A Study Of The Safety And Effects Of One Or More Doses Of HSP-130 Injected Under The Skin In Women With Breast Cancer That Has Not Spread To Distant Sites In The Body.

Non-metastatic Breast Cancer Clinical Trial

Official title:

A Phase 1-2 Ascending Dose Study To Assess The Pharmacodynamics, Pharmacokinetics, And Safety Of Hsp-130 In Subjects With Non-metastatic Breast Cancer Following Single-dose And Multiple-dose Administration By Subcutaneous Injection

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02650193
• Other study ID #: ZIN-130-1504
• Secondary ID: C12210022015-002
• Status: Completed
• Phase: Phase 2
• Start date: December 2015
• Est. completion date: October 2017

Study information

• Verified date: September 2018
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a study of how one or more injections of HSP-130 under the skin effect the white blood cell counts and drug levels in women with breast cancer that has not spread to distant sites in the body (non-metastatic). This will be studied in women before breast surgery or while receiving chemotherapy. Safety will also be studied.

Additionally, the purpose of this study is to evaluate the effects and safety of single and multiple doses of HSP-130 in subjects with non-metastatic breast cancer. This study will determine the dose to move forward for future clinical trials.

Description:

This is an open-label, sequential enrollment study characterizing the pharmacodynamic (PD), pharmacokinetic (PK) and safety of HSP-130 in subjects with non-metastatic breast cancer who have not previously received chemotherapy at any point prior to enrollment in this study (ZIN-130-1504).

The purpose of this study is to evaluate the effects and safety of single and multiple doses of HSP-130 in subjects with non-metastatic breast cancer. This study will determine the dose to move forward for future clinical trials.

There are two aspects of the study. In the initial part of the study, 6 subjects will be sequentially enrolled to receive HSP-130 treatment (3 mg , or 6 mg by subcutaneous injection) during the period between biopsy and definitive surgery. This will determine whether 3 mg and 6 mg have similar or different effects on the PD variables (absolute neutrophil counts and CD34+ cell counts). This part of the study is referred to as Cycle 0 since study subjects will receive no chemotherapy while receiving HSP-130 until the effect of HSP-130 on the PD variables is known. A total of 12 subjects may be enrolled in Cycle 0.

The objective of Cycle 1-4 is to determine the dose to be taken forward to Phase 3 clinical trials. Cycles 1-4 subjects will receive HSP-130 after their definitive breast surgery at the time they receive TAC chemotherapy (docetaxel, doxorubicin, and cyclophosphamide). Subjects will receive up to 4 cycles of every 3 week TAC chemotherapy with HSP-130 given on Day 2 of the chemotherapy regimen.

• If the 3 mg dose is found to be inferior (potentially subtherapeutic) to the 6 mg dose in Cycle 0, only the 6 mg dose will be studied in Cycles 1-4 (n=12), when subjects receive concomitant chemotherapy.

• If the 3 mg dose is found to be comparable to the PD results obtained in Cycle 0 with 6 mg, the 3 mg dose (n=12) will also be studied in women receiving TAC chemotherapy.

Data from the HSP-130 6 mg regimen (plus 3 mg, as appropriate) will be analysed, discussed with the FDA and determination if a dose greater than 6 mg is appropriate to study (e.g., 12 mg). If all three doses are studied, a total enrollment of up to 36 subjects is projected for Cycles 1-4.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: October 2017
• Est. primary completion date: October 2017
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• A subject will be eligible for study participation if all of the following criteria are met at Screening:

1. Is informed, has been given ample time and opportunity to read about participation in the study and has signed and dated the written informed consent form approved by an Independent Ethics committee (IEC) prior to any study related activities

2. Females = 18 years

3. Histologically confirmed and documented invasive breast cancer

4. Breast cancer without evidence of distant metastases (Stage 4) based on staging work-up

5. Chemotherapy naive, who have not received chemotherapy in the neoadjuvant setting and who are candidates for chemotherapy in the adjuvant setting of taxane/cyclophosphamide-based regimen, e.g., TAC, as background chemotherapy

