine that was in development in the 1980s, explained Philip M. Arlen, MD, CEO of Precision Biologics, Inc, Rockville, Maryland, the manufacturer.

"This unique antibody was not developed in a lab with recombinant proteins. It was a biologically functional process," he said.

Approximately 60% of patients with CRC express the MUC5AC variant. This could serve as a biomarker to select patients for the treatment, Kim noted.

An earlier, phase I study established the maximum tolerated dose at 3.0 mg/kg IV every 2 weeks. Using this dose, investigators conducted this single-arm, open-label, multicenter phase II trial of adults with mCRC who progressed after at least two lines of standard chemotherapy. An immunohistochemistry-based companion diagnostic assay was used to select eligible patients whose tumors express the target in >20% of tumor cells. The study enrolled 53 patients, with 48 patients evaluable for the primary endpoint, OS.

"This was a heavily pretreated population. Patients had failed an average of 5 prior lines of therapy, including chemotherapy, cetuximab and panitumumab, regorafenib, and aflibercept, and a number of investigational agents (but not TAS102, which was not available at the start of the study).

The median OS for patients who received at least 2 doses of ensituximab at 3 mg/kg was 6.8 months.

"We assumed an OS of about 7 months, and we almost got there," he said. "We basically hit our goal."

Of the 48 subjects evaluable for response, 15 (31%) remained alive as of December 31, 2015.

Response (RECIST) was evaluated in 37 patients, 13 of whom received more than 4 doses. Despite advanced disease in this population, 18 subjects (48.6%) exhibited stable disease in target lesions at the end of the first course (Day 57), the researchers reported.

"But the main point is the drug was very well tolerated," he emphasized. "Grade 3/4 toxicity was very rare."

The only grade 3/4 adverse effect (AE) seen in more than 1% of patients was anemia, which occurred in three patients (1.3%). Hyperbilirubinemia and fatigue were seen in two patients each, and nausea, vomiting, diarrhea, headache and hypoxia were observed in one patient each.

The grade 1/2 events that were somewhat common were fatigue (10.6%), anemia (10.2%), and nausea (4.9%).

The investigators hope to conduct a larger phase III trial of the drug in various combinations. They are also evaluating the immune correlates of response in the current study.

"If we could come up with a combination in the refractory setting, with a low toxicity profile, that could really move the needle in this field," Arlan commented.

Richard D. Kim, Nilofer Saba Azad, Michael Morse, et al. A phase II therapeutic, open label, multi-center clinical trial of NPC-1C, a chimeric monoclonal antibody(mAb), in adults with chemotherapy refractory metastatic colorectal cancer (mCRC), initial results.

In patients with chemotherapy-refractory metastatic colorectal cancer (mCRC), ensituximab (NPC-1C), a chimeric immunoglobulin IgG1 monoclonal antibody, produced stable disease in almost half the patients in a phase II study, without contributing toxicity.

Ensituximab (NPC-1C) Shows Promise and Good Tolerability in Refractory Metastatic Colorectal Cancer

Patients with pancreatic adenocarcinoma enrolled on clinical trials have "profoundly improved survival" compared with patients in the general population, suggesting that oncologists who use trial data to prognosticate may be missing the mark, according to researchers whose work was presented at the 2016 Gastrointestinal Cancers Symposium.

"Physicians often use clinical trial data to estimate expected survival for their patients; however, clinical trial results may not generalize to a broader population," said first author Reith R. Sarkar, BA, a medical student at the University of California, San Diego (UCSD), School of Medicine, who presented the poster.

The paper's senior author was James D. Murphy, MD, MS, of UCSD.

"We believe that lots of clinicians use trial data to predict their own patients' survival, but our findings suggest that physicians should use caution when extrapolating survival estimates from clinical trials to the real world," he said.

"We know that clinical trial patients, in general, are somewhat different from the real-world population," he acknowledged. "We know they have to be fit to enroll, and they tend to live near academic centers (ie, trial sites), be wealthier, and to have better access to health care. If they are on a trial, they are also likely to have closer follow-up. Still, there have not been many studies determining if being on a trial actually translates into a difference in survival."

The authors' aim, therefore, was to produce a more accurate idea of survival of patients with pancreatic adenocarcinoma "in the real world," he said.

The researchers conducted a literature search of phase III trials published between 2005 and 2012. They excluded secondary or pooled analyses trials with second-line treatments and nonrandomized studies. They compared clinical trial patients with a cohort of patients from the Surveillance, Epidemiology, and End Results (SEER) program, matching for diagnosis year, age, and stage of disease, looking for differences in median survival, 1-year survival, and 2-year survival between the SEER registry patients and clinical trial cohorts.

The search resulted in 27 trials that fit the search criteria, consisting of 55 clinical trial arms involving 8438 patients.

They analyzed the studies by these categories: (1) patients with mixed metastatic and locally advanced unresectable metastatic pancreatic cancer, (2) those with unresectable locally advanced disease, and (3) patients deemed resectable.

Almost 100% of all the randomized trials had survival outcomes that were better than those outcomes seen in the SEER registry, and this held true for each of the three different populations, Sarkar reported.

The average increases in median overall survival for trial patients were as follows:

3.23 months in the mixed metastatic/locally advanced unresectable group, a 92% increase (

2.96 months in the unresectable locally advanced group, a 41% increase (

6.1 months in the resectable group, a 36% increase (

The average increase in 1-year survival, in these respective groups, was 88.8% (

<.0001). Absolute differences in 1-year survival were more than 12% in each category.

Average increases in 2-year survival were 72.7% (

= 0.0094), and 34.0% (P <.0001), which were associated with absolute differences of 2.5%, 4.6%, and 11.9%, respectively.

"We saw that for metastatic patients, average survival was almost double for clinical trial patients, versus real-world patients. The differences were greatest for the worst-prognosis cancers," Sarkar said. "We think this is a pretty profound difference."

Sarkar acknowledged that he and his team could not assess the SEER database for patient performance status, underlying comorbidities, and differences in treatment-factors that may help explain some of the survival differences.

Sarkar RR, Matsuno R, Murphy JD. Pancreatic cancer: Survival in clinical trials versus the real world.

Sandra Hanner | Authors

Articles

Novel IDO Inhibitor Yields Durable Responses in Metastatic Pancreatic Cancer

Ensituximab Proves Promising in Refractory mCRC

Ensituximab (NPC-1C) Shows Promise and Good Tolerability in Refractory Metastatic Colorectal Cancer

Analysis Shows Pancreatic Cancer Survival Rates Lower in Real World Than Clinical Trials