Clinical Trial Tracker: An Update on Promising Phase 2 and 3 Clinical Trials in Pancreatic Cancer

Introduction
Despite recent progress involving adjuvant and neoadjuvant approaches, treatment options for pancreatic ductal adenocarcinoma remain unsatisfying, especially in the salvage setting of locally advanced and metastatic disease. Immune therapies have been successful in a number of other tumor types, but pancreatic cancer has been largely refractory to these otherwise exciting approaches. Fortunately, many novel compounds are in development that may well improve long-term outcomes of this challenging malignancy.

J. Randolph Hecht, MD J. Randolph Hecht, MD
Professor of Clinical Medicine
David Geffen School of Medicine
at UCLA
Director, UCLA Gastrointestinal
Oncology Program
Los Angeles, California

Caroline Helwick (CH): Dr. Hecht, new targets are being identified in pancreatic cancer, and new ways to harness the immune system are being explored. If these advances pan out, how could this change the outlook for pancreatic cancer?

Dr. Hecht: We haven’t really had a lot of positive trials in pancreatic cancer in a number of years. The outlook until recently has been fairly dismal, but now I would say there is reason to be hopeful. There are many new drugs in development, and many for which we have positive clinical trials that could be practice-changing. All it takes is a positive trial or two and you really can alter the entire landscape. Unfortunately, trials take time to mature.

CH: Let’s talk about some of those drugs. One of the obstacles in treating pancreatic cancer relates to the fact that the tumor is hard to penetrate. The pegylated hyaluronidase enzyme PEGPH20 is an interesting compound in that it attempts to tackle this problem. Can you describe the current status for this drug?

Dr. Hecht: PEGPH20’s mechanism of action relates to the tumor stroma, which is particularly important in pancreatic cancer. As the immunotherapy revolution has taken hold, the question is also how to get immune-effector cells into pancreatic cancers. The stromal defense is part of the problem, and one of its components is hyaluronan (hyaluronic acid, HA). HA increases interstitial pressure, decreases blood flow, impairs drug delivery, and creates a nutrient- and oxygen-deprived microenvironment.1 PEGPH20 is designed to break down stromal HA so that the delivery of chemotherapy is enhanced. The compound is being developed with a companion assay to determine HA levels, under the assumption that high levels of HA predict for benefit with PEGPH20, is supported by preclinical and clinical data.

CH: Can you describe the clinical trials of PEGPH20?

Dr. Hecht: There have been two important clinical trials and others are underway. Hingorani and colleagues presented a Phase 2 study at the 2017 ASCO Annual Meeting2 (See Box). When the researchers evaluated the subset of patients with high HA levels—meaning they expressed the stromal component—they saw the most benefit.

A phase 2 study of PEGPH20 in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel alone found that median progression-free survival improved with the addition of the novel agent in patients whose tumors had high HA levels (9.2 months vs 5.2 months; P = .048).2 PEGPH20 does not appear to add efficacy, however, to modified FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin.3 A registration trial evaluating PEGPH20 in combination with gemcitabine/nab-paclitaxel versus chemotherapy alone in biomarker-selected patients is recruiting (NCT02715804).4

But there is no such thing as a free lunch, and targeted therapies can have side effects. For PEGPH20, it was an increase in thromboembolic events, which was not surprising since pancreatic cancer has the highest incidence of thromboembolic events among all tumor types. Now patients are prophylactically anticoagulated with low molecular weight heparin.

We also learned that the chemotherapy partner seems to matter with PEGPH20. In contrast to the benefit shown by combining this drug with nab-paclitaxel/gemcitabine, the drug was not shown to be more effective than modified FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) alone in the Phase 2 SWOG S1313 trial.3

CH: So, what studies are currently underway for PEGPH20?

Dr. Hecht: Current studies will focus on the biomarker-driven, HA-high subset of patients. The Phase 3 HALO 109-301 trial is currently evaluating PEGPH20 plus nab-paclitaxel/gemcitabine in the first-line setting.4 It is a randomized, double-blind, placebo-controlled study involving 570 stage IV HA-high pancreatic cancer patients enrolled at 249 sites. The company is conducting the right trial, they are doing it well, and the result should be interpretable.