6. Zubrod/WHO/ECOG performance status = 2

7. Adequate bone marrow, hepatic, and renal function reserve as evidenced by:

1. Hemoglobin = 10 mg/dl

2. ANC = 1.5 x 10^9/L

3. Platelet count of = 100 x 10^9/L

4. Total bilirubin = 2 mg/dl

5. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) = 3 x the upper limit of normal (ULN) of the reference lab

6. Serum creatinine of = 1.5 x ULN for reference lab or estimated glomerular filtration rate (eGFR) of = 60 mg/min

8. Body mass index (BMI) of 19 to 40 kg/m^2 , inclusive

9. Subjects of childbearing potential, and their partners, agree to pregnancy prevention throughout the duration of the study (through the Follow-up Visit). Specific type of pregnancy prevention should be discussed with, and acceptable to, the treating oncologist in the context of the tumoral hormone receptor status. Subjects and their partners must agree to use of an effective method of contraception, to avoid impregnation of females throughout the course of the study

Medically acceptable forms of birth control can include, with approval of the treating physician:

1. Barrier methods (condom or diaphragm with spermicide)

2. Intrauterine device (IUD)

3. Hormone contraceptives (such as oral [pill], injection, skin patch, implant, cervical ring)

4. Subjects using oral contraceptives must be on a stable regimen for at least 3 months prior to Screening. Sexually active subjects must use contraception while on HSP-130 from admission to the final Follow-up Visit

10. Able to understand verbal or written instructions and comply with all study requirements, to communicate effectively with study personnel and is available for the planned duration of the study

Exclusion Criteria:

• A subject will NOT be eligible for study participation if any of the following criteria are met at Screening:

1. Previous G-CSF exposure, including filgrastim, lenograstim, pegfilgrastim, lipegfilgrastim, granulocyte/macrophage colony stimulating growth factor (GM-CSF), or any other branded or biosimilar G-CSF

2. Prior autologous stem cell harvest of any type

3. Drug sensitivity, allergic reaction, or known hypersensitivity or idiosyncratic reaction to E. coli - derived proteins, filgrastim, other G-CSFs, or pegylated agents

4. Known hypersensitivity to docetaxel, polysorbate 80, or doxorubicin

5. For subjects receiving doxorubicin, no concurrent use of inhibitors and inducers of CYP3A4, CYP2D6, and/or P-gp or with trastuzumab due to increased risk of cardiac dysfunction

6. Chemotherapy other than that included in this study (taxane/cyclophosphamide-based regimen, e.g., TAC or TC) or neoadjuvant chemotherapy; or known immunosuppressive agents including chronic oral corticosteroid use, or radiation therapy within 4 weeks of first dose of HSP-130, prior bone marrow or stem cell transplantation, or malignancy within 5 years

7. Known HER2 + ( overexpressing breast cancer)

8. Known triple negative (estrogen receptor-negative, progesterone receptor-negative and HER2-negative) breast cancer

9. = Grade 2 underlying neuropathy

10. Current diagnosis of active tuberculosis or other severe infection, such as sepsis, abscesses or opportunistic infections

11. Treatment with systemically active antibiotics within 72 hours before chemotherapy

12. Known infection with HIV

13. Known sickle cell disease

14. Known severe persistent drug-induced myelosuppression

15. New York Heart Association (NYHA) class III or IV heart failure, severe uncontrolled cardiac disease (unstable angina, clinically significant ECG abnormalities) or MI within the previous 6 months before the first administration of HSP-130

16. Any malignancy other than breast cancer, with exception of adequately treated squamous or basal cell carcinoma of the skin or cervical carcinoma in situ, within 5 years before the first administration of the HSP-130

17. Current or recent treatment (within 30 days before the first administration of the HSP-130) with any other investigational medicinal product

18. Pregnancy or lactation; Subjects planning to be pregnant or to breastfeed before, during, or within 12 months after administration of the HSP-130 are not permitted to enroll in the study

