Solid tumors and brain metastases or recurrent malignant glioma, HER2-positive adenocarcinoma of the breast with brain metastases MedDRA version: 14.1 Level: LLT Classification code 10065147 Term: Malignant solid tumor System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 14.1 Level: LLT Classification code 10065252 Term: Solid tumor System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: 2B3-101
Product Code: 2B3-101
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: DOXORUBICIN HYDROCHLORIDE
CAS Number: 25316-40-9
Concentration unit: mg/ml milligram(s)/mill
Sponsors
to-BBB technologies B.V.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: To be eligible to participate in this study, candidates must meet the following eligibility criteria: 1. Age = 18 years. 2. Measurable intracranial disease by MRI. 3. ECOG Performance Status = 2. 4. Estimated life expectancy of at least 8 weeks. 5. Toxicities incurred as a result of previous anticancer therapy (radiation therapy, chemotherapy, or surgery) must be resolved to = grade 2 (as defined by CTCAE version 4.0). 6. No evidence of (cortical) cognitive impairment as defined by a Mini-Mental Status Exam (MMSE) score = 25/30. 7. Written informed consent according to local guidelines. In addition to the above listed eligibility criteria, the following criteria are applicable: 8. 2B3-101 single agent dose-escalation phase: Patients with pathologically confirmed diagnosis of advanced, recurrent solid tumors and unequivocal evidence of brain metastases that are refractory to standard therapy or for whom no standard therapy exists or with unequivocal evidence of newly diagnosed untreated brain metastases and controlled extracranial disease. OR Patients with pathology confirmed diagnosis of advanced, recurrent primary malignant (grade III and IV) glioma that are refractory to standard therapy or for whom no standard therapy exists. 2B3-101 in combination with trastuzumab dose-escalation phase: Patients with histologically-confirmed HER2-positive adenocarcinoma of the breast with unequivocal evidence of brain metastases that are refractory to standard therapy or for which no standard therapy exist or with unequivocal evidence of newly diagnosed untreated brain metastases and controlled extracranial disease. Breast cancer brain metastases study- arm of the expansion phase: Patients with pathologically confirmed diagnosis of advanced, recurrent breast cancer with unequivocal evidence of brain metastases that are refractory to standard therapy or for whom no standard therapy exist. OR Patients with pathologically confirmed diagnosis of advanced breast cancer with newly diagnosed, untreated, brain metastases, which per multi-disciplinary team decision do not require immediate radiotherapy or surgery. Patients with histologically-confirmed HER2-positive adenocarcinoma of the breast with unequivocal evidence of brain metastases that are refractory to standard therapy or for which no standard therapy exist or with unequivocal evidence of newly diagnosed untreated brain metastases, which per the multi-disciplinary team decision do not require immediate radiotherapy or surgery SCLC brain metastases study arm of the expansion phase: Patients with pathologically confirmed diagnosis of advanced, recurrent SCLC with unequivocal evidence of brain metastases that are refractory to standard therapy or for whom no standard therapy exist. OR Patients with pathologically confirmed diagnosis of advanced SCLC with newly diagnosed, untreated, brain metastases, which per multi-disciplinary team decision do not require immediate radiotherapy or surgery. Melanoma brain metastases study arm of the expansion phase: - Patients with pathologically confirmed diagnosis of advanced, recurrent melanoma with unequivocal evidence of brain metastases that are refractory to standard therapy or for whom no standard therapy exist. OR Patients with pathologically confirmed diagnosis of advanced mel;anoma with newly diagnosed, untreated, brain metastases, which per multi-disciplinary team decision do not require
Exclusion criteria
Exclusion criteria: Candidates will be excluded from study entry if any of the following exclusion criteria exist: Prior Treatment: 1. Less than 1 week since the last treatment of lapatinib, less than 2 weeks since the last treatment of vemurafenib, less than 4 weeks since the last treatment of chemotherapy, biological therapy, immunotherapy and systemicradiotherapy (except palliative radiation delivered to 360mg/m2 or free epirubicin > 600mg/m2 Current Treatment: 3. Current or recent (within 30 days of first study treatment) treatment with another investigational drug or participation in another investigational study. Hematology, coagulation and biochemistry: 4. Inadequate bone marrow function: Absolute Neutrophil Count (ANC): 1.5 x the ULN for the institution if no liver metastases (> 2 x ULN in patients with liver metastases); • ASAT or ALAT > 2.5 x ULN if no liver metastases (> 4 x ULN in patients with liver metastases); • Alkaline phosphatase levels > 2.5 x ULN if no liver metastases (> 5 x ULN in patients with liver metastases, or > 10 x ULN in patients with bone metastases). 6. Inadequate renal function, defined as: • Serum creatinine > 1.5 x ULN. Other: 7. Leptomeningeal carcinomatosis as the only site of CNS involvement. 8. Pregnancy or lactation. Serum pregnancy test to be performed within 7 days prior to study treatment start, or within 14 days followed by a confirmatory urine pregnancy test within 7 days prior to study treatment start. 9. For female subjects of childbearing potential (defined as 150 mm Hg and/or diastolic > 100mm Hg). 13. Clinically significant (i.e. active) cardiovascular disease defined as: • Stroke within = 6 months prior to day 1; • Transient Ischemic Attack (TIA) within = 6 months prior to day 1; • Myocardial infarction within = 6 months prior to day 1; • Unstable angina; • New York Heart Association (NYHA) Grade II or greater Congestive Heart Failure (CHF); • Serious cardiac arrhythmia requiring medication; • Clinically relevant pathologic findings in ECG. 14. 14. Left Ventricle Ejection Fraction (LVEF) by MUGA or ECHO < 55% for patients recei
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the safety and tolerability of 2B3-101 when administered intravenously (IV) as single agent in patients with solid tumors and brain metastases or recurrent malignant glioma in order to determine the Maximum Tolerated Dose (MTD).;Secondary Objective: •Characterize the PK of 2B3-101 after multiple i.v. infusions as single agent and in combination with trastuzumab; •Evaluate the preliminary efficacy of 2B3-101 as single agent in terms of anti-tumor activity in patients with breast cancer with treated or untreated brain metastases. •Evaluate the preliminary efficacy of 2B3-101 as single agent in terms of anti-tumor activity in patients with other solid tumors with treated or untreated brain metastases, treated in the dose-escalation phase. •Evaluate the preliminary antitumor activity of 2B3-101 in combination with trastuzumab in patients with HER2+ breast cancer with treated or untreated brain metastases. •Evaluate the preliminary anti-tumor activity of 2B3-101 as single agent in patients with small cell lung cancer (SCLC) or melanomas with treated or untreated brain metastases. •To evaluate the preliminary efficacy of 2B3-101 in terms of anti-tumor activity as single agent in patients with recurrent malignant glioma. ;Primary end point(s): The incidence rate of DLTs duringin the DLT observation period (cycle 1) at each 2B3-101 dose level is based on predefined safety parameters in order to and will determine the MTD of 2B3-101 as single agent and in combination with trastuzumab, respectively. These safety parameters are: Adverse drug reactions (ADR) and serious ADRs, changes in hematology and chemistry values, including those associated with hepatic and renal function, and assessment of physical examinations, vital signs and cardiac function (i.e. repeated electrocardiograms). Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used.;Timepoint(s) of evaluation of this end point: The dose limiting toxicity (DLT) observat | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Pharmacokinetics of 2B3-101 as single agent in plasma; Cmax, Vss, T1/2, AUC, CL; - Pharmacokinetics of 2B3-101 when combined with trastuzumab in plasma; Cmax, Vss, T1/2, AUC, CL; - Preliminary efficacy: Antitumor effects of 2B3-101 as single agent and when combined with trastuzumab according to RECIST 1.1 (solid tumors) and RANO (malignant gliomas).;Timepoint(s) of evaluation of this end point: Blood samples will be taken on day 1, 2, 3, 5, 8 and 11 of cycle 1 and day 1, 8 and 15 of cycle 2 and on day 1 of cycle 3 and 4 to assess the PK profile during the first 4 cycles. Preliminary clinical efficacy of 2B3-101 will be measured by CT/MRI-scan on the last day of every even cycle (cycle 2, 4, etc.). A bone scan should only be obtained if clinically indicated and is to be performed as needed during the study if the patient develops symptoms or signs of bone disease. If bone metastases are present at screening, bone scans during treatment should be performed in addition to and at the same time as the CT/MRI-scans. | — |
Countries
Belgium, Netherlands, United States
Contacts
Public ContactProject Manager
SMS-oncology
Outcome results
None listed