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Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive pembrolizumab IV over 10 minutes on day 1 and pegylated recombinant human hyaluronidase PH20 SC on days 1, 8, and 15. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity.

Pegylated Recombinant Human Hyaluronidase PH20

David R Fogelman

This phase II trial studies how well pembrolizumab and PEGPH20 work in treating patients with pancreatic cancer that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. PEGPH20 is an enzyme that breaks down hyaluronic acid coating tumor cells which may inhibit growth of tumor cells. Giving pembrolizumab and PEGPH20 may work better in treating patients with pancreatic cancer compared to pembrolizumab alone.

PRIMARY OBJECTIVES:

I. To assess the progression free survival duration of patients treated with the combination of pegylated recombinant human hyaluronidase PH20 (PEGPH20) and pembrolizumab.

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of the combination of PEGPH20 and pembrolizumab.

EXPLORATORY OBJECTIVES:

I. To evaluate objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) and Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST) criteria, duration of response (DOR), disease control rate (DCR), time to progression (TTP) and progression-free survival (PFS) per RECIST and iRECIST as assessed by M.D. Anderson investigators and overall survival (OS) of the combination of pembrolizumab and PEGPH20.

II. To explore the association between PD-L1 expression by immunohistochemistry (IHC), shed PD-L1 level, hyaluronan (HA) levels, somatic gene expression profiling and antitumor efficacy of the combination of pembrolizumab and PEGPH20 based on RECIST 1.1 as well as OS.

III. To explore the relationship between genomic variation and response to study treatment.

IV. To examine the effect of pembrolizumab and PEGPH20 on immune cell infiltration into tumor.

V. To explore the effect of PEGPH20 on serum HA levels, and to compare changes in serum HA with clinical efficacy.

VI. To determine the impact of the combination of pembrolizumab and PEGPH20 on circulating immune cells.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 10 minutes on day 1 and pegylated recombinant human hyaluronidase PH20 subcutaneously (SC) on days 1, 8, and 15. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 9 and 12 weeks.

Pembrolizumab and PEGPH20 in Treating Patients With Metastatic Pancreatic Cancer

A Pilot Study to Assess the Efficacy and Safety Effects of Pembrolizumab and PEGPH20 (Pegvorhyaluronidase Alfa) in Patients With Metastatic Pancreatic Cancer

ORR will be evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) and Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST) criteria. Descriptive statistics including with 90% confidence interval will be computed.

DOR will be evaluated per RECIST and iRECIST. Descriptive statistics including with 90% confidence interval will be computed.

DCR will be evaluated per RECIST and iRECIST. Descriptive statistics including with 90% confidence interval will be computed.

TTP will be evaluated per RECIST and iRECIST. Descriptive statistics including with 90% confidence interval will be computed.

PFS will be evaluated per RECIST and iRECIST. Descriptive statistics including with 90% confidence interval will be computed.

Descriptive statistics including with 90% confidence interval will be computed.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Respiratory Tract (Lung and Bronchial) Diseases

Symptoms and General Pathology

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Recurrence

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Docetaxel

Tubulin Modulators

Antimitotic Agents

PEGylated recombinant human hyaluronidase PH20 (PEGPH20) (1.6, 3.0, or 2.2 micrograms per kilogram (ug/kg)) was administered on Day 1 of each 21-day cycle (every 3 weeks) as an intravenous (IV)-infusion over 10 minutes, approximately 1 milliliter/minute (mL/min) (a window of +2 minutes allowed, i.e., infusion could be 10 to 12 minutes). Docetaxel (75 milligrams/meter squared (mg/m\^2)) was administered on Day 2 of each 21-day cycle.

PEGylated recombinant human hyaluronidase PH20

A Phase 1b study for participants with Stage IIIB/IV Non-Small Cell Lung Cancer (NSCLC) to participate in 1 of 2 portions of this study. The first portion is Dose Escalation in which participants are tested with PEGPH20 at various doses (1.6, 3.0, 2.2 and 2.8 micrograms/kilogram (ug/kg)) in addition to dosing with the standard dose of docetaxel (PDoc) of 75 milligrams/meter squared (mg/m\^2) once every 21-day cycle. Based on observations on the safety and tolerability of study treatment from dose escalation cohorts dosed to date (1.6 and 3.0 ug/kg of PEGPH20), two additional dose levels will be tested, 2.2 and 2.8 ug/kg. Up to 30 additional participants may be enrolled to test these dose levels. The second portion of Phase 1b is Cohort Expansion in which the recommended Phase 2 dose (RP2D) of PDoc identified in dose escalation is administered every 21 days to approximately 50 participants with high hyaluronan (HA-high) prospectively measured in their tumor tissue.

The study was planned to include a Dose Escalation portion utilizing a standard 3 + 3 dose escalation design. Participants were enrolled sequentially into their assigned dose cohort. The Treatment Period consisted of 21-day treatment cycles with administration of PEGPH20 on Day 1 (doses tested were 1.6, 3.0, and 2.2 ug/kg) and docetaxel (standard dosing 75 mg/m\^2 for all participants) on Day 2 of each cycle.

A Phase 1b Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) Combined With Docetaxel in Subjects With Recurrent Previously Treated Locally Advanced or Metastatic NSCLC

PRIMAL STUDY: A Phase 1b, Open-label, Multicenter, Multinational Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) Combined With Docetaxel (PDoc) in Subjects With Recurrent Previously Treated Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)

DLTs were defined as adverse events (AEs) that occurred during Cycle 1 in the Dose Escalation portion of the study, and deemed by the Investigator as related to study treatment.

Throughout the Treatment Period, the assessment of safety was based on AEs, including deaths, non-serious AEs, and serious adverse events, AEs leading to discontinuation of study treatment, and results of vital sign measurements and clinical laboratory assessments (including hematology, clinical chemistry, coagulation parameters, and urinalysis). Additionally, thromboembolic (TE) events were deemed by the Sponsor as AEs of special interest. AEs and laboratory values were graded for severity using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Blood samples were collected from all participants per protocol and analyzed for plasma PEGPH20 concentration using a validated electrochemiluminescence (ECL) immunoassay. Plasma docetaxel concentrations were analyzed using a validated liquid chromatography with tandem mass spectrometry assay (LS-MS/MS). The following blood draw schedule was used, PEGPH20: Cycle 1 Day 1 (C1D1) (predose, 15 minutes (min), 1, 2 to 4, and 24 hours (hr) postdose), C2 and all subsequent Cycles (predose, 1 hr postdose). Docetaxel: C1D2 (30 min after the start of the 1-hr infusion, 30 min post completion of the infusion, 4 to 6 and 24 hr post infusion), C1D3 (24 hr post infusion), C2D2 and C3D2 (30 min after the start of the 1-hour infusion, 30 min post completion of the infusion).

Blood samples were collected from all participants per protocol and analyzed for plasma PEGPH20 concentration using a validated ECL immunoassay. Plasma docetaxel concentrations were analyzed using a validated liquid chromatography with LS-MS/MS. The following blood draw schedule was used, PEGPH20: C1D1 (predose, 15 min, 1, 2 to 4, and 24 hr postdose), C2 and all subsequent Cycles (predose, 1 hr postdose). Docetaxel: C1D2 (30 min after the start of the 1-hr infusion, 30 min post completion of the infusion, 4 to 6 and 24 hr post infusion), C1D3 (24 hr post infusion), C2D2 and C3D2 (30 min after the start of the 1-hour infusion, 30 min post completion of the infusion).

ORR = complete response + partial response (CR + PR)

Halozyme Therapeutics

Treatment-emergent adverse events (TEAEs) and serious adverse events were reported. Adverse event severity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. The Safety Population was evaluated and included all participants who received at least one dose of study treatment.

1.6 micrograms/kilograms (ug/kg) PEGylated recombinant human hyaluronidase PH20 (PEGPH20) was administered on Day 1 of each 21-day cycle (every 3 weeks) as an intravenous (IV)-infusion over 10 minutes, approximately 1 milliliter/minute (mL/min) (a window of +2 minutes allowed, i.e., infusion could be 10 to 12 minutes). Docetaxel (75 milligrams/meter squared (mg/m\^2)) was administered as an IV-infusion on Day 2 of each 21-day cycle.

Cohort 1: 1.6 ug/kg PEGPH20 + Docetaxel

3.0 ug/kg PEGPH20 was administered on Day 1 of each 21-day cycle (every 3 weeks) as an IV-infusion over 10 minutes, approximately 1 mL/min (a window of +2 minutes allowed, i.e., infusion could be 10 to 12 minutes). Docetaxel (75 mg/m\^2) was administered as an IV-infusion on Day 2 of each 21-day cycle.