Other smaller studies are evaluating whether this drug might also be a good partner for anti-PD-1/PD-L1 agents [drugs targeting programmed death protein receptor-1 or its ligand]. NCT03634332 is evaluating PEGPH20 plus pembrolizumab in HA-high patients,5 and NCT03481920 will study it in combination with avelumab.6 One thing we know with pancreatic cancer is that single-agent therapy with PD-1 or PD-L1 agents does not work. Perhaps adding a drug that targets the microenvironment can make these potentially game-changing drugs more effective.

CH: Dr. Hecht, you are principal investigator of a study of the novel compound PEGylated IL-10 (AM0010, pegilodecakin). Tell us about this drug.

Dr. Hecht: Tumor-specific cytotoxic CD8+ T cells have low expression in most pancreatic tumors, which potentially reflects on the relatively lower mutational burden of this malignancy compared to immune-sensitive cancers. PEGylated IL-10, or pegilodecakin, consists on a form of human interleukin-10 (IL-10), which is a messenger molecule that promotes the growth and killing activity of T-cells. In particular, pegilodecakin stimulates the survival, expansion and cytotoxicity of intratumoral CD8+ T cells and these cells mediate the cytotoxic effect of this immunotherapeutic.7,8

In early studies of pegilodecakin, we saw dramatic increases in novel T-cell clones not previously detected in patients. We believe, therefore, that pegilodecakin is remodeling the T-cell repertoire to a certain extent. This particular form of IL-10 is linked to a molecule called polyethylene glycol, which prolongs the time IL-10 stays in circulation and enables pegilodecakin’s immunologic effect to be long-acting.

Pegilodecakin has shown activity in immuno-sensitive tumors, including renal cell carcinoma and non-small-cell lung cancer.9 In pancreatic cancer (which is not immunosensitive), a multi-armed Phase 1b study in multiple tumor types showed its activity as a single agent and in combination with different chemotherapy regimens, in heavily pretreated patients.10 (See Box). For pegilodecakin given in combination with FOLFOX [5-FU, leucovorin, oxaliplatin], the 1-year survival rate among metastatic pancreatic cancer patients was 43%, which is unusually high for salvage treatment. Once again with the usual caveats—patients who enroll on trials may not represent all patients—this was a good result.

In a Phase 1b clinical trial, 47 patients with advanced pancreatic cancer were treated with pegilodecakin alone or pegilodecakin in combination with FOLFOX.10 Pegilodecakin plus FOLFOX produced a disease control rate of 74%, an objective response rate of 16%, and a complete response rate of 11%. With single-agent pegilodecakin, 53% of patients achieved disease control, but there were no responders. Median overall survival with the combination was 10.2 months, with 43% of patients alive at 1 year. The combination increased immune stimulatory cytokines and also the presence of new T-cell clones. The magnitude of the expansion of new T-cell clones correlated with a longer overall survival. Combination treatment was well tolerated, and when pegilodecakin was given on a modified dose schedule (5 days on, 2 days off), no grade 3/4 hematologic adverse events occurred.

Pegilodecakin is being further evaluated in a large international Phase 3 trial called SEQUOIA (NCT02923921), for which I am the principal investigator.11 The study will compare the efficacy of pegilodecakin in combination with FOLFOX chemotherapy versus FOLFOX alone in 566 patients with metastatic pancreatic cancer who progressed during or after gemcitabine. The FDA has already granted pegilodecakin Fast Track status, in combination with FOLFOX chemotherapy in the second-line setting.

CH: Moving away from immune-targeting agents, let’s discuss CPI-613. I understand a clinical trial of this agent will soon begin in the first-line setting.

Dr. Hecht: With CPI-613 we go back to the idea that we can still help cancer patients without immunotherapy. CPI-613, which is first in its class, takes advantage of the metabolic differences between pancreatic cancer cells and normal cells that make them resistant to standard chemotherapies. CPI-613 targets enzymes that are involved in cancer cell energy metabolism and are located in the mitochondria of cancer cells. It was designed to block two pathways in the mitochondrial tricarboxylic acid (TCA) cycle, which is a necessary process for tumor cell multiplication and survival. The drug’s attack on the TCA cycle is thought to substantially increase the sensitivity of cancer cells to a diverse range of cytotoxic agents.12

In preclinical studies, this approach appeared to be very effective, and in a small Phase 1b trial of 20 previously untreated patients the combination of CPI-613 and a modified FOLFIRINOX produced an extremely high response rate.13 Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective response, with a few complete responses. This is very unusual in pancreatic cancer, and the duration of the response in the robust responders was extremely long.

CH: A Phase 3 trial of CPI-613 has been planned, correct?

Dr. Hecht: Yes. The Phase 3 trial (NCT03504423) is opening its first study center soon in the U.S., and it will ultimately involve 100 study sites in 10 countries.14 The targeted enrollment is 500 patients with metastatic adenocarcinoma of the pancreas. Patients will be receiving FOLFIRINOX or modified FOLFIRINOX plus CPI-613.

CH: The “stemness inhibitor” napabucasin (BBI608) seems to be a very different type of agent in the pipeline. What can you tell us about this drug?

Dr. Hecht: Napabucasin is another drug that is not an immunotherapeutic. One of the reasons that we don’t cure cancer with chemotherapy pertains to stem cells. Stem cells are immortal, chemotherapy-resistant cells that may remain after we kill off other cancer cells. The idea is that if we could inhibit stem cells or “stemness” we could either control cancer long-term or make cancer cells more sensitive to chemotherapy. To tackle this problem a number of drugs are in development, and the one that is furthest along is the orally available small molecule napabucasin. It specifically blocks STAT3, which is part of the signaling pathway and which is critical for maintaining cancer stemness, and then downstream from that the stemness markers Nanog, Klf4, survivin, C-myc, and β-catenin.15

Boston BioMedical has launched several large trials in combination with other agents. In pancreatic cancer, a Phase 1b/2 trial of 59 patients treated with napabucasin plus nab-paclitaxel/gemcitabine was reported at the 2018 ASCO Annual Meeting. For the 50 patients with on-study tumor assessments, the disease control rate was 92%, with 2 complete responses (4%) and 26 partial responses (52%).16 Median overall survival was 9.6 months. The large Phase 3 CanStem111P trial (NCT02993731) is currently underway.17

CH: Let’s discuss the monoclonal antibody cabiralizumab (FPA008).

Dr. Hecht: Again, with cabiralizumab, we are trying to do something novel—wake up the immune response. One way the immune response is inhibited is through immunosuppressive tumor-associated macrophages (TAMs), which are abundant in pancreatic cancer and which are associated with poor response to treatment. We want to inhibit inhibitory TAMs and one way is through the CSF-1 (colony-stimulating factor-1) receptor on the surface of TAMs. A number of companies are developing CSF-1 receptor inhibitors, but cabiralizumab may be the furthest along.

The use of cabiralizumab to inhibit TAMs may increase the efficacy of checkpoint inhibitors, therefore, the drug is being studied in combination with anti-PD-1/PD-L1 agents. A Phase 1b trial of cabiralizumab plus nivolumab was presented at SITC [Society for Immunotherapy of Cancer] last year by my colleague at UCLA, Dr. Zev Wainberg.18 As we know, while only a small subset of patients derive benefit from immunotherapy, when they do, they benefit a great deal. In his study, the response rate was only 13%, but durable clinical benefit was seen in 16% of patients.

CH: What’s next with this drug?

Dr. Hecht: The company has opened a large Phase 2 trial (NCT03336216) with three arms: cabiralizumab plus nivolumab; cabiralizumab plus nivolumab and nab-paclitaxel/gemcitabine; and cabiralizumab plus nivolumab and FOLFOX.19

CH: Would you comment on a large study of a drug that is already available to clinicians, olaparib. What are your thoughts about olaparib maintenance, which is being evaluated in the large Phase 3 POLO trial?

Dr. Hecht: PARP inhibitors cause double stranded breaks in DNA and are particularly effective in tumors with BRCA mutations. These are relatively uncommon in pancreatic cancer (3%-5%) but which can be detected with next-generation sequencing. Combining with agents like platins that cause DNA breaks may be even more effective. A prospective, randomized trial funded by the National Cancer Institute is evaluating cisplatin and gemcitabine with or without a PARP inhibitor in patients with germline BRCA mutations.20 There is also a registration trial called POLO (NCT021841) that is evaluating the PARP inhibitor olaparib as maintenance therapy in patients whose disease has been controlled on platinum-based therapy, similar to an approach now taken with ovarian and breast cancer.21

While there is some optimism that PARP inhibitors will become part of the treatment approach for patients with germline and somatic BRCA mutations, it’s still unclear as to whether they have a role beyond those tight criteria in a broader pancreatic cancer patient population. PARP inhibitors also have toxicities and they can overlap with those related to chemotherapy, particularly hematologic toxicity, so it’s hard to combine them with full-dose chemotherapy. This is one reason the maintenance concept makes sense. You can treat patients with chemotherapy, then put them on a maintenance therapy that is oral, which is very attractive.

