Condition or disease | Intervention/treatment | Phase |
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Pancreatic Ductal Adenocarcinoma | Drug: Atezolizumab Drug: PEGPH20 | Phase 2 |
Presently, surgical resection offers the only therapeutic means of cure. However only 15%-20% of patients are found to have resectable disease at time of initial diagnosis. Of the patients who undergo curative surgery, most will relapse and eventually succumb to the disease. 5-year survival rates for node-negative and -positive disease at time of pancreatic duodenectomy are 25%-30% and 10%, 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.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 1 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Intervention Model Description: | Randomized phase 2 trial for a total of 20 patients per cohort |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A Phase 2, Open-Label, Multicenter, Randomized Study Evaluating NEOadjuvant Immunotherapy Based Combinations in Patients With Resectable PANCreatic Ductal Adenocarcinoma |
Actual Study Start Date : | November 1, 2019 |
Actual Primary Completion Date : | November 3, 2019 |
Actual Study Completion Date : | November 3, 2019 |
Arm | Intervention/treatment |
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Active Comparator: Atezolizumab
Atezolizumab 840mg IV every 2 weeks for 2 doses prior to surgery and 4 doses after surgery.
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Drug: Atezolizumab
840mg IV every 2 weeks for 2 doses prior to surgery and 4 doses after surgery.
Other Name: Tecentriq
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Experimental: Atezolizumab in combination with PEGPH20
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.
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Drug: Atezolizumab
840mg IV every 2 weeks for 2 doses prior to surgery and 4 doses after surgery.
Other Name: Tecentriq
Drug: PEGPH20 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.
Other Name: pegvorhyaluronidase alfa
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Ages Eligible for Study: | 18 Years to 99 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Exclusion Criteria for PEGPH20-Containing Arm Patients who meet any of the following criteria will be excluded from the PEGPH20- containing arm:
Criteria to initiate chemotherapy
United States, New York | |
Columbia University | |
New York, New York, United States, 10032 |
Principal Investigator: | Gulam Manji, MD, PhD | Columbia University |
Tracking Information | |||||||
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First Submitted Date ICMJE | June 6, 2019 | ||||||
First Posted Date ICMJE | June 7, 2019 | ||||||
Results First Submitted Date ICMJE | December 1, 2020 | ||||||
Results First Posted Date ICMJE | December 23, 2020 | ||||||
Last Update Posted Date | December 23, 2020 | ||||||
Actual Study Start Date ICMJE | November 1, 2019 | ||||||
Actual Primary Completion Date | November 3, 2019 (Final data collection date for primary outcome measure) | ||||||
Current Primary Outcome Measures ICMJE |
Change in the Number of CD8+ T Cells Within the Tumor [ Time Frame: At time of surgery (approximately 3 weeks) ] 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.
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Original Primary Outcome Measures ICMJE |
Number of CD8+ T cells within the tumor [ Time Frame: At time of surgery (approximately 3 weeks) ] 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.
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Change History | |||||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE |
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Current Other Pre-specified Outcome Measures | Not Provided | ||||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||||
Descriptive Information | |||||||
Brief Title ICMJE | Study Evaluating NEOadjuvant Immunotherapy in Resectable PANCreatic Ductal Adenocarcinoma | ||||||
Official Title ICMJE | A Phase 2, Open-Label, Multicenter, Randomized Study Evaluating NEOadjuvant Immunotherapy Based Combinations in Patients With Resectable PANCreatic Ductal Adenocarcinoma | ||||||
Brief Summary | The purpose of this study is to determine if study treatment with atezolizumab and PEGPH20 given before and after surgery, followed by chemotherapy is safe and if it can further increase the immune response against the tumor rather than increase the chance of cure. | ||||||
Detailed Description |
Presently, surgical resection offers the only therapeutic means of cure. However only 15%-20% of patients are found to have resectable disease at time of initial diagnosis. Of the patients who undergo curative surgery, most will relapse and eventually succumb to the disease. 5-year survival rates for node-negative and -positive disease at time of pancreatic duodenectomy are 25%-30% and 10%, 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. |
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Study Type ICMJE | Interventional | ||||||
Study Phase ICMJE | Phase 2 | ||||||
Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: Randomized phase 2 trial for a total of 20 patients per cohort Masking: None (Open Label)Primary Purpose: Treatment |
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Condition ICMJE | Pancreatic Ductal Adenocarcinoma | ||||||
Intervention ICMJE |
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Study Arms ICMJE |
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Publications * | Not Provided | ||||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||||
Recruitment Status ICMJE | Terminated | ||||||
Actual Enrollment ICMJE |
1 | ||||||
Original Estimated Enrollment ICMJE |
40 | ||||||
Actual Study Completion Date ICMJE | November 3, 2019 | ||||||
Actual Primary Completion Date | November 3, 2019 (Final data collection date for primary outcome measure) | ||||||
Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
Exclusion Criteria for PEGPH20-Containing Arm Patients who meet any of the following criteria will be excluded from the PEGPH20- containing arm:
Criteria to initiate chemotherapy
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years to 99 Years (Adult, Older Adult) | ||||||
Accepts Healthy Volunteers ICMJE | No | ||||||
Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||||
Listed Location Countries ICMJE | United States | ||||||
Removed Location Countries | |||||||
Administrative Information | |||||||
NCT Number ICMJE | NCT03979066 | ||||||
Other Study ID Numbers ICMJE | AAAS1908 | ||||||
Has Data Monitoring Committee | Yes | ||||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE | Not Provided | ||||||
Responsible Party | Gulam Manji, Columbia University | ||||||
Study Sponsor ICMJE | Gulam Manji | ||||||
Collaborators ICMJE |
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Investigators ICMJE |
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PRS Account | Columbia University | ||||||
Verification Date | December 2020 | ||||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |