NSCLC, Gastric Cancer
Conditions
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.
Interventions
DRUGPEGPH20
PEGPH20 will be administered as an intravenous (IV) infusion as per the dose schedule specified in the arm description.
DRUGPembrolizumab
Pembrolizumab will be administered as an IV infusion as per the dose schedule specified in the arm description.
Sponsors
Halozyme Therapeutics
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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: 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- 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 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: 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 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: 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-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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
The study was conducted in 2 parts: dose escalation and dose expansion. A total of 56 participants were enrolled (35 with gastric adenocarcinoma \[GAC\] and 21 with non-small cell lung cancer \[NSCLC\]).
Pre-assignment details
14 participants (10 with GAC and 4 with NSCLC) were enrolled in dose escalation part. Due to evolving standard-of-care in the immuno-oncology treatment landscape, this study discontinued further enrollment on 31 May 2018. At the time of the early termination, 42 participants (25 with GAC and 17 with NSCLC) had been enrolled in dose expansion part.
Participants by arm
| Arm | Count |
|---|---|
| GAC: PEGPH20 1.6 µg/kg/2.2 µg/kg + Pembrolizumab Dose escalation part: Participants with relapsed/refractory locally advanced or metastatic GAC received 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 locally advanced or metastatic GAC received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (maximum exposure: 60 weeks). | 34 |
| NSCLC: PEGPH20 1.6 µg/kg/2.2 µg/kg + Pembrolizumab Dose escalation part: Participants with relapsed/refractory Stage IIIB or IV NSCLC received 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 received 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 was continued until death, withdrawal of consent from the study, disease progression, or unacceptable toxicity (maximum exposure: 46 weeks). | 21 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Dose Escalation (Up to 46 Weeks) | Adverse Event | 2 | 0 | 0 | 1 | 0 | 0 |
| Dose Escalation (Up to 46 Weeks) | Clinical Progression | 0 | 0 | 3 | 0 | 0 | 0 |
| Dose Escalation (Up to 46 Weeks) | Radiological Progression | 1 | 2 | 2 | 0 | 0 | 0 |
| Dose Escalation (Up to 46 Weeks) | Withdrawal by Subject | 0 | 0 | 2 | 1 | 0 | 0 |
| Dose Expansion (Up to 60 Weeks) | Adverse Event | 0 | 0 | 0 | 0 | 1 | 8 |
| Dose Expansion (Up to 60 Weeks) | Clinical Progression | 0 | 0 | 0 | 0 | 6 | 0 |
| Dose Expansion (Up to 60 Weeks) | Enrolled but not treated | 0 | 0 | 0 | 0 | 1 | 0 |
| Dose Expansion (Up to 60 Weeks) | Increased brain lesions | 0 | 0 | 0 | 0 | 0 | 1 |
| Dose Expansion (Up to 60 Weeks) | Investigator or Sponsor Decision | 0 | 0 | 0 | 0 | 0 | 2 |
| Dose Expansion (Up to 60 Weeks) | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 2 |
| Dose Expansion (Up to 60 Weeks) | Radiological Progression | 0 | 0 | 0 | 0 | 15 | 3 |
| Dose Expansion (Up to 60 Weeks) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | NSCLC: PEGPH20 1.6 µg/kg/2.2 µg/kg + Pembrolizumab | Total | GAC: PEGPH20 1.6 µg/kg/2.2 µg/kg + Pembrolizumab |
|---|---|---|---|
| Age, Continuous | 67.7 years STANDARD_DEVIATION 10.66 | 64.4 years STANDARD_DEVIATION 9.87 | 62.3 years STANDARD_DEVIATION 8.89 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 50 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 17 Participants | 47 Participants | 30 Participants |
| Sex: Female, Male Female | 11 Participants | 16 Participants | 5 Participants |
| Sex: Female, Male Male | 10 Participants | 39 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 34 | 2 / 21 |
| other Total, other adverse events | 33 / 34 | 21 / 21 |
| serious Total, serious adverse events | 10 / 34 | 8 / 21 |
Outcome results
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).
Time frame: Cycle 1 (21 days)
Population: After 9 participants enrolled in Dose Escalation: PEGPH20 2.2 µg/kg + Pembrolizumab group with only 1 DLT, the Sponsor decided to stop further dose escalation beyond 2.2 μg/kg, hence MTD was not established.
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).
