Clinical trial NCT02650193: 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.
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-metastatic Breast Cancer
Keywords: HSP-130 Phase 1-2 Study in patients with Breast cancer
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: Hospira, now a wholly owned subsidiary of Pfizer
First posted: 2016-01-08
Enrollment: 25
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: OTHER

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Area Under the Effect Curve for Absolute Neutrophil Count (AUECANC): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time Infinity (AUCinf): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Maximum Observed Serum Concentration (Cmax): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Duration of Severe Neutropenia (DSN): Cycle 1
timeFrame: Cycle 1: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time of Last Measurable Concentration (AUCt): Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Maximum Observed Serum Concentration (Cmax): Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Secondary outcomes:
measure: Maximum Effect for Absolute Neutrophil Count (ANC_Emax): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Time of Maximum Effect for Absolute Neutrophil Count (ANC_Tmax): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Area Under the Effect Curve for CD34+ (AUECCD34+): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Maximum Effect for CD34+ Count (CD34+_Emax): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Time of Maximum Effect for CD34+ Count (CD34+ Tmax): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Area Under the Effect Curve for Absolute Neutrophil Count From Time of Dose Administration to Time Infinity (AUEC_ANC Inf): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Area Under the Effect Curve From Time of Dose Administration to Time Infinity for CD34 + (AUEC_CD34+ Inf): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Area Under the Serum Concentration Time Curve From the Time of Dose Administration to the Time of Last Measurable Concentration (AUCt): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Time To Achieve Maximum Serum Concentration (Tmax): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Elimination Half-Life (t1/2): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Elimination Rate Constant (λz): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Apparent Clearance (CL/F): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Protein-Content Corrected Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time Infinity (AUCinf): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Protein-Content Corrected Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time of Last Measurable Concentration (AUCt): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Protein-Content Corrected Maximum Observed Serum Concentration (Cmax): Cycle 0
timeFrame: Cycle 0: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Duration of Severe Neutropenia (DSN): Cycle 4
timeFrame: Cycle 4: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Absolute Neutrophil Count Nadir Concentration: Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240, and 312 hours post-dose
measure: Time of ANC Nadir Concentration: Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240, and 312 hours post-dose
measure: Area Under the Effect Curve (AUEC_ANCt): Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240, and 312 hours post-dose
measure: 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
timeFrame: Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Incidence of Febrile Neutropenia: Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Incidence of Severe Neutropenia: Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240, and 312 hours post-dose
measure: Time to ANC Recovery: Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time Infinity (AUCinf): Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Time To Achieve Maximum Serum Concentration (Tmax): Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Elimination Half-Life (t1/2): Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Elimination Rate Constant (λz): Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Apparent Clearance (CL/F): Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: 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
timeFrame: Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Protein-Content Corrected Area Under the Serum Concentration Time Curve From Time of Dose Administration to Time Infinity (AUCinf): Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
measure: Protein-Content Corrected Maximum Observed Serum Concentration (Cmax): Cycle 1 and Cycle 4
timeFrame: Cycle 1 and 4: Predose (0 hour), 6, 12, 24, 48, 96, 144, 192, 240 and 312 hours post-dose
Other outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to approximately Day 94
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) of Special Interest
timeFrame: Baseline up to approximately Day 94
measure: Number of Participants With Laboratory Abnormalities
timeFrame: Baseline up to approximately Day 94
measure: Number of Participants With Clinically Significant Vital Sign Abnormalities
timeFrame: Baseline up to approximately Day 94
measure: Number of Participants With Clinically Significant Physical Examination Abnormalities
timeFrame: Baseline up to approximately Day 94
measure: Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities
timeFrame: Baseline up to approximately Day 94
measure: Number of Participants With At Least 1 Concomitant Medication
timeFrame: Baseline up to approximately Day 94
measure: Duration of Exposure to Study Drug Medication
timeFrame: Baseline up to approximately Day 94
measure: Number of Participants With Positive Anti-pegfilgrastim (Anti-drug) Antibodies
timeFrame: Baseline up to approximately Day 94
Locations:
city: Miskolc
country: Hungary
facility: CRU Hungary Kft.,CRU Early Phase Unit, Miskolci Semmelweis Kórház és Egyetemi Oktató Kórház
state: BAZ Megye
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Központ, ÁOK, Onkológiai Klinika
state: Hajdú-bihar Megye
city: Budapest
country: Hungary
facility: Országos Onkológiai Intézet
city: Lleida
country: Spain
facility: Hospital Universitario Arnau de Vilanova
state: Cataluna
city: Fuenlanbrada
country: Spain
facility: Hospital Universitario de Fuenlabrada, Servicio de oncologia
state: Madrid
city: Madrid
country: Spain
facility: START Madrid - CIOCC, Unidad de fases 1 planta 3, Hospital Universitario HM Sanchinarro
city: Valencia
country: Spain
facility: Hospital Arnau de Vilanova. planta 6, unidad de Oncología
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Yao HM, Jones SR, Morales S, Moosavi S, Zhang J, Freyman A, Ottery FD. Phase I/II study to assess the clinical pharmacology and safety of single ascending and multiple subcutaneous doses of PF-06881894 in women with non-distantly metastatic breast cancer. Cancer Chemother Pharmacol. 2021 Dec;88(6):1033-1048. doi: 10.1007/s00280-021-04355-6. Epub 2021 Oct 7.