Cohort 2: 3.0 ug/kg PEGPH20 + Docetaxel

2.2 ug/kg PEGPH20 was administered on Day 1 of each 21-day cycle (every 3 weeks) as an IV-infusion over 10 minutes, approximately 1 mL/min (a window of +2 minutes allowed, i.e., infusion could be 10 to 12 minutes). Docetaxel (75 mg/m\^2) was administered as an IV-infusion on Day 2 of each 21-day cycle.

Cohort 3: 2.2 ug/kg PEGPH20 + Docetaxel

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Safety population included all participants who received at least one dose of study treatment.

This study was discontinued early by the Sponsor during the Dose Escalation Period.

Halozyme Study Information

Neutropenia

Gastroenteritis Escherichia coli

Sepsis

Deep vein thrombosis

The DLT-Evaluable population included all participants who received a full dose of study treatment and completed the initial 21 days of the study after the first dose or who experienced a DLT within the initial 21 days after the first dose and discontinued from the study (if they received a full dose of study drug).

Number of Dose Limiting Toxicities (DLTs)

AEs greater than or equal to grade 3

PEGPH20-related AEs

Docetaxel-related AEs

AEs with outcome of death

SAEs

Treatment-related SAEs

AEs leading to discontinuation of study drug

1.6 ug/kg PEGPH20 was administered on Day 1 of each 21-day cycle (every 3 weeks) as an IV-infusion over 10 minutes, approximately 1 mL/min (a window of +2 minutes allowed, i.e., infusion could be 10 to 12 minutes). Docetaxel (75 mg/m\^2) was administered as an IV-infusion on Day 2 of each 21-day cycle.

Number of Participants With the Indicated Type of Adverse Events for PEGPH20 and Docetaxel

PEGPH20 (1.6, 3.0, or 2.2 ug/kg) was administered on Day 1 of each 21-day cycle (every 3 weeks) as an IV-infusion over 10 minutes, approximately 1 mL/min (a window of +2 minutes allowed, i.e., infusion could be 10 to 12 minutes). Docetaxel (75 mg/m\^2) was administered as an IV-infusion on Day 2 of each 21-day cycle.

PEGPH20 + Docetaxel

The MTD and RP2D were not established due to early study discontinuation.

Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of PEGPH20

Due to early discontinuation of the study, Cmax was not assessed.

Phase 1b: Maximum Plasma Concentration (Cmax) of PEGPH20 and Docetaxel

Due to early discontinuation of the study, Cmin was not assessed.

Phase 1b: Minimum Plasma Concentration (Cmin) of PEGPH20 and Docetaxel

Due to early discontinuation of the study, Tmax was not assessed.

Phase 1b: Time to Maximum Plasma Concentration (Tmax) of PEGPH20 and Docetaxel

Due to early discontinuation of the study, t1/2 was not assessed.

Phase 1b: Terminal Half-life (t1/2) of PEGPH20 and Docetaxel

Due to early discontinuation of the study, the AUC was not assessed.

Phase 1b: Area Under the Plasma Concentration-Time Curve for PEGPH20 and Docetaxel

Due to early discontinuation of the study, Vd was not assessed.

Phase 1b: Volume of Distribution (Vd) of PEGPH20 and Docetaxel

Due to early discontinuation of the study, CL was not assessed.

Phase 1b: Clearance (CL) of PEGPH20 and Docetaxel

Due to early discontinuation of the study, ORR was not assessed.

Objective Response Rate (ORR)

Due to early discontinuation of the study, DCR was not assessed.

Disease Control Rate (DCR)

Due to early discontinuation of the study, DoR was not assessed.

Duration of Response (DoR)

Due to early discontinuation of the study, PFS was not assessed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab and PEGPH20 in Treating Patients With Metastatic Pancreatic Cancer	NCT04058964	Metastatic Panc... Stage IV Pancre...	Pegylated Recom... Pembrolizumab	18 Years -	M.D. Anderson Cancer Center
A Phase 1b Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) Combined With Docetaxel in Subjects With Recurrent Previously Treated Locally Advanced or Metastatic NSCLC	NCT02346370	Non-small Cell ...	PEGylated recom... Docetaxel	18 Years -	Halozyme Therapeutics
A Phase 1b Study of PEGylated Recombinant Human Hyaluronidase (PEGPH20) Combined With Docetaxel in Subjects With Recurrent Previously Treated Locally Advanced or Metastatic NSCLC	NCT02346370	Non-small Cell ...	PEGylated recom... Docetaxel	18 Years -	Halozyme Therapeutics

Spots Global Cancer Trial Database for pegylated recombinant human hyaluronidase ph20