BP-C1 in Metastatic Breast Cancer Patients

Study Overview
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Brief Summary
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This study is an open label, non-randomized phase I single-armed study in women with metastatic breast cancer (MBC) who have previously undergone all available standard chemotherapy regimens. The purpose of the study is to estimate the pharmacokinetics (PK) after single dose and multiple dose of BP-C1, investigate interleukin levels during BP-C1 treatment and assess treatment response according to RECIST criteria.

Detailed Description
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BP-C1, solution for injections 0.05%, is currently being developed for treatment of patients with metastatic breast cancer with palliative intent. Active substance of the product, which is a novel platinum-containing anticancer agent developed for intramuscular administration, is а cis-diammineplatinum(II) complexed with a polymer containing benzene polycarboxylic acids derived from lignin. The amphiphilic characteristics of the polymer have resulted in a product with clear and significantly altered and improved properties compared to other platinum analogues, e.g. cisplatin, carboplatin and oxaliplatin. BP-C1 preserves antitumour activity of its predecessors (e.g. cisplatin and carboplatin), additionally offering the following advantages that ensure favourable outcome of treatment of metastatic breast cancer patients: injectable solution (intramuscular) does not cause injection site reactions; can be administered at home by a nurse or a patient; has an improved pharmacokinetic profile; demonstrates efficacy comparable to cisplatin and much higher than carboplatin (in-vitro; in-vivo data); exerts an additional immunomodulatory activity. In this study six female patients with MBC who have previously undergone at least third line therapy will be enrolled. Each included patient will participate in a screening period (maximum duration of 21 days) following by 32-day treatment period and 28-day follow-up period. The patients will be treated with BP-C1(daily intramuscular injections) for 32 consecutive days. The study is undertaken to evaluate pharmacokinetics, pharmacodynamics and treatment effect of BP-C1.

Official Title
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Pharmacokinetic, Pharmacodynamic and Interleukin Profile of Intramuscularly Administered BP-C1 in Women With Metastatic Breast Cancer. A Phase ID Study

