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.

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Non-metastatic Breast Cancer

Intervention / Treatment
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* Drug: HSP-130


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A subject will be eligible for study participation if all of the following criteria are met at Screening: 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 Females ≥ 18 years Histologically confirmed and documented invasive breast cancer Breast cancer without evidence of distant metastases (Stage 4) based on staging work-up 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 Zubrod/WHO/ECOG performance status ≤ 2 Adequate bone marrow, hepatic, and renal function reserve as evidenced by: Hemoglobin ≥ 10 mg/dl ANC ≥ 1.5 x 10^9/L Platelet count of ≥ 100 x 10^9/L Total bilirubin ≤ 2 mg/dl Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3 x the upper limit of normal (ULN) of the reference lab Serum creatinine of ≤ 1.5 x ULN for reference lab or estimated glomerular filtration rate (eGFR) of ≥ 60 mg/min Body mass index (BMI) of 19 to 40 kg/m^2 , inclusive 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: Barrier methods (condom or diaphragm with spermicide) Intrauterine device (IUD) Hormone contraceptives (such as oral [pill], injection, skin patch, implant, cervical ring) 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 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: 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 Prior autologous stem cell harvest of any type Drug sensitivity, allergic reaction, or known hypersensitivity or idiosyncratic reaction to E. coli - derived proteins, filgrastim, other G-CSFs, or pegylated agents Known hypersensitivity to docetaxel, polysorbate 80, or doxorubicin 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 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 Known HER2 + ( overexpressing breast cancer) Known triple negative (estrogen receptor-negative, progesterone receptor-negative and HER2-negative) breast cancer ≥ Grade 2 underlying neuropathy Current diagnosis of active tuberculosis or other severe infection, such as sepsis, abscesses or opportunistic infections Treatment with systemically active antibiotics within 72 hours before chemotherapy Known infection with HIV Known sickle cell disease Known severe persistent drug-induced myelosuppression 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 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 Current or recent treatment (within 30 days before the first administration of the HSP-130) with any other investigational medicinal product 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 Received a live, live-attenuated, or non-live vaccine within 4 weeks before the first administration of the HSP-130 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HSP-130<br>Cycle 0: Regimen A: HSP 130, 3 mg, single SC injection in the deltoid region (n = 6) Regimen B: HSP 130, 6 mg, single SC injection in the deltoid region (n = 6) Cycles 1-4: Regimen B (n = 12): HSP 130, 6 mg, single SC injection in the deltoid region, at least 24 hours after administration of chemotherapy in Cycle 1, Cycle 2, Cycle 3, and Cycle 4. Potential Regimen A (n = 12): 3 mg with background chemotherapy: Inclusion of this cohort will be based on assessment of comparability between Regimens A and B in Cycle 0 for ANC and CD34+ as defined above. If performed, this regimen will be HSP 130, 3 mg, single SC injection in the deltoid region, at least 24 hours after administration of chemotherapy in Cycle 1, Cycle 2, Cycle 3, and Cycle 4, as appropriate. Conditional Regimen C (12 mg):This cohort will not be initiated until data from cycle 0 for 3 mg and 6 mg and Cycles 1-4 for 6 mg has been reviewed and analyzed. | Drug: HSP-130<br>* 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<br>* Other names: Pegylated filgrastim;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| Maximum Effect for CD34+ Count (CD34+_Emax): Cycle 0 |  | Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Elimination Rate Constant (λz): 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Elimination Rate Constant (λz): 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HSP-130 Phase 1-2 Study in patients with Breast cancer