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

Gastric Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02563548
• Other study ID #: HALO-107-101
• Status: Completed
• Phase: Phase 1
• Start date: October 22, 2015
• Est. completion date: March 26, 2019

Study information

• Verified date: December 2019
• Source: Halozyme Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: March 26, 2019
• Est. primary completion date: March 26, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Gastric Cancer
• NSCLC
• Stomach Neoplasms

Intervention

Drug:
• PEGPH20
PEGPH20 will be administered as an intravenous (IV) infusion as per the dose schedule specified in the arm description.
• Pembrolizumab
Pembrolizumab will be administered as an IV infusion as per the dose schedule specified in the arm description.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Halozyme Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose-Escalation Phase: Number of Participants With Dose-Limiting Toxicity (DLT)	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).	Cycle 1 (21 days)
Primary	Dose-Escalation Phase: Maximum Tolerated Dose (MTD) of PEGPH20 in Combination With Pembrolizumab	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).	Cycle 1 (21 days)
Primary	Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of PEGPH20 in Combination With Pembrolizumab	The RP2D was determined based on the overall safety profile of the participants enrolled during the dose-escalation part of the study.	Cycle 1 (21 days)
Primary	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	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.	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	Dose-Escalation Phase: ORR: Percentage of Participants With Objective Response, as Assessed by Investigator Based on RECIST Version 1.1	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.	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)
Secondary	Dose-Escalation and Expansion Phase: Duration of Response (DOR), as Assessed by Investigator Based on RECIST v1.1	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.	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)
Secondary	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)	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.	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)
Secondary	Dose-Escalation and Expansion Phase: Progression-Free Survival (PFS), as Assessed by Investigator Based on RECIST v1.1	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.	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)
Secondary	Dose-Escalation and Expansion Phase: Overall Survival	Overall survival was defined as the time from first dose date until death from any cause. Overall survival was analyzed using Kaplan-Meier methods.	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)
Secondary	Dose Expansion Phase: Objective Response Rate (ORR): Percentage of Participants With Objective Response, as Assessed by Investigator Based on Immune-Response Related Criteria (irRC)	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.	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	Dose- Expansion Phase: DOR, as Assessed by Investigator Based on irRC	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.	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)
Secondary	Dose- Expansion Phase: DCR, as Assessed by Investigator Based on irRC: Percentage of Participants Who Achieved CR, PR or SD	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.	From first dose until first occurrence of CR, PR or SD (maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC)
Secondary	Dose- Expansion Phase: PFS, as Assessed by Investigator Based on irRC	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.	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)
Secondary	Dose-Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of PEGPH20	Pharmacokinetic (PK) parameters for PEGPH20 were calculated using noncompartmental methods and summarized using descriptive statistics by dose.	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)
Secondary	Dose-Escalation and Expansion Phase: Terminal Elimination Half-Life (t1/2) of PEGPH20	PK parameters for PEGPH20 were calculated using noncompartmental methods and summarized using descriptive statistics by dose.	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)
Secondary	Dose-Escalation and Expansion Phase: Area Under the Plasma Concentration Vs. Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) of PEGPH20	PK parameters for PEGPH20 were calculated using noncompartmental methods and summarized using descriptive statistics by dose.	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)
Secondary	Dose-Escalation and Expansion Phase: Volume of Distribution (Vd) of PEGPH20	PK parameters for PEGPH20 were calculated using noncompartmental methods and summarized using descriptive statistics by dose.	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)
Secondary	Dose-Escalation and Expansion Phase: Clearance (CL) of PEGPH20	PK parameters for PEGPH20 were calculated using noncompartmental methods and summarized using descriptive statistics by dose.	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)
Secondary	Number of Participants With Adverse Events (AEs)	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'.	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)
Secondary	Dose-Expansion Phase: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters and Vital Signs	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.	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)
Secondary	Dose-Expansion Phase: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG)	ECGs including clinical significance was evaluated by the Investigator. Criteria for clinical significance were as per investigator's discretion.	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)