Conditions
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Metastatic Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: BP-C1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients with metastatic breast cancer (MBC, stage IV). 18 and 80 years of age. Measurable lesions / lymph nodes. Have previously undergone at least third line chemotherapy. Expected survival time at least 3 months. Exclusion Criteria: Abnormal liver function classified as total bilirubin >34 μmol/L or ALAT > 3 times the upper limit of normal range (ULN). In case of metastases in the liver, the ALAT limit for exclusion is set to 5xULN. Re-test results of blood samples taken again up to 2 days before Day-1 must keep meeting eligibility criteria. Abnormal kidney function defined by serum creatinine >120 μmol/L. Re-test results of blood samples taken again up to 2 days before Day-1 must keep meeting eligibility criteria. Abnormal coagulation capacity defined by the relative arbitrary concentration of coagulation factors 2,7,10 INR >1.3. Re-test results of blood samples taken again up to 2 days before Day-1 must keep meeting eligibility criteria. Brain metastases in symptomatic patients requiring ≥4 mg dexamethasone/day. However, patients with treated brain metastases by surgery or radiation who are stable and symptom-free (<4 mg dexamethasone/day) for a minimum period of 4 weeks prior to study treatment are eligible. Synchronous cancer except for non-melanoma skin cancer and early stage of cervical cancer. Abnormal haematology status defined by Hb < 9.0 g/dL, platelet count < 75,000/mm^3 and leukocytes < 3x10^9/L. Re-test results of blood samples taken again up to 2 days before Day-1 must keep meeting eligibility criteria. Clinically significant abnormal ECG. Karnofsky Performance Status Score < 50%. Pregnant or breast feeding women. Women of fertile age who do not want to be tested for possible pregnancy. Fertile female who do not want to use safe protection against pregnancy, starting one month before start of the trial treatment and lasting at least six weeks after. Uncontrolled bacterial, viral, fungal or parasite infection. Under systemic treatment with corticosteroids or other immunosuppressive drugs during the last 21 days before start of the trial treatment. Systemic treatment with <4 mg dexamethasone/day is allowed Participating in another clinical trial with pharmaceuticals during the last six weeks before start of this trial treatment. Not able to understand written or oral information. Do not want or is not able to give written consent to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BP-C1 IM Injections<br>BP-C1 given in daily intramuscular doses of 0.035 mg/kg bodyweight in one syringe per day during a total treatment of 32 days. | Drug: BP-C1<br>* BP-C1, 0.05% solution for injection; doses: 0.035 mg/kg body weight (0.07 mL/kg) intramuscularly once daily for 32 consecutive days<br>* Other names: Cis-diammineplatinum(II) complex, containing mono-deprotonated benzene-poly-carboxylic acids, derived from lignin, and hydroxyl group as O-donor ligands;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single-dose PK: Maximum Observed Serum Concentration (Cmax) for Platinum | Maximum Observed Serum Concentration (Cmax) for Platinum after the single dose of BP-C1 during the period of Day-1 to Day 1 | Pre-dose, 10, 20, 30, 35, 40, 45, 60, 120 min and 6, 24, 48 hours post dose | 
| Single-dose PK: Time to Reach Maximum Observed Serum Concentration (Tmax) for Platinum | Time to Reach Maximum Observed Serum Concentration (Tmax) for Platinum after the single dose of BP-C1 during the period of Day-1 to Day 1 | Pre-dose, 10, 20, 30, 35, 40, 45, 60, 120 min and 6, 24, 48 hours post dose | 
| Single-dose PK: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC(0-t)) for Platinum | AUC(0-t) = Area under the serum concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration after the single dose of BP-C1 during the period of Day-1 to Day 1 | Pre-dose, 10, 20, 30, 35, 40, 45, 60, 120 min and 6, 24, 48 hours post dose | 
| Single-dose PK: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC(0-∞)) | after the single dose of BP-C1 during the period of Day-1 to Day 1 | Pre-dose, 10, 20, 30, 35, 40, 45, 60, 120 min and 6, 24, 48 hours post dose | 
| Single-dose PK: Serum Decay Half-Life (T1/2) for Platinum | Serum decay half-life is the time measured for the serum concentration of Platinum to decrease by one half after the single dose of BP-C1 during the period of Day-1 to Day 1 | Pre-dose, 10, 20, 30, 35, 40, 45, 60, 120 min and 6, 24, 48 hours post dose during the period of Day-1 to Day 1 | 
| Multiple-dose PK: Maximum Observed Serum Concentration at Steady State (Css,max) for Platinum | Maximum Observed Serum Concentration at steady state (Css,max) for Platinum during the period of Day 32 to Day 34 | Pre-dose, 10, 20, 30, 35, 40, 45, 60, 120 min and 6, 24, 48 hours post dose | 
| Multiple-dose PK: Time to Reach Maximum Observed Serum Concentration at steady state (Tss,max) for Platinum | Time for Css,max at steady state for Platinum during the period of Day 32 to Day 34 | Pre-dose, 10, 20, 30, 35, 40, 45, 60, 120 min and 6, 24, 48 hours post dose | 
| Multiple-dose PK: Minimum Observed Serum Concentration at Steady State (Css,min) for Platinum | Minimum Observed Serum Concentration at Steady State (Css,min) for Platinum during the period of Day 32 to Day 34 | Pre-dose, 10, 20, 30, 35, 40, 45, 60, 120 min and 6, 24, 48 hours post dose | 
| Multiple-dose PK: Average Serum concentration at steady state (Css,av) for Platinum | Average Serum concentration at steady state (Css,av) for Platinum during the period of Day 32 to Day 34 | Pre-dose, 10, 20, 30, 35, 40, 45, 60, 120 min and 6, 24, 48 hours post dose | 
| Multiple-dose PK: Area Under the Curve within a dosing interval of tau (=24 hr) at steady state (AUCss,tau) for Platinum | Area under the serum concentration versus time curve within a dosing interval of tau (=24 hr) at steady state (AUCss,tau) during the period of Day 32 to Day 34 | Pre-dose, 10, 20, 30, 35, 40, 45, 60, 120 min and 6, 24, 48 hours post dose | 
| Multiple-dose PK: Serum Decay Half-Life (T1/2) for Platinum | Serum decay half-life is the time measured for the plasma concentration of Platinum to decrease by one half during the period of Day 32 to Day 34 | Pre-dose, 10, 20, 30, 35, 40, 45, 60, 120 min and 6, 24, 48 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interleukin Serum levels (Interferon γ and β, Tumour Necrosis Factor (TNF-α), IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-21 and IL-25) |  | Day-1, Day 1, Day 16, Day 32, Day 34 | 
| Change (%) in the sum of diameters of target lesions | Diameter of target lesions will be measured by computer tomography (CT) with contrasting using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | baseline to Day 32 of treatment | 
| Number of target lesions | Number of target lesions per each patient will be evaluated by CT with contrasting. Change in number of target lesions from baseline to Day 32 of treatment will be presented in shift tables | baseline to Day 32 of treatment | 
| Treatment response | In accordance with RECIST v1.1 the treatment response will be classified as 'complete response', 'partial response', 'stable disease' or 'progressive disease': Complete response (CR): disappearance of all target lesions. Partial response (PR): at least 30% decrease in the sum of longest diameters of target lesions, taking as reference the baseline sum of diameters. Progressive disease (PD): at least 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum might also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions will also be considered progression. Stable disease (SD): neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study | baseline to Day 32 of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Cis-diammineplatinum(II) complexed with a polymer containing benzene polycarboxylic acids derived from lignin, Cisplatin, Metastatic Breast Cancer, BP-C1, Metronomic chemotherapy, Platinum analogue, Benzene polycarboxylic acids complex with cis-diammineplatinum(II), Cis-diammineplatinum(II) complex, containing mono-deprotonated benzene-poly-carboxylic acids, derived from lignin, and hydroxyl group as O-donor ligands