%, respectively.
Although early phase trials have not offered great success in the metastatic setting for patients with pancreas adenocarcinoma (PDA), interim analysis of a multicenter, phase 1 trial with durvalumab presented at European Society for Medical Oncology (ESMO) indicated a disease control rate of 21%. As mentioned previously, PD-L1 expression correlates with poor prognosis and decreased CD4+ and CD8+ T cell infiltration within the tumor. Targeting PD-L1 in the micrometastatic setting (resectable disease), when robust mature immunosuppressive pathways may not have yet formed, may be the optimum time to investigate anti-PD-L1 therapy. This arm of the study aims to test if atezolizumab is able to modulate CD8+ T-cell infiltration compared to historical matched controls. As a secondary endpoint we will also evaluate how clinical outcomes compare to matched historical controls.
Neoplastic, immune, and stromal cells within PDA reside in a highly dense desmoplastic environment composed of an extracellular matrix of which hyaluronidase (HA) is an abundant component. HA is a linear glycosaminoglycan and an integral component of not only PDA tumors, but has also been shown to accumulate in many solid tumors and is associated with a poor prognosis and increased immunosuppression. In a preclinical autochthonous mouse model of PDA, Sunil Hingorani's group demonstrated that the interstitial fluid pressures were unusually high within tumors that exhibited a high HA content. Furthermore, high HA tumors contained low vascularity, which compromised delivery of chemotherapeutic agents, such as gemcitabine. Mice treated with hyaluronidase resulted in decreased HA content and microvasculature re-expansion within tumors which led to a survival benefit. These preclinical studies led to early phase clinical studies in metastatic PDA where addition of PEGPH20 to gemcitabine and nab-paclitaxel (GA) in a randomized phase 2 study demonstrated a survival benefit in patients with HA-high tumors. The objective response rate for patients who were treated with a combination of PEGPH20 and GA compared to GA alone was 45% versus 31%, respectively, and the median overall survival was 11.5 versus 8.5 months, respectively (hazard ratio (HR), 0.96; 95% Confidence Interval (CI), 0.57 to 1.61). A large phase 3 randomized clinical trial in the high HA stage IV PDA population in the first line setting is ongoing.
PDA likely invokes multiple immune evading mechanisms which result in its aggressive behavior; it is expected that multiple agents will likely be needed to develop effective therapies. One such rationale is the combination of PEGPH20 and immune checkpoint blockade to allow increased cytotoxic T-cell infiltration by increasing vascular permeability and decreasing interstitial pressure. In a breast cancer preclinical model, PEGPH20 resulted in an increase accumulation of CD8+ tumor-infiltrating lymphocytes (TIL) by 176% (p=0.0025) and improved tumor growth inhibition by 38% relative to anti-PD-L1 alone (86% vs 62.4%, p=0.0024). Other preclinical studies are also demonstrating increased CD8+ T-cell infiltration with addition of PEGPH20 and improved tumor control in combination with immune checkpoint blockade. These and other preclinical studies suggest that this combination is worth pursuing in patients with resectable PDA. The combination is hoped to increase CD8+ T-cell infiltration within the primary tumor for improved immune mediated cytotoxicity and decreased interstitial pressure to allow improved surgical resections. Hypothetically, the combination should also be effective in foci of micrometastasis, where the tumor microenvironment (TME) may not be as mature.
Identified risks for PEGPH20 include musculoskeletal events (MSEs), infusion-related reactions (IRRs), and thromboembolic (TE) events.
Atezolizumab 840mg IV every 2 weeks for 2 doses prior to surgery and 4 doses after surgery.
Atezolizumab 840mg IV every 2 weeks for 2 doses prior to surgery and 4 doses after surgery in combination with PEGPH20 3ug/kg IV twice weekly for 3 weeks prior to surgery and once weekly for 3 weeks (of 28 day cycle) for two cycles after surgery.
The change in number of intratumoral CD8+ T-cells the at time of surgery between treatment arm(s) compared to the atezolizumab arm. The CD8+ T-cell count within the tumor with neoadjuvant atezolizumab vs atezolizumab + PEGPH20 at the time of surgery will be reported using means and standard deviations by group and will be compared using a twosample T-test. If the data are not normally distributed, non-parametric models such as the Wilcoxon Rank Sum test will be used. Moreover, the distribution of CD8+ T-cell count by treatment arm will be assessed using box plots, histograms, and q-q plots.
To estimate the 18-month survival rate in patients treated with atezolizumab vs atezolizumab + PEGPH20 followed by surgery and adjuvant therapy.
To estimate the overall survival in patients treated with atezolizumab vs atezolizumab + PEGPH20 followed by surgery and adjuvant therapy.
To determine the R0 resection rates with atezolizumab vs atezolizumab + PEGPH20 administered in the neoadjuvant setting. R0 resection rate is defined by the proportion of patients in whom an R0 resection was achieved during surgery. R0 resection is defined by complete removal of macroscopic tumor which contains negative microscopic surgical margins. The R0 resection rate will be estimated by the number of patients in whom R0 resection was performed divided by total number of patients in each study arm. The R0 resection rate will be reported along with the exact 95% confidence interval. The investigators will compare the R0 resection rates using Fisher's exact test.
To determine the safety profile with atezolizumab vs atezolizumab + PEGPH20 or other therapies followed by surgery and adjuvant therapy. The frequency and count of grade 3 or higher adverse events will be reported by treatment group. The maximum grade for each type of adverse event will also be reported.
No prior surgical, systemic or radiotherapy for PDA.
Minimum age of at least 18 years.
Women of child-bearing potential must have a negative serum pregnancy test at screening and must agree to use two forms of effective contraception from the time of the negative pregnancy test and for a minimum of 5 months after the last dose of study drug. Women will be considered not of child-bearing potential if amenorrheic at least for one year or have undergone surgical sterilization.
Fertile men must agree to use an effective method of birth control during the study and for up to 5 months after the last dose of study drug.
Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, including but not limited to anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
Patient receiving therapeutic doses of anticoagulation.
Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy.
Positive HIV test at screening or at any time prior to screening. Patients without a prior positive HIV test result will undergo an HIV test at screening, unless not permitted per local regulations.
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment except for biliary tract infection due to bile duct obstruction from the pancreas mass. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 12 months prior to initiation of study treatment, seizure disorder, uncontrolled hypertension, or unstable arrhythmia or unstable angina within 3 months prior to initiation of study treatment.
Grade ≥3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment.
Prior autologous stem cell, allogeneic stem cell, or solid organ transplantation.
History of malignancy other than PDA within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year overall survival of > 90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. Patients with history of prior malignancies should have risk of recurrence within 3 years after screening to be less than 90% (to be discussed with the PI for final determination of eligibility).
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during treatment with atezolizumab or within 5 months after the last dose of atezolizumab.
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2) within 4 weeks or five half-lives of the drug (whichever is longer) prior to initiation of study treatment.
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study if receiving equivalent to less than 10mg of prednisone daily.
Patients who received a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after approval from the PI has been obtained.
Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents and breastfeeding should be discontinued.
Major surgical procedure or significant traumatic injury within 14 days of initiating study.
Previous radiotherapy to 25% or more of the bone marrow.
Any other disease, metabolic dysfunction, physical examination finding, or