A Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) With Pembrolizumab in Participants With Selected Hyaluronan High Solid Tumors

Phase 1

Completed

Conditions: NSCLC
Gastric Cancer

Interventions: Drug: PEGPH20
Drug: Pembrolizumab

Registration Number: NCT02563548

Lead Sponsor: Halozyme Therapeutics

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 56

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GAC: PEGPH20 1.6 µg/kg/2.2 µg/kg + Pembrolizumab	PEGPH20	Dose escalation part: Participants with relapsed/refractory locally advanced or metastatic gastric adenocarcinoma (GAC) will receive PEGPH20 1.6 micrograms/kilogram (µg/kg) or 2.2 µg/kg on Day 1, Day 8 and Day 15 of each 21-day cycle (i.e. 3 doses/cycle) and pembrolizumab 2 milligrams/kilogram (mg/kg) every 21 days on Day 1 of each cycle (i.e. 1 dose/cycle), 4-6 hours after the completion of PEGPH20 administration. Dose expansion part: Participants with relapsed/refractory locally advanced or metastatic GAC will receive PEGPH20 2.2 µg/kg on Day 1, Day 8 and Day 15 of each 21-day cycle and pembrolizumab 200 mg on Day 1 of each cycle, 4-6 hours after the completion of PEGPH20 administration. Treatment in both phases of the study will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (maximum exposure: 60 weeks).
NSCLC: PEGPH20 1.6 µg/kg/2.2 µg/kg + Pembrolizumab	PEGPH20	Dose escalation part: Participants with relapsed/refractory Stage IIIB or IV non-small cell lung cancer (NSCLC) will receive PEGPH20 1.6 µg/kg or 2.2 µg/kg on Day 1, Day 8 and Day 15 of each 21-day cycle (i.e. 3 doses/cycle) and pembrolizumab 2 mg/kg every 21 days on Day 1 of each cycle (i.e. 1 dose/cycle), 4-6 hours after the completion of PEGPH20 administration. Dose expansion part: Participants with relapsed/refractory Stage IIIB or IV NSCLC will receive PEGPH20 2.2 µg/kg on Day 1, Day 8 and Day 15 of each 21-day cycle and pembrolizumab 200 mg on Day 1 of each cycle, 4-6 hours after the completion of PEGPH20 administration. Treatment in both phases of the study will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (maximum exposure: 46 weeks).
GAC: PEGPH20 1.6 µg/kg/2.2 µg/kg + Pembrolizumab	Pembrolizumab	Dose escalation part: Participants with relapsed/refractory locally advanced or metastatic gastric adenocarcinoma (GAC) will receive PEGPH20 1.6 micrograms/kilogram (µg/kg) or 2.2 µg/kg on Day 1, Day 8 and Day 15 of each 21-day cycle (i.e. 3 doses/cycle) and pembrolizumab 2 milligrams/kilogram (mg/kg) every 21 days on Day 1 of each cycle (i.e. 1 dose/cycle), 4-6 hours after the completion of PEGPH20 administration. Dose expansion part: Participants with relapsed/refractory locally advanced or metastatic GAC will receive PEGPH20 2.2 µg/kg on Day 1, Day 8 and Day 15 of each 21-day cycle and pembrolizumab 200 mg on Day 1 of each cycle, 4-6 hours after the completion of PEGPH20 administration. Treatment in both phases of the study will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (maximum exposure: 60 weeks).
NSCLC: PEGPH20 1.6 µg/kg/2.2 µg/kg + Pembrolizumab	Pembrolizumab	Dose escalation part: Participants with relapsed/refractory Stage IIIB or IV non-small cell lung cancer (NSCLC) will receive PEGPH20 1.6 µg/kg or 2.2 µg/kg on Day 1, Day 8 and Day 15 of each 21-day cycle (i.e. 3 doses/cycle) and pembrolizumab 2 mg/kg every 21 days on Day 1 of each cycle (i.e. 1 dose/cycle), 4-6 hours after the completion of PEGPH20 administration. Dose expansion part: Participants with relapsed/refractory Stage IIIB or IV NSCLC will receive PEGPH20 2.2 µg/kg on Day 1, Day 8 and Day 15 of each 21-day cycle and pembrolizumab 200 mg on Day 1 of each cycle, 4-6 hours after the completion of PEGPH20 administration. Treatment in both phases of the study will continue until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (maximum exposure: 46 weeks).