CH: Drugs targeting PD-1 have been shown to effectively treat solid tumors that are microsatellite instable-high (MSI-H) or mismatch repair-deficient (dMMR), and in 2017 pembrolizumab was approved for this indication. Is this impacting research in and treatment of pancreatic cancer?

Dr. Hecht: Yes. It’s very important to check patients for MSI status. While MSI-H is rarer in pancreatic cancer than in colon or gastric cancers, when we find it, it can make a world of difference. Treatment with pembrolizumab has showed robust benefit in pancreatic cancer patients, though the study populations have been very small.22-24 The PD-1 inhibitor nivolumab may also prove effective in pancreas cancer patients with dMMR/MSI-high tumors, based on a 17-patient study reported at the 2017 ASCO Annual Meeting in which all 6 treatment-naïve patients achieved stable disease or better.25 Testing for dMMR, therefore, has been included in the NCCN Guidelines for Pancreatic Cancer.

This is one reason I emphasize that patients should have their tumors genetically examined by next-generation sequencing. Even though most will not have a tumor that is sensitive to a current drug, if you don’t ask, you’ll never find the patients who do.

CH: Any final comments on clinical trials in pancreatic cancer?

Dr. Hecht: Especially with a disease that is as challenging as pancreatic cancer, clinical trials are critical. It’s really important for physicians to know about these clinical trials and for patients to at least consider enrolling, if one is available to them.

References

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  2. Hingorani SR, Harris WP, Hendifar AE, et al. High response rate and PFS with PEGPH20 added to nab-paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients with high-HA tumors: Interim results of a randomized phase II study. J Clin Oncol. 2015;33(suppl). Abstract 4006.
  3. Ramanathan RK, McDonough S, Philip PA, et al. A phase IB/II randomized study of mFOLFIRINOX (mFFOX) + pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma: SWOG S1313 (NCT #01959139). 2018 Gastrointestinal Cancers Symposium. Abstract 208.
  4. Clinicaltrials.gov. Identifier NCT02715804. A Study of PEGylated Recombinant Human Hyaluronidase in Combination with Nab-Paclitaxel Plus Gemcitabine in Participants With Hyaluronan-High Stage IV Previously Untreated Pancreatic Ductal Adenocarcinoma. Accessed September 24, 2018.
  5. Clinicaltrials.gov. Identifier NCT03634332. Second-line Study of PEGPH20 and Pembro for HA High Metastatic PDAC. Accessed September 24, 2018.
  6. Clinicaltrials.gov. Identifier NCT03481920. A Trial of PEGPH20 in Combination With Avelumab in Chemotherapy Resistant Pancreatic Cancer
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  11. Clinicaltrials.gov. Identifier NCT02923921. A Study of AM0010 with FOLFOX Compared to FOLFOX Alone as Second-Line Treatment in Patients with Metastatic Pancreatic Cancer. Accessed September 24, 2018.
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  14. Clinicaltrials.gov. Identifier NCT03504423. This is a Trial of 500 Patients with Metastatic Adenocarcinoma of the Pancreas. Accessed September 24, 2018.
  15. Boston Biomedical. STAT3 Pathway. https://www.bostonbiomedical.com/science/cancer-stem-cells/stat3-pathway/. Accessed September 24, 2018.
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  17. Clinicaltrials.gov. Identifier NCT02993731. A Study of Napabucasin Plus Nab-Paclitaxel With Gemcitabine in Adult Patients With Metastatic Pancreatic Adenocarcinoma. Accessed September 24, 2018.
  18. Wainberg Z, Piha-Paul S, Luke J, et al. First-in-human phase 1 dose escalation and expansion of a novel combination, anti–CSF-1 receptor (cabiralizumab) plus anti–PD-1 (nivolumab), in patients with advanced solid tumors. Society for Immunotherapy of Cancer 2017 Annual Conference. Abstract O42.
  19. Clinicaltrials.gov Identifier NCT03336216. A Study of Cabiralizumab Given With Nivolumab With and Without Chemotherapy in Patients With Advanced Pancreatic Cancer. Accessed September 24, 2018.
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