19. Received a live, live-attenuated, or non-live vaccine within 4 weeks before the first administration of the HSP-130

20. Patient has evidence of any other coexisting disease or medical or psychological condition, metabolic dysfunction, physical examination finding or clinical lab finding giving reasonable suspicion of a disease or condition that contraindicated the use of an HSP-130, or patient is high risk for treatment complication

Related Conditions & MeSH terms

• Breast Neoplasms
• Non-metastatic Breast Cancer

Intervention

Drug:
• HSP-130
Dosage will vary per each cohort: (Five independent cohorts) Cycle 0 Regimen A - 3 mg Cycle 0 Regimen B - 6 mg Cycles 1-4 Regimen B - 6 mg Cycles 1-4 Regimen A (Potential)- 3 mg Cycles 1-4 Regimen C (Conditional)- 12 mg

Locations

Country	Name	City	State
Hungary	Országos Onkológiai Intézet	Budapest
Hungary	Debreceni Egyetem Klinikai Központ, ÁOK, Onkológiai Klinika	Debrecen	Hajdú-bihar Megye
Hungary	CRU Hungary Kft.,CRU Early Phase Unit, Miskolci Semmelweis Kórház és Egyetemi Oktató Kórház	Miskolc	BAZ Megye
Spain	Hospital Universitario de Fuenlabrada, Servicio de oncologia	Fuenlanbrada	Madrid
Spain	Hospital Universitario Arnau de Vilanova	Lleida	Cataluna
Spain	START Madrid - CIOCC, Unidad de fases 1 planta 3, Hospital Universitario HM Sanchinarro	Madrid
Spain	Hospital Arnau de Vilanova. planta 6, unidad de Oncología	Valencia

Sponsors (2)

Lead Sponsor	Collaborator
Pfizer	Hospira, now a wholly owned subsidiary of Pfizer

Countries where clinical trial is conducted

Hungary,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in participants who received study drug without regard to possibility of causal relationship. 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. Treatment Emergent Adverse Event (TEAE) was adverse event that started or worsened in severity after the HSP-130 administration up to and including 30 days post HSP-130 administration (up to Day 94). AEs included both serious and non-serious.	Baseline up to approximately Day 94
Other	Number of Participants With Treatment-Emergent Adverse Events (AEs) of Special Interest	AEs of Special Interest (AESI) included Potential Allergic Reactions, Splenomegaly, Splenic Rupture, Acute Respiratory Distress Syndrome, Alveolar Hemorrhage, Hemoptysis, Leukocytosis, Thrombocytopenia, Capillary Leak Syndrome, Cytokine Release Syndrome, Cutaneous Vasculitis and Glomerulonephritis.	Baseline up to approximately Day 94
Other	Number of Participants With Laboratory Abnormalities	Criteria: hematology (hemoglobin, hematocrit, platelet count, white blood cell count, neutrophils); chemistry (alkaline phosphatase, glucose, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, albumin, creatinine and gamma-glutamyl transpeptidase, blood urea nitrogen, total protein, phosphate, and uric acid); urinalysis. The clinical laboratory results and patterns observed were consistent with the known therapeutic response and the safety profile for the US and EU approved pegylated filgrastim (Neulasta).	Baseline up to approximately Day 94
Other	Number of Participants With Clinically Significant Vital Sign Abnormalities	Vital sign assessment included body temperature (tympanic or axillary), heart rate (sitting), blood pressure (sitting systolic and diastolic), and respiratory rate. Clinically significant abnormality was based upon investigator's discretion.	Baseline up to approximately Day 94
Other	Number of Participants With Clinically Significant Physical Examination Abnormalities	Physical examination included physical assessment of the spleen. Clinically significant abnormality was based on investigator's discretion.	Baseline up to approximately Day 94
Other	Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities	Clinically significant abnormality was based upon investigator's discretion.	Baseline up to approximately Day 94
Other	Number of Participants With At Least 1 Concomitant Medication		Baseline up to approximately Day 94
Other	Duration of Exposure to Study Drug Medication		Baseline up to approximately Day 94
Other	Number of Participants With Positive Anti-pegfilgrastim (Anti-drug) Antibodies		Baseline up to approximately Day 94
Primary	Area Under the Effect Curve for Absolute Neutrophil Count (AUECANC): Cycle 0	Absolute neutrophil count (ANC) is a measure of the number of neutrophil granulocytes (also known as polymorphonuclear cells, PMN's, polys, granulocytes, segmented neutrophils or segs) present in the blood.	Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Primary	Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time Infinity (AUCinf): Cycle 0	AUCinf = Area under the serum concentration of HSP-130 versus time curve (AUC) from the time of dose administration to extrapolated infinite time (0-inf).	Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Primary	Maximum Observed Serum Concentration (Cmax): Cycle 0		Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Primary	Duration of Severe Neutropenia (DSN): Cycle 1	Severe Neutropenia was defined as grade 4 neutropenia in which the ANC was < 0.5 x10^9 per liter. DSN was defined as the days with grade 4 neutropenia (ANC < 0.5 x10^9/L).	Cycle 1: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Primary	Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time of Last Measurable Concentration (AUCt): Cycle 1 and Cycle 4	AUC0-t= Area under the serum concentration of HSP-130 versus time curve from the time of dose administration to time of last quantifiable concentration (0-t).	Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Primary	Maximum Observed Serum Concentration (Cmax): Cycle 1 and Cycle 4		Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Maximum Effect for Absolute Neutrophil Count (ANC_Emax): Cycle 0	ANC was a measure of the number of neutrophil granulocytes (also known as polymorphonuclear cells, PMN's, polys, granulocytes, segmented neutrophils or segs) present in the blood.	Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Time of Maximum Effect for Absolute Neutrophil Count (ANC_Tmax): Cycle 0	ANC was a measure of the number of neutrophil granulocytes (also known as polymorphonuclear cells, PMN's, polys, granulocytes, segmented neutrophils or segs) present in the blood.	Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Area Under the Effect Curve for CD34+ (AUECCD34+): Cycle 0		Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Maximum Effect for CD34+ Count (CD34+_Emax): Cycle 0		Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Time of Maximum Effect for CD34+ Count (CD34+ Tmax): Cycle 0		Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Area Under the Effect Curve for Absolute Neutrophil Count From Time of Dose Administration to Time Infinity (AUEC_ANC Inf): Cycle 0	ANC is a measure of the number of neutrophil granulocytes (also known as polymorphonuclear cells, PMN's, polys, granulocytes, segmented neutrophils or segs) present in the blood.	Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Area Under the Effect Curve From Time of Dose Administration to Time Infinity for CD34 + (AUEC_CD34+ Inf): Cycle 0		Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Area Under the Serum Concentration Time Curve From the Time of Dose Administration to the Time of Last Measurable Concentration (AUCt): Cycle 0	AUC0-t= Area under the serum concentration of HSP-130 versus time curve from the time of dose administration to time of last quantifiable concentration (0-t).	Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Time To Achieve Maximum Serum Concentration (Tmax): Cycle 0		Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Elimination Half-Life (t1/2): Cycle 0	t1/2 is the time taken for plasma concentration of HSP 130 to reduce by 50 percent (%) of its initial value.	Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Elimination Rate Constant (?z): Cycle 0	Elimination rate constant was defined as the rate at which the drug was removed from the body.	Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Apparent Clearance (CL/F): Cycle 0	Clearance of a drug was defined as the rate at which a drug was metabolized or eliminated by normal biological processes.	Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Protein-Content Corrected Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time Infinity (AUCinf): Cycle 0	The protein-content correction was conducted for AUCinf parameter: Protein-content corrected AUCinf = Nominal Protein-content AUCinf / (Actual protein concentration/10.0 mg/mL).	Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Protein-Content Corrected Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time of Last Measurable Concentration (AUCt): Cycle 0	The protein-content correction was conducted for AUCt parameter: Protein-content corrected AUCt= Nominal Protein-content AUCt / (Actual protein concentration/10.0 mg/mL).	Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Protein-Content Corrected Maximum Observed Serum Concentration (Cmax): Cycle 0	The protein-content correction was conducted for Cmax parameter: Protein-content corrected Cmax = Nominal Protein-content Cmax / (Actual protein concentration/10.0 mg/mL).	Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Duration of Severe Neutropenia (DSN): Cycle 4	Severe Neutropenia was defined as grade 4 neutropenia in which the ANC was < 0.5 x10^9/L. DSN was defined as the days with grade 4 neutropenia (ANC < 0.5 x10^9/L).	Cycle 4: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Absolute Neutrophil Count Nadir Concentration: Cycle 1 and Cycle 4	Nadir was defined as the lowest count for ANC concentration reported after first dose of study treatment.	Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240, and 312 hours post-dose
Secondary	Time of ANC Nadir Concentration: Cycle 1 and Cycle 4	Time of ANC Nadir (in hours) was defined as the time from the first dose of study treatment on Day 2 of Cycle 1 and 4 to the time the lowest value was recorded.	Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240, and 312 hours post-dose
Secondary	Area Under the Effect Curve (AUEC_ANCt): Cycle 1 and Cycle 4	ANC is a measure of the number of neutrophil granulocytes (also known as polymorphonuclear cells, PMN's, polys, granulocytes, segmented neutrophils or segs) present in the blood.	Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240, and 312 hours post-dose
Secondary	Area Under the Effect Curve for Absolute Neutrophil Count From Time of Dose Administration to Time Infinity (AUEC_ANC Inf): Cycle 1 and Cycle 4	Absolute neutrophil count (ANC) is a measure of the number of neutrophil granulocytes (also known as polymorphonuclear cells, PMN's, polys, granulocytes, segmented neutrophils or segs) present in the blood.	Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Incidence of Febrile Neutropenia: Cycle 1 and Cycle 4	Febrile Neutropenia was defined as tympanic or axillary body temperature greater than (>) 38.5 °C for >1 hour and ANC less than (<) 1.0 *10^9/L.	Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Incidence of Severe Neutropenia: Cycle 1 and Cycle 4	Severe Neutropenia was defined as grade 4 neutropenia in which the ANC was < 0.5 x10^9/L.	Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240, and 312 hours post-dose
Secondary	Time to ANC Recovery: Cycle 1 and Cycle 4	Time to ANC recovery was defined as the time from documentation of the first day with ANC greater than equal to (>=) 2.0 x10^9/L after any day with ANC <2.0 x10^9/L.	Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time Infinity (AUCinf): Cycle 1 and Cycle 4	AUC0-inf = Area under the serum concentration versus time curve (AUC) from the time of dose administration to extrapolated infinite time (0-inf).	Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Time To Achieve Maximum Serum Concentration (Tmax): Cycle 1 and Cycle 4		Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Elimination Half-Life (t1/2): Cycle 1 and Cycle 4	t1/2 is the time taken for plasma concentration of a drug to reduce by 50% of its initial value.	Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Elimination Rate Constant (?z): Cycle 1 and Cycle 4	Elimination rate constant was defined as the rate at which the drug was removed from the body.	Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Apparent Clearance (CL/F): Cycle 1 and Cycle 4	CL/F was defined as a quantitative measure of the rate at which a drug substance is removed from the body.	Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Protein-Content Corrected Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time of Last Measurable Concentration (AUCt): Cycle 1 and Cycle 4	The protein-content correction was conducted for AUCt parameter: Protein-content corrected AUCt= Nominal Protein-content AUCt / (Actual protein concentration/10.0 mg/mL).	Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Protein-Content Corrected Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time Infinity (AUCinf): Cycle 1 and Cycle 4	The protein-content correction was conducted for AUCinf parameter: Protein-content corrected AUCinf = Nominal Protein-content AUCinf / (Actual protein concentration/10.0 mg/mL).	Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary	Protein-Content Corrected Maximum Observed Serum Concentration (Cmax): Cycle 1 and Cycle 4	The protein-content correction was conducted for Cmax parameter: Protein-content corrected Cmax = Nominal Protein-content Cmax / (Actual protein concentration/10.0 mg/mL).	Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose