A Study in Healthy Male Subjects to Investigate the Comparability of Pharmacokinetics of the Fixed-Dose Combination of Pertuzumab and Trastuzumab Administered Subcutaneously Using a Handheld Syringe or Using the On-Body Delivery System

Hoffmann-La Roche151 enrolled

Overview

This is a randomized, open-label, 2-arm, parallel-group, single-dose, multi-center study in healthy male subjects to investigate the comparability of the pharmacokinetics of the fixed-dose combination of pertuzumab and trastuzumab administered subcutaneously using the proprietary on-body delivery system or a handheld syringe with hypodermic needle.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

151

Conditions

Healthy Male Subjects

Interventions

Fixed-Dose Combination of Pertuzumab and Trastuzumab SC (PH FDC SC)

A single dose of PH FDC SC (600 mg pertuzumab/600 mg trastuzumab) will be administered by a healthcare professional subcutaneously (SC) into the anterior thigh, using either a handheld syringe with hypodermic needle (Arm 1) or the on-body delivery system (Arm 2).

Handheld Syringe with Hypodermic NeedleDEVICE

A single 10-mL dose of PH FDC SC will be administered as a subcutaneous (SC) injection using a handheld manual syringe.

On-Body Delivery SystemDEVICE

A single 10-mL dose of PH FDC SC will be administered as a subcutaneous (SC) injection using the on-body delivery system (OBDS).

Eligibility

Sex: MALEMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy male subjects age 18-45 years at time of signing Informed Consent Form * Ability to comply with the study protocol * Agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, during the treatment period and for 7 months after the dose of PH FDC SC * A body mass index (BMI) between 18 and 32 kilograms per metre squared (kg/m2), inclusive * Intact normal skin without potentially obscuring tattoos, pigmentation, or lesions in the area for intended injection on the thighs * Baseline LVEF≥55% measured by echocardiogram (ECHO) * No history of hypersensitivity or confirmed, clinically significant and clinically relevant allergic reactions, either spontaneously or following any drug administration * No history of any clinically significant and clinically relevant cardiac condition * No history of previous anticancer treatments including pertuzumab, trastuzumab, anthracyclines, or any cardiotoxic drugs * No apparent family history of clinically significant and clinically relevant hypersensitivity, allergy, and severe cardiac diseases * No contraindications from detailed medical and surgical history and physical examinations * No previous enrollment in this study protocol and no concurrent enrollment in any other study protocol Exclusion Criteria: * Positive urine test for drugs of abuse as per local standard (for alcohol abuse, positive breath test is also acceptable) * Positive test result for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) 1 or 2, showing: History of exposure to HBV, HCV, or HIV; or Active viral hepatitis infection (HBV or HCV) or HIV infection * Systolic blood pressure ≥140 millimetres of mercury (mmHg) or \<90 mmHg, or diastolic blood pressure \>90 mmHg or \<50 mmHg * Use of prohibited medications including non-prescription medications, nutraceuticals, nutritional supplements or any herbal remedies taken within 10 days or 5 times the elimination half-life (whichever is longer) prior to randomization into the study * Concomitant subcutaneous, intravenous, or any parenteral drugs within 90 days prior to screening * Participation in an investigational drug or device study within 90 days or five times the elimination half-life (whichever is longer) prior to screening * Donation of blood over 500 millilitres (mL) within 3 months prior to enrollment * Known severe hypersensitivity to plaster, medical adhesive tapes, or bandages * Known allergy to murine proteins, hyaluronidase, bee, or vespid venom, or any other ingredient in the formulation of rHuPH20 (Hylenex® recombinant \[hyaluronidase human injection\]) or any other ingredients and excipients in the formulation of PH FDC SC * Clinically significant abnormalities in laboratory test results (including hepatic and renal panels, CBC, chemistry panel, and urinalysis) * Clinically relevant electrocardiogram abnormalities at screening or Day -1 * History of any cardiac condition * Lower extremity edema or pathology (e.g., cellulitis, lymphatic disorder or prior surgery, pre-existing pain syndrome, previous lymph node dissection etc.) that could interfere with any protocol-specified outcome assessment * Any history of clinically significant and clinically relevant allergies, oncologic, psychiatric, gastrointestinal, renal, hepatic, cardiovascular or pulmonary disease * Concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in this study * Any clinically relevant history of systemic disease (e.g., malignancy, diabetes mellitus, gastrointestinal, renal, hepatic, cardiovascular, rheumatological, or pulmonary disease) * History of breast cancer or treatment for breast cancer * Current chronic daily treatment (continuous for \>3 months) with corticosteroids (dose ≥10 mg/day methylprednisolone), excluding inhaled corticosteroids * Receipt of intravenous antibiotics for infection within 7 days prior to enrollment into the study

Locations (5)

