Second-line Study of PEGPH20 and Pembro for HA High Metastatic PDAC

Brief summary public domain (ClinicalTrials.gov)

This study is the study of the combination of PEGPH20 and Pembrolizumab (MK-3475) for patients with previously treated Hyaluronan High (HA-high) metastatic pancreatic ductal adenocarcinoma. This study is an interventional, unblinded, open label study. Approximately 35 subjects will be enrolled. The trial will require approximately a total of 18 months, including 12 months for enrollment, with an additional 6 months for patient follow-up, data collection and study closure. Each subject will participate in the trial from the time the subject signs the Informed Consent Form (ICF) through the final contact. After a screening phase of up to 21 days, eligible subjects will receive PEGPH20 beginning with Cycle 1 Day 1, on Days 1, 8 15 of every 3 week-cycles and pembrolizumab beginning on Cycle 1 Day 1 (2-4 hrs after PEGPH20), every 3-week-cycles. Treatment with PEGPH20 and pembrolizumab will continue until progressive disease (PD), unacceptable adverse events (AEs), intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or procedure requirements, subject receives 35 treatments (approximately 24 months) of pembrolizumab, or administrative reasons requiring cessation of treatment. Subjects who discontinue for reasons other than PD will have post-treatment follow-up for disease status until PD, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. All subjects will be followed by telephone for overall survival (OS) until death, withdrawal of consent, or the end of the study. After the end of treatment, each subject will be followed for 30 days for AE monitoring. Serious adverse events (SAE) and events of clinical interest (ECI) will be collected for 90 days after the end of treatment or for 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.

Detailed description public domain (ClinicalTrials.gov)

Combination strategies geared towards blocking the PD1/PD-L1 inhibitory pathway, such as with pembrolizumab, concurrent with stroma depletion (PEGPH20) may induce synergistic anti-cancer activity and immune responses in pancreatic cancer. Effective harnessing of the immune system and rational combinations with stroma-targeting biological agents (PEGPH20) is a novel field that needs to be explored in pancreatic cancer. This phase II trial will determine the efficacy of pembrolizumab plus PEGPH20 in metastatic pancreatic cancer patients who have HA-high tumor expression. Stroma and immune-related biomarkers will be tested prospectively in blood and tumor biopsies at baseline, after 6 weeks of therapy, and at time of cancer progression. A phase I study with pembrolizumab and PEGPH20 is ongoing in lung and gastric cancer patients (NCT02563548), and demonstrated safety and tolerability of this combination at the doses administered in this study (Halozyme data). Immunotherapies have the potential to induce durable therapeutic responses although this typically occurs in a small fraction of patients. Biomarker-guided patient selection can, in principle, identify those patients most likely to benefit. The investigators hypothesize that stroma remodeling with PEGPH20 will potentiate effector CD8 T cell lymphocyte infiltration and sensitize pancreatic cancer to immune therapy, and that immunologic, and/or genomic biomarkers will identify patient subsets most likely to benefit. As examples, MSI-high status and high tumor mutational burden (hypermutation) have been linked to sensitivity to immune checkpoint inhibitors (Le et al. 2015, Le et al. 2016). Assays may include but are not limited to: Immunohistochemical analysis, profiling of the immune transcriptome, circulating cytokine analyses, flow cytometric analyses of peripheral and intratumoral immune response. This is an open label non-randomized Phase II trial for patients with previously treated metastatic ductal pancreatic adenocarcinoma with HA-high expression, to assess the progression-free survival rate (PFS) of patients treated with this combination therapy. Secondary endpoints will assess safety and tolerability, overall response rate (ORR), disease control rate (DCR= CR+PR+SD), duration of response and stable disease (DOR), and overall survival (OS). There will be an estimated 35 patients enrolled into the study, using 5 centers in the U.S. Overall response rates as well as individual categories of response (CR, PR, SD, and PD) will be determined using RECIST 1.1. Time-to-event endpoints, including PFS and OS will be assessed using the Kaplan-Meier method. Toxicity (adverse events) will be recorded using the NCI CTCAE, version 5.0 (published Nov 2017, Appendix B). All patients will start treatment with PEGPH20 3 microgram/kg IV weekly x 3, and pembrolizumab 200 mg IV every 3 weeks, in 3-week cycles. Patients may remain on treatment with PEGPH20 in combination with pembrolizumab as long as they are receiving clinical benefit, until disease progression per RECIST 1.1 criteria, or until untolerable toxicity develops, whichever comes first. If no disease progression, patients will be allowed to remain on study treatment for up to 24 months. If no disease progression, but with unacceptable toxicity from PEGPH20, patients will be allowed to continue on pembrolizumab alone for up to 24 months if deemed appropriate by the investigator. If pembrolizumab needs to be discontinued for toxicity, patients may continue treatment with PEGPH20 alone. The estimated duration for accrual is anticipated to be 12 months. Patients will be followed up for a minimum of 6 months. The overall study duration is estimated at approximately 18 months.

