An open-label, Phase I/IIa, dose escalating study of 2B3-101 in patients with solid tumors and brain metastases or recurrent malignant glioma.

Recruiting

• Conditions: or recurrent malignant glioma; solid neoplasms; solid tumors and brain metastases; 10006291

• Registration Number: NL-OMON39207
• Lead Sponsor: to-BBB technologies B.V.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 29 April 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: Not specified
• Target Recruitment: 45

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, which per the multi-disciplinary team decision do not require immediate radiotherapy, surgery, or standard systemic chemotherapy. Brain metastases may be stable, progressive, symptomatic or asymptomatic brain metastasis/es. Stable or decreasing dosages of steroids (e.g. dexamethasone) for 7 days prior to baseline MRI and/or non-enzyme inducing anti-epileptic drugs are allowed.;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. Stable or decreasing dosages of steroids (e.g. dexamethasone) for 7 days prior to baseline MRI and/or non-enzyme inducing anti-epileptic drugs are allowed.;2B3-101 in combination with trastuzumab dose-escalation phase:
Patients with histologically-confirmed HER2-positive (IHC 3+ or fluorescence in situ hybridization [FISH] amplified; by clinical assay on either primary or metastatic tumor) 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, which per the multi-disciplinary team decision do not require immediate radiotherapy, surgery, or standard systemic chemotherapy can be included to this escalation phase as well.;Breast cancer brain metastases study arm of the expansion phase:
Patients with pathologically confirmed diagnosis of advanced, recurrent breast cancer with at least one progressive and/or new metastatic brain lesion, that are refractory to standard therapy or for whom no standard therapy exist. Stable or decreasing dosages of steroids (e.g. dexamethasone) for 7 days prior to baseline MRI and/or non-enzyme inducing anti-epileptic drugs are allowed.;Or -;Patients with pathologically confirmed diagnosis of advanced breast cancer with newly diagnosed, untreated, brain metastases and controlled extracranial disease, which per the multi-disciplinary team decision do not require immediate radiotherapy, surgery, or standard systemic chemotherapy.;Once the MTD of 2B3-101 with trastuzumab has been determined, patients with histologically-confirmed HER2-positive (IHC 3+ or fluorescence in situ hybridization [FISH] amplified; by clinical assay on either primary or metastatic tumo

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, dabrafenib, everolimus, capecitabine, anastrazole, letrozole and exemestane; less than 2 weeks since the last treatment of vemurafenib; less than 4 weeks since the last treatment of trametinib, chemotherapy , biological therapy, immunotherapy and systemic radiotherapy (except palliative radiation delivered to <20% of bone marrow), less than 6 weeks for nitrosoureas and mitomycin C and less than 8 weeks since the latest cranial radiotherapy. Previous trastuzumab treatment will be allowed to continue without interruption in patients that are included in either the 2B3-101 in combination with trastuzumab dose-escalation phase or in the breast cancer study-expansion phase once the MTD for the combination has been established.
2. Patients that have received a maximum cumulative dose of free (i.e., non-liposomal) or liposomal doxorubicin > 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 109/L, or platelet count < 100 x 109/L or hemoglobin < 6 mmol/L.
5. Inadequate liver function, defined as:
• Serum (total) bilirubin > 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 in female subjects of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) 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 < 2 years after last menstruation and not surgically sterile) and male subjects who are not surgically sterile or with partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel).
10. Major surgical procedure (including open biopsy, excluding central line IV and portacath) within 28 days prior to the first study treatment, or anticipation of the need for major surgery during the course of the study treatment.
11. Grade 3 or 4 motor, sensory, or cranial neuropathy symptoms (as defined by CTCAE version 4.0).
12. Uncontrolled hypertension (systolic > 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 Y

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The primary study endpoint includes:<br /><br><br /><br>• The incidence rate of DLTs during the DLT observation period (cycle 1) at<br /><br>each 2B3-101 dose level is based on predefined safety parameters and will<br /><br>determine the MTD of 2B3-101 as single agent and in combination with<br /><br>trastuzumab, respectively. These safety parameters are: Adverse drug reactions<br /><br>(ADR) and serious ADRs, changes in hematology and chemistry values, including<br /><br>those associated with hepatic and renal function, and assessment of physical<br /><br>examinations, vital signs and cardiac function (i.e. repeated<br /><br>electrocardiograms). Common Terminology Criteria for Adverse Events (CTCAE)<br /><br>version 4.0 will be used.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Secondary endpoints include:<br /><br><br /><br>• Pharmacokinetics of 2B3-101 as single agent in plasma; Cmax, Vss, T1/2, AUC,<br /><br>CL;<br /><br>• Pharmacokinetics of 2B3-101 when combined with trastuzumab in plasma; Cmax,<br /><br>Vss, T1/2, AUC, CL;<br /><br>• Preliminary efficacy: Antitumor effects of 2B3-101 as single agent and when<br /><br>combined with trastuzumab according to RECIST 1.1 (solid tumors) and RANO<br /><br>(malignant gliomas).</p><br>