Q-Pharm Pty Ltd; Nucleus Network Brisbane Clinic

Herston, Queensland, Australia

CMAX Pty Ltd

Adelaide, South Australia, Australia

Linear Clinical Research Ltd

Nedlands, Western Australia, Australia

New Zealand Clinical Research - Auckland

Auckland, New Zealand

New Zealand Clinical Research - Christchurch

Christchurch, New Zealand

Outcomes

Primary Outcomes

Area Under the Time-Concentration Curve From the Start of Dosing to 63 Days (AUC0-62) for Serum Pertuzumab

For the analysis of AUC0-62days, participants in the Per Protocol Pharmacokinetics (PK) Analysis Population (PAP) with missing Day 63 PK pertuzumab concentration data or with a Day 63 PK sample time deviation outside a +/-120-hour window of planned sampling time were excluded. Participants were excluded from the PAP for the following reasons: 1. The participant violates inclusion or exclusion criteria regarding body mass index (BMI), use of prohibited medications and concomitant subcutaneous, intravenous (IV), or any parenteral drugs, participation in an investigational drug or device study, current chronic daily treatment with corticosteroids, and receipt of IV antibiotics for infection. 2. An SC injection site other than thigh is used; 3. Any participant whose injection is not successfully performed.

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Area Under the Time-Concentration Curve From the Start of Dosing to 63 Days (AUC0-62) for Serum Trastuzumab

For the analysis of AUC0-62days, participants in the Per Protocol Pharmacokinetics (PK) Analysis Population (PAP) with missing Day 63 PK trastuzumab concentration data or with a Day 63 PK sample time deviation outside a +/-120-hour window of planned sampling time were excluded. Participants were excluded from the PAP for the following reasons: 1. The participant violates inclusion or exclusion criteria regarding body mass index (BMI), use of prohibited medications and concomitant subcutaneous, intravenous (IV), or any parenteral drugs, participation in an investigational drug or device study, current chronic daily treatment with corticosteroids, and receipt of IV antibiotics for infection. 2. An SC injection site other than thigh is used; 3. Any participant whose injection is not successfully performed.

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Maximum Serum Concentration (Cmax) of Pertuzumab

For analysis of Cmax, participants from the Per Protocol PK Analysis Population (PAP) with two or more missing PK pertuzumab concentration data on any of Days 3, 5, 7, 9 or 11 were excluded. Participants were excluded from the PAP for the following reasons: 1. The participant violates inclusion or exclusion criteria regarding body mass index (BMI), use of prohibited medications and concomitant subcutaneous, intravenous (IV), or any parenteral drugs, participation in an investigational drug or device study, current chronic daily treatment with corticosteroids, and receipt of IV antibiotics for infection. 2. An SC injection site other than thigh is used; 3. Any participant whose injection is not successfully performed.

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Maximum Serum Concentration (Cmax) of Trastuzumab

For analysis of Cmax, participants from the Per Protocol PK Analysis Population (PAP) with two or more missing PK trastuzumab concentration data on any of Days 3, 5, 7, 9 or 11 were excluded. Participants were excluded from the PAP for the following reasons: 1. The participant violates inclusion or exclusion criteria regarding body mass index (BMI), use of prohibited medications and concomitant subcutaneous, intravenous (IV), or any parenteral drugs, participation in an investigational drug or device study, current chronic daily treatment with corticosteroids, and receipt of IV antibiotics for infection. 2. An SC injection site other than thigh is used; 3. Any participant whose injection is not successfully performed.

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Secondary Outcomes

Observed Serum Concentration of Pertuzumab on Day 22

Time frame: Day 22

Observed Serum Concentration of Trastuzumab on Day 22

Time frame: Day 22

Observed Serum Concentration of Pertuzumab on Day 63

Time frame: Day 63

Observed Serum Concentration of Trastuzumab on Day 63

Time frame: Day 63

Area Under the Time-Concentration Curve From the Start of Dosing Extrapolated to Infinity (AUC0-∞) for Serum Pertuzumab

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Area Under the Time-Concentration Curve From the Start of Dosing Extrapolated to Infinity (AUC0-∞) for Serum Trastuzumab

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Observed Time to Maximum Serum Concentration (Tmax) of Pertuzumab

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Observed Time to Maximum Serum Concentration (Tmax) of Trastuzumab

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Terminal Elimination Half-Life (t1/2) of Pertuzumab

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Terminal Elimination Half-Life (t1/2) of Trastuzumab

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Data from ClinicalTrials.gov

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Apparent Drug Clearance (CL/F) of Pertuzumab

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Apparent Drug Clearance (CL/F) of Trastuzumab

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Apparent Volume of Distribution (Vd/F) of Pertuzumab

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Apparent Volume of Distribution (Vd/F) of Trastuzumab

Time frame: Predose (0 hour) and 2, 6, and 12 hours postdose on Day 1, and postdose on Days 2, 3, 5, 7, 9, 11, 15, 22, 35, 49, and 63

Summary of the Number of Participants With at Least One Adverse Event, With Severity Determined According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0)

The adverse event (AE) severity grading scale NCI CTCAE v5.0 was used for assessing AE severity. Any AEs for which the NCI CTCAE v5.0 did not provide a grading scale, the standard four-point scale from 1 to 4 (mild, moderate, severe, life-threatening) was used. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. AEs to monitor included administration-related reactions, hypersensitivity and anaphylaxis, diarrhoea, rash, cardiac dysfunction, neutropenia or febrile neutropenia, mucositis, and interstitial lung disease.

Time frame: From study drug dose until safety follow-up visit (up to 7 months)

Change From Baseline Left Ventricular Ejection Fraction (LVEF) Over Time

Echocardiography was used to assess left ventricular ejection fraction (LVEF) values. The screening LVEF assessment had to be performed within ≤28 days prior to randomization and the LVEF value must have been ≥55% to be eligible for the study.

Time frame: Baseline, once between Days 20 and 35, and once between Days 56 and 63

Change From Baseline Pulse Rate Over Time

Vital sign measurements were taken after the participant had remained resting in a semi-supine position for at least 5 minutes. The minimum and maximum values are, respectively, the smallest and largest values obtained at any point after baseline, including any repeat and unscheduled measurements.

Time frame: Baseline, Days 2, 7, 22, and 63

Change From Baseline Respiratory Rate Over Time

Time frame: Baseline, Days 2, 7, 22, and 63

Change From Baseline Systolic Blood Pressure Over Time

Time frame: Baseline, Days 2, 7, 22, and 63

Change From Baseline Diastolic Blood Pressure Over Time

Time frame: Baseline, Days 2, 7, 22, and 63

Number of Participants With Normal or Abnormal Electrocardiogram Results at Baseline and Post-Baseline Anytime, as Determined by the Investigator

For safety monitoring purposes, the investigator was required to review, sign, and date all electrocardiogram (ECG) reports. Any morphologic waveform changes or other ECG abnormalities were documented by the investigator. Post-baseline, if all examinations were normal, then it was categorized as 'Normal'. If any abnormality was reported, then it was categorized as 'Abnormal'. 'Clinically significant' is a subset of the abnormal category.

Time frame: At Baseline (predose) and Post-Baseline (postdose Days 2, 7, 22, and 63)

Number of Participants With Adverse Events Based on Laboratory Test Abnormalities

Not every laboratory abnormality qualified as an adverse event. A laboratory test result had to be reported as an adverse event if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment; resulted in a medical intervention or a change in concomitant therapy; was clinically significant in the investigator's judgment.

Time frame: From Baseline until Day 63

Pain Score at the Injection Site, Assessed by the Participant Using the 100-millimetre (mm) Visual Analog Scale

Pain intensity scores were assessed by the participants using the Visual Analog Scale (VAS) on a line measuring between 0 mm ('no pain') and 100 mm ('unbearable pain'). The VAS was completed in both study arms to assess the level of pain experienced by the participant in relation to the injection of Phesgo. On Day 1, pain assessments were performed prior to, during, and immediately after injection of Phesgo when the needle or device was removed, and 2 hours after injection.

Time frame: Day 1: pre-dose, during drug injection, after drug injection while removing the device or syringe, and 2 hours after drug injection

Number of Participants With Skin Irritation and Sensitization Reactions at the Injection Site, as Reported by Investigators in the Device Monitoring Questionnaire

Skin irritation and sensitization reactions at the site of injection caused by the adhesion of the OBDS to the skin were assessed by the study staff using the device monitoring questionnaire in the eCRF. Dermal effects were reported on a scale from 0 (no evidence or irritation) to 7 (strong reaction spreading beyond test site). Other effects were reported on a separate scale from 0 (no evidence) to 7 (small petechial eruptions or scabs).

Time frame: Prior to injection and after injection on Day 1

Number of Participants by Their Ratings of the Comfort of Wearing the On-Body Delivery System Device, as Reported in the Device Monitoring Questionnaire

Participants in the Phesgo OBDS arm completed the device monitoring questionnaire the injection with the OBDS. The questionnaire assessed the following criteria: ease of device attachment, attachment during the injection, ease of device removal, and overall wearing comfort, which were each rated on a three-point scale as "Good", "Acceptable", or "Poor".

Time frame: Day 1

Number of Healthcare Professionals by Their Responses to the Device Monitoring Questionnaire Regarding Use of the On-Body Delivery System Device

Details of performance and ease of use of the on-body delivery system (OBDS) were reported by site staff, using the device monitoring questionnaire in the eCRF. This included the following: Preparation of the injection site, Preparation of the OBDS, Prefilled cartridge inspection before insertion in the OBDS, Positioning and attachment of the OBDS on the anterior thigh, Drug delivery, and OBDS administration failures.

Time frame: Day 1