Time frame: Cycle 1 (21 days)
Population: DLT evaluable population included all participants enrolled in dose escalation part who received at least 1 of the 3 full planned doses of PEGPH20 and 1 complete dose of pembrolizumab in Cycle 1 and had been followed for the first 21 days of treatment or had experienced a DLT during the initial 21 days (Cycle 1) of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation Phase: Number of Participants With Dose-Limiting Toxicity (DLT) | 0 Participants |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Escalation Phase: Number of Participants With Dose-Limiting Toxicity (DLT) | 0 Participants |
| Dose Escalation (NSCLC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation Phase: Number of Participants With Dose-Limiting Toxicity (DLT) | 0 Participants |
| Dose Escalation (NSCLC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Escalation Phase: Number of Participants With Dose-Limiting Toxicity (DLT) | 1 Participants |
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.
Time frame: Cycle 1 (21 days)
Population: DLT evaluable population included all participants enrolled in dose escalation part who received at least 1 of the 3 full planned doses of PEGPH20 and 1 complete dose of pembrolizumab in Cycle 1 and had been followed for the first 21 days of treatment or had experienced a DLT during the initial 21 days (Cycle 1) of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose Escalation Phase: Recommended Phase 2 Dose (RP2D) of PEGPH20 in Combination With Pembrolizumab | 2.2 µg/kg |
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.
Time frame: 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)
Population: Tumor response evaluable population included all hyaluronan- high (HA-high) participants who received at least 1 dose of the RP2D of PEGPH20 and at least 1 dose of pembrolizumab; and who had at least one post-baseline tumor assessment on or post Cycle 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | 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 | 9.5 percentage of participants |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | 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 | 28.6 percentage of participants |
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.
Time frame: 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)
Population: Evaluable PK population included participants with at least one PK parameter for PEGPH20 following dosing on Day 1 of Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Area Under the Plasma Concentration Vs. Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) of PEGPH20 | 579 h*ng/mL | Geometric Coefficient of Variation 18.3 |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Area Under the Plasma Concentration Vs. Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) of PEGPH20 | 698 h*ng/mL | Geometric Coefficient of Variation 48.7 |
| Dose Escalation (NSCLC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Area Under the Plasma Concentration Vs. Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) of PEGPH20 | 822 h*ng/mL | Geometric Coefficient of Variation 31.9 |
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.
Time frame: 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)
Population: CL could not be determined due to the AUC% extrapolation of greater than 20%.
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.
Time frame: 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)
Population: Tumor response evaluable population included all HA-high participants who received at least 1 dose of the RP2D of PEGPH20 and at least 1 dose of pembrolizumab; and who had at least one post-baseline tumor assessment on or post Cycle 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | 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) | 12.5 percentage of participants |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | 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) | 66.7 percentage of participants |
| Dose Escalation (NSCLC): PEGPH20 1.6 µg/kg + Pembrolizumab | 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) | 47.6 percentage of participants |
| Dose Escalation (NSCLC): PEGPH20 2.2 µg/kg + Pembrolizumab | 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) | 71.4 percentage of participants |
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.
Time frame: 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)
Population: Tumor response evaluable population included all HA-high participants who received at least 1 dose of the RP2D of PEGPH20 and at least 1 dose of pembrolizumab; and who had at least one post-baseline tumor assessment on or post Cycle 2. 'Overall number of participants analyzed'=participants with a confirmed objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation (NSCLC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Duration of Response (DOR), as Assessed by Investigator Based on RECIST v1.1 | 8.5 months |
| Dose Escalation (NSCLC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Duration of Response (DOR), as Assessed by Investigator Based on RECIST v1.1 | 2.8 months |
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.
Time frame: 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)
Population: Evaluable PK population included participants with at least one PK parameter for PEGPH20 following dosing on Day 1 of Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of PEGPH20 | 38.3 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 21.4 |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of PEGPH20 | 48.7 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 26.4 |
| Dose Escalation (NSCLC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of PEGPH20 | 54.1 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 21.7 |
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.
Time frame: 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)
Population: Efficacy evaluable population included all HA-high participants who received at least 1 dose of the RP2D of PEGPH20 and at least 1 dose of pembrolizumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Overall Survival | 2.9 months |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Overall Survival | 4.7 months |
| Dose Escalation (NSCLC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Overall Survival | 4.4 months |
| Dose Escalation (NSCLC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Overall Survival | 12.9 months |
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.
Time frame: 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)
Population: Efficacy evaluable population included all HA-high participants who received at least 1 dose of the RP2D of PEGPH20 and at least 1 dose of pembrolizumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Progression-Free Survival (PFS), as Assessed by Investigator Based on RECIST v1.1 | 1.2 months |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Progression-Free Survival (PFS), as Assessed by Investigator Based on RECIST v1.1 | 1.7 months |
| Dose Escalation (NSCLC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Progression-Free Survival (PFS), as Assessed by Investigator Based on RECIST v1.1 | 1.4 months |
| Dose Escalation (NSCLC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Progression-Free Survival (PFS), as Assessed by Investigator Based on RECIST v1.1 | 4.2 months |
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.