Primary Outcome Measures

Name	Time	Method
Dose-Escalation Phase: Number of Participants With Dose-Limiting Toxicity (DLT)	Cycle 1 (21 days)	DLTs were defined as any of the following: i) Any treatment-emergent Grade greater than or equal to (≥) 3 toxicity that was considered related to either PEGPH20 or pembrolizumab or the combination of PEGPH20 and pembrolizumab (nausea, vomiting, MSEs, and diarrhea were considered DLTs only if they reached Grade ≥ 3 despite adequate supportive care measures); ii) Grade 3 musculoskeletal events (MSEs) were considered DLTs only if they did not reduce to Grade ≤ 2 within 48 hours despite therapeutic intervention; iii) Hypersensitivity/infusion reactions related to PEGPH20 or pembrolizumab dosing were not considered DLTs (hypersensitivity reactions were generally not related to the dose level of a drug since they could occur even upon a low level of exposure).
Dose-Escalation Phase: Maximum Tolerated Dose (MTD) of PEGPH20 in Combination With Pembrolizumab	Cycle 1 (21 days)	MTD of PEGPEM combination (PEGPH20 + Pembrolizumab) was defined as the highest dose level at which no more than 1 of 6 evaluable participants had experienced a DLT in the first 3 weeks of treatment. DLT was defined as any of the following: i) Any treatment-emergent Grade greater than or equal to (≥) 3 toxicity that was considered related to either PEGPH20 or pembrolizumab or the combination of PEGPH20 and pembrolizumab (nausea, vomiting, MSEs, and diarrhea were considered DLTs only if they reached Grade ≥ 3 despite adequate supportive care measures); ii) Grade 3 musculoskeletal events (MSEs) were considered DLTs only if they did not reduce to Grade ≤ 2 within 48 hours despite therapeutic intervention; iii) Hypersensitivity/infusion reactions related to PEGPH20 or pembrolizumab dosing were not considered DLTs (hypersensitivity reactions were generally not related to the dose level of a drug since they could occur even upon a low level of exposure).
Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of PEGPH20 in Combination With Pembrolizumab	Cycle 1 (21 days)	The RP2D was determined based on the overall safety profile of the participants enrolled during the dose-escalation part of the study.
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	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)	ORR was defined as percentage of participants who achieved either a complete response (CR) or partial response (PR), as assessed by investigator based on RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions; Any pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

Name	Time	Method
Dose-Escalation and Expansion Phase: Progression-Free Survival (PFS), as Assessed by Investigator Based on RECIST v1.1	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)	PFS was defined as the time from first dose date until the first occurrence of either radiographic or clinical disease progression as determined by the Investigator or death from any cause before discontinuation from treatment. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study thus far, the sum must also demonstrate an absolute increase of at least 5 mm, or the appearance of one or more new lesions; and unequivocal progression of existing non-target lesions. PFS was analyzed using Kaplan-Meier methods.
Dose-Escalation and Expansion Phase: Overall Survival	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)	Overall survival was defined as the time from first dose date until death from any cause. Overall survival was analyzed using Kaplan-Meier methods.
Dose- Expansion Phase: DOR, as Assessed by Investigator Based on irRC	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)	DOR was defined as the time from the date on which objective response (CR or PR) was first determined until the first date on which radiographic disease progression was determined. CR was defined as disappearance of all lesions including non-index lesions and new non-measurable lesions, lymph nodes must be \<10 mm in short axis). PR was defined as at least a 30% decrease in tumor burden from baseline. Disease progression was defined as at least a 20% increase in tumor burden from nadir. DOR was analyzed using Kaplan-Meier methods.
Dose- Expansion Phase: DCR, as Assessed by Investigator Based on irRC: Percentage of Participants Who Achieved CR, PR or SD	From first dose until first occurrence of CR, PR or SD (maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC)	DCR was defined as percentage of participants who achieved CR, PR, or stable disease (SD). CR was defined as disappearance of all lesions including non-index lesions and new non-measurable lesions, lymph nodes must be \<10 mm in short axis). PR was defined as at least a 30% decrease in tumor burden from baseline. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in tumor burden from nadir.
Dose- Expansion Phase: PFS, as Assessed by Investigator Based on irRC	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)	PFS was defined as the time from first dose date until the first occurrence of either radiographic or clinical disease progression as determined by the Investigator or death from any cause before discontinuation from treatment. Disease progression was defined as at least a 20% increase in tumor burden from nadir. PFS was analyzed using Kaplan-Meier methods.
Dose-Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of PEGPH20	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)	Pharmacokinetic (PK) parameters for PEGPH20 were calculated using noncompartmental methods and summarized using descriptive statistics by dose.
Dose-Escalation and Expansion Phase: Terminal Elimination Half-Life (t1/2) of PEGPH20	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)	PK parameters for PEGPH20 were calculated using noncompartmental methods and summarized using descriptive statistics by dose.
Dose-Escalation and Expansion Phase: Area Under the Plasma Concentration Vs. Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) of PEGPH20	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)	PK parameters for PEGPH20 were calculated using noncompartmental methods and summarized using descriptive statistics by dose.
Dose-Escalation and Expansion Phase: Volume of Distribution (Vd) of PEGPH20	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)	PK parameters for PEGPH20 were calculated using noncompartmental methods and summarized using descriptive statistics by dose.
Dose-Escalation and Expansion Phase: Clearance (CL) of PEGPH20	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)	PK parameters for PEGPH20 were calculated using noncompartmental methods and summarized using descriptive statistics by dose.
Number of Participants With Adverse Events (AEs)	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)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Dose-Expansion Phase: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters and Vital Signs	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)	Clinical laboratory parameters included hematology (haemoglobin \[Hb\], hematocrit, red blood cell count, white blood cell count, neutrophils \[ANC\], lymphocytes, monocytes, eosinophils, basophils, granulocytes, mean corpuscular Hb, mean corpuscular volume, and platelet count) and blood chemistry (glucose, blood urea nitrogen \[BUN\], alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], albumin, bilirubin, bicarbonate, calcium, chloride, magnesium, potassium, sodium, thyrotropin, thyroxin, triiodothyronine, alkaline phosphatase \[ALP\], electrolytes, and creatinine). Vital signs included measurement of blood pressure (systolic and diastolic), pulse, respiratory rate, and body temperature. Criteria for clinical significance were as per investigator's discretion.
Dose-Expansion Phase: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)	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)	ECGs including clinical significance was evaluated by the Investigator. Criteria for clinical significance were as per investigator's discretion.
Dose-Escalation Phase: ORR: Percentage of Participants With Objective Response, as Assessed by Investigator Based on RECIST Version 1.1	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)	ORR was defined as percentage of participants who achieved either a CR or PR, as assessed by investigator based on RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions; Any pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Dose-Escalation and Expansion Phase: Duration of Response (DOR), as Assessed by Investigator Based on RECIST v1.1	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)	DOR was defined as the time from the date on which objective response (CR or PR) was first determined until the first date on which radiographic disease progression was determined. CR was defined as disappearance of all target and non-target lesions; Any pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study thus far, the sum must also demonstrate an absolute increase of at least 5 mm, or the appearance of one or more new lesions; and unequivocal progression of existing non-target lesions. DOR was analyzed using Kaplan-Meier methods.
Dose Expansion Phase: Objective Response Rate (ORR): Percentage of Participants With Objective Response, as Assessed by Investigator Based on Immune-Response Related Criteria (irRC)	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)	ORR was defined as percentage of participants who achieved either CR or PR, as assessed by investigator based on irRC. CR was defined as disappearance of all lesions including non-index lesions and new non-measurable lesions, lymph nodes must be \<10 mm in short axis). PR was defined as at least a 30% decrease in tumor burden from baseline.
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)	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)	DCR was defined as percentage of participants who achieved CR, PR, or stable disease (SD). CR was defined as disappearance of all target and non-target lesions; Any pathological or non-pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study thus far, the sum must also demonstrate an absolute increase of at least 5 mm, or the appearance of one or more new lesions; and unequivocal progression of existing non-target lesions.

