Clinical trial NCT02563548: A Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) With Pembrolizumab in Participants With Selected Hyaluronan High Solid Tumors
Official title: A Phase 1B Open-Label Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) Combined With Pembrolizumab in Subjects With Selected Hyaluronan-High Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: NSCLC
Gastric Cancer
Lead sponsor: Halozyme Therapeutics
Sponsor class: INDUSTRY
First posted: 2015-09-30
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 1b study evaluating a combination of PEGPH20 and pembrolizumab in hyaluronan-high (HA-high) participants with relapsed/refractory non-small cell lung cancer (NSCLC) and HA-high participants with relapsed/refractory gastric adenocarcinoma (GAC).

Detailed description: Study involves dose escalation phase (completed in Nov-2016) to assess the safety and tolerability of PEGPEM (PEGylated recombinant human hyaluronidase \[PEGPH20\] combined with pembrolizumab \[Keytruda®\]) and to find the recommended Phase 2 dose (RP2D) ; and an expansion phase to assess the efficacy, safety and tolerability of PEGPEM in stage III b/IV NSCLC and relapsed/refractory GAC participants. Plan was to include approximately 51 HA-high participants (30 NSCLC and 21 GAC participants) in the dose expansion phase on the obtained RP2D from dose escalation phase of the study.

Eligibility criteria: Inclusion Criteria:

* Dose Expansion: Histologically confirmed and documented, previously untreated or treated stage IIIB or IV NSCLC having failed no more than 1 previous platinum containing chemotherapy regimen for locally-advanced or metastatic disease or relapsed/refractory locally advanced or metastatic gastric adenocarcinoma having failed no more than 2 previous chemotherapy regimens for locally advanced or metastatic disease. Participants with NSCLC who are known to be epidermal growth factor receptor (EGFR)-mutation positive must have received an EGFR inhibitor and participants known to be anaplastic lymphoma kinase (ALK)-mutation positive must have received an ALK inhibitor.

Prior to enrollment, confirmation of the following must be obtained:

• For participants in the dose expansion portion of the study, it is mandatory that available archived tumor tissue in formalin-fixed.

paraffin-embedded (FFPE) block or minimum 10-15 unstained consecutive core biopsy slides from 1 archival block that meet specific tissue requirements are available.

* For dose expansion: one or more tumors measurable on computed tomography (CT) scan/magnetic resonance imaging (MRI) scan per RECIST v 1.1., for dose escalation, participants need only have evaluable disease - Previously irradiated tumors may be eligible if they have clearly progressed in size.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
* Life expectancy greater than or equal to (≥) 3 months.

Participants must also satisfy the following inclusion criterion to be enrolled in the dose expansion portion:

* Participants (NSCLC and gastric adenocarcinoma) must be determined to have HA-high levels from their tumor biopsies.
* NSCLC and gastric adenocarcinoma participants must have tissue available for HA-selection and programmed cell death-1 (PD-L1) testing.

Exclusion Criteria:

* Previous treatment with pembrolizumab, nivolumab, or other antibody (anti-)-PD-1 or PD-1 ligand-antibody (anti-PD-L1) agents.
* New York Heart Association Class III or IV (Appendix D) cardiac disease or myocardial infarction within the past 12 months before screening, or preexisting atrial fibrillation.
* Prior history of cerebrovascular accident or transient ischemic attack.
* NSCLC participants with known brain metastases (certain exceptions allowed)
* Gastric adenocarcinoma participants with brain metastases
* History of active bleeding within the last 3 months requiring transfusion
* Anti-angiogenic therapy within the last month
* Participants with known interstitial fibrosis or interstitial lung disease.
* Previous history of pulmonary embolism or pulmonary embolism found on screening exam.
* History of:

  1. Pneumonitis that requires oral or IV steroids;
  2. Or known cases of hepatobiliary diseases (e.g., primary biliary cholangitis, primary sclerosing cholangitis, history of immune-mediated cholangitis);

     * Participants with cholangitis attributed to infectious etiology (e.g., ascending cholangitis, bacterial cholangitis) are eligible if the infection has been fully resolved prior to the screening visit.
  3. Or known cases of drug-induced hepatobiliary toxicities.
* Active autoimmune disease requiring systemic treatment within the past 3 months or documented history of clinically severe autoimmune disease, or syndrome that requires systemic steroids or immunosuppressive agents.
* History of another primary cancer within the last 3 years that required treatment, with the exception of non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical carcinoma in situ.