Time frame: 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)
Population: Evaluable PK population included participants with at least one PK parameter for PEGPH20 following dosing on Day 1 of Cycle 1. 'Overall number of participants analyzed'=participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Terminal Elimination Half-Life (t1/2) of PEGPH20 | 23.7 hours | Standard Deviation 5.25 |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Terminal Elimination Half-Life (t1/2) of PEGPH20 | 21.8 hours | Standard Deviation 8.98 |
| Dose Escalation (NSCLC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation and Expansion Phase: Terminal Elimination Half-Life (t1/2) of PEGPH20 | 24.9 hours | Standard Deviation 5.76 |
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.
Time frame: 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)
Population: Vd could not be determined due to the AUC% extrapolation of greater than 20%.
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.
Time frame: 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)
Population: Tumor response evaluable population included all HA-high participants who received at least 1 dose of the RP2D of PEGPH20 and at least 1 dose of pembrolizumab; and who had at least one post-baseline tumor assessment on or post Cycle 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Escalation Phase: ORR: Percentage of Participants With Objective Response, as Assessed by Investigator Based on RECIST Version 1.1 | 0 percentage of participants |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Escalation Phase: ORR: Percentage of Participants With Objective Response, as Assessed by Investigator Based on RECIST Version 1.1 | 0 percentage of participants |
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.
Time frame: From first dose until first occurrence of CR, PR or SD (maximum exposure: 60 weeks for GAC, and 46 weeks for NSCLC)
Population: Tumor response evaluable population included all HA-high participants who received at least 1 dose of the RP2D of PEGPH20 and at least 1 dose of pembrolizumab; and who had at least one post-baseline tumor assessment on or post Cycle 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose- Expansion Phase: DCR, as Assessed by Investigator Based on irRC: Percentage of Participants Who Achieved CR, PR or SD | 47.6 percentage of participants |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose- Expansion Phase: DCR, as Assessed by Investigator Based on irRC: Percentage of Participants Who Achieved CR, PR or SD | 78.6 percentage of participants |
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.
Time frame: 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)
Population: Tumor response evaluable population included all HA-high participants who received at least 1 dose of the RP2D of PEGPH20 and at least 1 dose of pembrolizumab; and who had at least one post-baseline tumor assessment on or post Cycle 2. 'Overall number of participants analyzed'=participants with a confirmed objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose- Expansion Phase: DOR, as Assessed by Investigator Based on irRC | 8.5 months |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose- Expansion Phase: DOR, as Assessed by Investigator Based on irRC | 2.8 months |
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.
Time frame: 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)
Population: Safety population included all enrolled participants in either the Dose Escalation or Dose Expansion portion of the study, who received at least 1 dose of any study medication (PEGPH20 or pembrolizumab).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Expansion Phase: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters and Vital Signs | 0 Participants |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Expansion Phase: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters and Vital Signs | 0 Participants |
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.
Time frame: 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)
Population: Safety population included all enrolled participants in either the Dose Escalation or Dose Expansion portion of the study, who received at least 1 dose of any study medication (PEGPH20 or pembrolizumab).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose-Expansion Phase: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) | 0 Participants |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose-Expansion Phase: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) | 0 Participants |
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.
Time frame: 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)
Population: Tumor response evaluable population included all HA-high participants who received at least 1 dose of the RP2D of PEGPH20 and at least 1 dose of pembrolizumab; and who had at least one post-baseline tumor assessment on or post Cycle 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose Expansion Phase: Objective Response Rate (ORR): Percentage of Participants With Objective Response, as Assessed by Investigator Based on Immune-Response Related Criteria (irRC) | 9.5 percentage of participants |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose Expansion Phase: Objective Response Rate (ORR): Percentage of Participants With Objective Response, as Assessed by Investigator Based on Immune-Response Related Criteria (irRC) | 28.6 percentage of participants |
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.
Time frame: 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)
Population: Efficacy evaluable population included all HA-high participants who received at least 1 dose of the RP2D of PEGPH20 and at least 1 dose of pembrolizumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Dose- Expansion Phase: PFS, as Assessed by Investigator Based on irRC | 1.4 months |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Dose- Expansion Phase: PFS, as Assessed by Investigator Based on irRC | 4.2 months |
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'.
Time frame: 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)
Population: Safety population included all enrolled participants in either the Dose Escalation or Dose Expansion portion of the study, who received at least 1 dose of any study medication (PEGPH20 or pembrolizumab).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation (GAC): PEGPH20 1.6 µg/kg + Pembrolizumab | Number of Participants With Adverse Events (AEs) | 34 Participants |
| Dose Escalation (GAC): PEGPH20 2.2 µg/kg + Pembrolizumab | Number of Participants With Adverse Events (AEs) | 21 Participants |