Trial Locations

Locations (27): Virginia Cancer Specialists, PC
🇺🇸
Fairfax, Virginia, United States
Gabrail Cancer Center
🇺🇸
Canton, Ohio, United States
University of Chicago
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Chicago, Illinois, United States
Cleveland Clinic
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Cleveland, Ohio, United States
Swedish Health Services
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Seattle, Washington, United States
New Jersey Hematology Oncology Associates
🇺🇸
Brick, New Jersey, United States
Washington University School of Medicine
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Saint Louis, Missouri, United States
University of Rochester
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Rochester, New York, United States
California Cancer Associates for Research and Excellence - Encinitas
🇺🇸
Encinitas, California, United States
Innovative Clinical Research
🇺🇸
Whittier, California, United States
St. Joseph's Hospital
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Santa Rosa, California, United States
Holy Cross Hospitals
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Fort Lauderdale, Florida, United States
Georgetown University Medical Center
🇺🇸
Washington, District of Columbia, United States
Cleveland Clinic Florida
🇺🇸
Weston, Florida, United States
Emory University
🇺🇸
Atlanta, Georgia, United States
Johns Hopkins Kimmel Cancer Center
🇺🇸
Baltimore, Maryland, United States
Ochsner Clinic Foundation
🇺🇸
New Orleans, Louisiana, United States
Ohio State University
🇺🇸
Columbus, Ohio, United States
Mary Crowley Cancer Research Center
🇺🇸
Dallas, Texas, United States
University of California San Diego - Moores Cancer Center
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La Jolla, California, United States
Mayo Clinic, Scottsdale, Arizona
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Scottsdale, Arizona, United States
University of California - Davis
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Sacramento, California, United States
University of Colorado Denver University of Colorado Anschutz Medical Campus
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Aurora, Colorado, United States
University of Miami/Sylvester Cancer Center
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Miami, Florida, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Barbara Ann Karmanos Cancer Center
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Detroit, Michigan, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States