Intervention public domain (ClinicalTrials.gov)

Drug: PEGPH20. PEGPH20 is a PEGylated, neutral-pH-active human hyaluronidase PH20 produced by recombinant DNA technology

Intervention public domain (ClinicalTrials.gov)

Biological: Pembrolizumab. Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2

Arm public domain (ClinicalTrials.gov)

PEGPH20 plus Pembrolizumab (experimental): All patients will receive treatment with PEGPH20 3 micrograms/kg IV weekly x 3, and pembrolizumab 200 mg IV every 3 weeks, in 3-week cycles.

Primary outcome public domain (ClinicalTrials.gov)

Progression Free Survival. Evaluate the progression-free survival (PFS) for patients treated with pembrolizumab and PEGPH20 Time frame: PFS will be assessed from Date of registration through study closure, up to 24 months. PFS is calculated as the number of days from date of registration to date of disease progression or symptomatic deterioration, or death due to any cause..

Secondary outcome public domain (ClinicalTrials.gov)

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0. Time frame: Safety and Tolerability using CTCAE v5.0 will be assessed from Day 1 of study treatment through 30-days past the last study treatment per patient, through study closure, up to 24 months..

Secondary outcome public domain (ClinicalTrials.gov)

Overall Response Rate. Time frame: ORR is assessed from Day 1 of treatment to study closure, up to 24 months. ORR is calculated by adding the Complete Responses (CR) with the Partial Responses (PR), based on RECIST v1.1, recorded at each disease evaluation for each patient..

Secondary outcome public domain (ClinicalTrials.gov)

Disease Control Rate. Time frame: DCR is assessed from Day 1 of treatment to study closure, up to 24 months. DCR is calculated by adding the Complete Responses, Partial Responses and Stable Disease, based on RECIST v1.1, recorded at each disease evaluation for each patient..

Secondary outcome public domain (ClinicalTrials.gov)

Duration of Response. Time frame: DOR is assessed from Day 1 of treatment to study closure, up to 24 months. DOR is calculated for patients who achieve a CR or PR, as the number of days from the date of response to the date of progression, or death, due to any cause..

Secondary outcome public domain (ClinicalTrials.gov)

Overall Survival. Time frame: Overall Survival is assessed from date of registration to study closure, up to 24 months. Overall Survival is calculated as the number of days from date of registration to date of death due to any cause..

Eligibility public domain (ClinicalTrials.gov)

Inclusion Criteria: 1. Be willing and able to provide written informed consent/assent for the trial. 2. Histologically confirmed metastatic pancreatic ductal adenocarcinoma, via archived or fresh core biopsy of either primary tumor or metastatic site. 3. Available tumor tissue (formalin-fixed paraffin-embedded \[FFPE\] block preferred) with enough tumor to make a minimum of 5-10 unstained, consecutive FFPE slides (10 slides are preferred) of 1 archival block that meets specific tissue sample requirements. Archived or fresh tissue from the primary lesion or a metastatic lesion is required. Note: Fine needle aspirates or brushing biopsies will not be acceptable. This tumor tissue requirement is for the determination of the HA-high or -low expression status. 4. Subjects must be determined to be HA-high based on archival or fresh tumor biopsy that meets the requirements noted in the previous inclusion criterion. 5. 18 years of age on day of signing informed consent. 6. Have measurable metastatic disease based on RECIST 1.1. 7. Life expectancy ≥ 12 weeks. 8. Have a performance status of 0 or 1 on the ECOG Performance Scale. 9. Received no more than 2 prior lines of systemic therapy for metastatic disease (1 or 2 prior lines of therapy for metastatic disease are allowed) 10. Be willing to provide tumor tissue from newly obtained tumor cores or excisional biopsy for research purposes. Newly-obtained is defined as a specimen obtained within 2 weeks (14 days) prior to initiation of treatment on Day 1. 11. Be willing to provide tumor tissue from tumor biopsy after 6 weeks of treatment (mandatory, if safe and feasible), and at the time of tumor progression (optional, if safe and feasible). Note: Fine needle aspirates or brushing biopsies will not be acceptable. 12. Demonstrate adequate organ function, all screening labs should be performed within 14 days of treatment initiation. 13. Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 14. Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 15. Male subjects of …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 35 participants (estimated).