Primary outcomes:
measure: Dose-Escalation Phase: Number of Participants With Dose-Limiting Toxicity (DLT)
timeFrame: Cycle 1 (21 days)
measure: Dose-Escalation Phase: Maximum Tolerated Dose (MTD) of PEGPH20 in Combination With Pembrolizumab
timeFrame: Cycle 1 (21 days)
measure: Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of PEGPH20 in Combination With Pembrolizumab
timeFrame: Cycle 1 (21 days)
measure: Dose Expansion Phase: Objective Response Rate (ORR): Percentage of Participants With Objective Response, as Assessed by Investigator Based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: Cycle 1 Day 1 of dose-expansion phase until death, disease progression, or unacceptable toxicity (maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC)
Secondary outcomes:
measure: Dose-Escalation Phase: ORR: Percentage of Participants With Objective Response, as Assessed by Investigator Based on RECIST Version 1.1
timeFrame: Cycle 1 Day 1 of dose-escalation phase until death, disease progression, or unacceptable toxicity (maximum exposure: 46 weeks for GAC, and 27 weeks for NSCLC)
measure: Dose-Escalation and Expansion Phase: Duration of Response (DOR), as Assessed by Investigator Based on RECIST v1.1
timeFrame: From date of first objective response (CR or PR) until date of first radiographic disease progression (maximum exposure: 46 weeks for GAC, and 27 weeks for NSCLC in dose-escalation; 60 weeks for GAC, and 46 weeks for NSCLC in dose-expansion)
measure: Dose-Escalation and Expansion Phase: Disease Control Rate (DCR), as Assessed by Investigator Based on RECIST v1.1: Percentage of Participants Who Achieved CR, PR or Stable Disease (SD)
timeFrame: From first dose until first occurrence of CR, PR or SD (maximum exposure: 46 weeks for GAC, and 27 weeks for NSCLC in dose-escalation phase; maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC in dose-expansion phase)
measure: Dose-Escalation and Expansion Phase: Progression-Free Survival (PFS), as Assessed by Investigator Based on RECIST v1.1
timeFrame: From first dose until first occurrence of either radiographic or clinical disease progression or death (maximum exposure: 46 weeks for GAC, and 27 weeks for NSCLC in dose-escalation; 60 weeks for GAC, and 46 weeks for NSCLC in dose-expansion)
measure: Dose-Escalation and Expansion Phase: Overall Survival
timeFrame: From first dose until death from any cause (maximum exposure: 46 weeks for GAC, and 27 weeks for NSCLC in dose-escalation phase; maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC in dose-expansion phase)
measure: Dose Expansion Phase: Objective Response Rate (ORR): Percentage of Participants With Objective Response, as Assessed by Investigator Based on Immune-Response Related Criteria (irRC)
timeFrame: Cycle 1 Day 1 of dose-expansion phase until death, disease progression, or unacceptable toxicity (maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC)
measure: Dose- Expansion Phase: DOR, as Assessed by Investigator Based on irRC
timeFrame: From the date of first objective response (CR or PR) until the date of first radiographic disease progression (maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC)
measure: Dose- Expansion Phase: DCR, as Assessed by Investigator Based on irRC: Percentage of Participants Who Achieved CR, PR or SD
timeFrame: From first dose until first occurrence of CR, PR or SD (maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC)
measure: Dose- Expansion Phase: PFS, as Assessed by Investigator Based on irRC
timeFrame: From first dose until the first occurrence of either radiographic or clinical disease progression or death from any cause (maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC)
measure: Dose-Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of PEGPH20
timeFrame: Pre PEGPH20 dose (within 2 hours [hrs] pre-dose); 0.25,1, 2-4, and 6-8 hrs post PEGPH20 dose at Cycle 1 Day 1 (cycle length = 21 days)
measure: Dose-Escalation and Expansion Phase: Terminal Elimination Half-Life (t1/2) of PEGPH20
timeFrame: Pre PEGPH20 dose (within 2 hours [hrs] pre-dose); 0.25,1, 2-4, and 6-8 hrs post PEGPH20 dose at Cycle 1 Day 1 (cycle length = 21 days)
measure: Dose-Escalation and Expansion Phase: Area Under the Plasma Concentration Vs. Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) of PEGPH20
timeFrame: Pre PEGPH20 dose (within 2 hours [hrs] pre-dose); 0.25,1, 2-4, and 6-8 hrs post PEGPH20 dose at Cycle 1 Day 1 (cycle length = 21 days)
measure: Dose-Escalation and Expansion Phase: Volume of Distribution (Vd) of PEGPH20
timeFrame: Pre PEGPH20 dose (within 2 hours [hrs] pre-dose); 0.25,1, 2-4, and 6-8 hrs post PEGPH20 dose at Cycle 1 Day 1 (cycle length = 21 days)
measure: Dose-Escalation and Expansion Phase: Clearance (CL) of PEGPH20
timeFrame: Pre PEGPH20 dose (within 2 hours [hrs] pre-dose); 0.25,1, 2-4, and 6-8 hrs post PEGPH20 dose at Cycle 1 Day 1 (cycle length = 21 days)
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Cycle 1 Day 1 up to 30 days after last dose of study drug (maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC)
measure: Dose-Expansion Phase: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters and Vital Signs
timeFrame: Cycle 1 Day 1 up to 30 days after last dose of study drug (maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC)
measure: Dose-Expansion Phase: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)
timeFrame: Cycle 1 Day 1 up to 30 days after last dose of study drug (maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic, Scottsdale, Arizona
state: Arizona
city: Encinitas
country: United States
facility: California Cancer Associates for Research and Excellence - Encinitas
state: California
city: La Jolla
country: United States
facility: University of California San Diego - Moores Cancer Center
state: California
city: Orange
country: United States
facility: St. Joseph's Hospital
state: California
city: Sacramento
country: United States
facility: University of California - Davis
state: California
city: Santa Rosa
country: United States
facility: St. Joseph's Hospital
state: California
city: Whittier
country: United States
facility: Innovative Clinical Research
state: California
city: Aurora
country: United States
facility: University of Colorado Denver University of Colorado Anschutz Medical Campus
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospitals
state: Florida
city: Miami
country: United States
facility: University of Miami/Sylvester Cancer Center
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Kimmel Cancer Center
state: Maryland
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Center
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Brick
country: United States
facility: New Jersey Hematology Oncology Associates
state: New Jersey
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Seattle
country: United States
facility: Swedish Health Services
state: Washington
Study officials:
affiliation: Halozyme Therapeutics
name: VP, Clinical Development
role: STUDY_DIRECTOR
References: