A study of 2B3-101 in patients with solid tumors and brain metastases or recurrent malignant glioma.

1. Age at least 18 years;

2. Measurable or evaluable brain disease;

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. No evidence of sub cortical cognitive impairment as defined by a score on HIV Dementia Scale (HDS) > 10;

8. Written informed consent according to local guidelines.



In addition to the above listed eligibility criteria, the following criteria are applicable:

9. Dose-Escalation Phase: Female and male patients with pathologically confirmed diagnosis of advanced, recurrent solid tumors and unequivocal evidence of brain metastases that are refractory to standard therapy or for which no standard therapy exists. Brain metastases may be stable, progressive, symptomatic or asymptomatic brain metastasis/es. Stable or decreasing dosage of steroids (e.g. dexamethason) for 7 days prior to baseline MRI or non-enzyme inducing anti-epileptic drugs is allowed OR;

Female and male patients with pathology confirmed diagnosis of advanced, recurrent primary malignant (grade III and IV) glioma that are refractory to standard therapy or for which no standard therapy exists. Stable or decreasing dosage of steroids (e.g. dexamethason) for 7 days prior to baseline MRI or non-enzyme inducing anti-epileptic drugs are allowed;

10. Expansion Phase: Female patients with pathologically confirmed diagnosis of advanced, recurrent breast cancer with unequivocal evidence of brain metastases that are refractory to standard therapy or for which no standard therapy exist. Brain metastases may be stable, progressive, symptomatic or asymptomatic brain metastasis/es. Stable or decreasing dosage of steroids (e.g. dexamethason) for 7 days prior to baseline MRI or non-enzyme inducing anti-epileptic drugs is allowed.

Prior Treatment:

1. Less than 4 weeks since the last treatment of chemotherapy, biological therapy, immunotherapy and systemic radiotherapy (except palliative radiation delivered to <20% of bone marrow), less than 8 weeks for cranial radiotherapy, and less than 6 weeks for nitrosoureas and mitomycin C;

2. Patients that have received a maximum cumulative dose of > 360mg/m2 for doxorubicin or > 600mg/m2 for epirubicin.



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:

A. Serum (total) bilirubin > 1.5 x the ULN for the institution if no liver metastases (> 2 x ULN in patients with liver metastases);

B. ASAT or ALAT > 2.5 x ULN if no liver metastases (> 4 x ULN in patients with liver metastases);

C. 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:

A. Serum creatinine > 1.5 x ULN.



Other:

7. Clinical suspicion or radiological evidence of leptomeningeal metastases;

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 < 2 years after last menstruation and not surgically sterile) and male subjects who are not surgically sterile or with female 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:

A. Stroke within ≤ 6 months prior to day 1;

B. Transient Ischemic Attack (TIA) within ≤ 6 months prior to day 1;

C. Myocardial infarction within ≤ 6 months prior to day 1;

D. Unstable angina;

E. New York Heart Association (NYHA) Grade II or greater Congestive Heart Failure (CHF);

F. Serious cardiac arrhythmia requiring medication;

G. Clinically relevant pathologic findings in ECG.

14. Left Ventricle Ejection Fraction (LVEF) by MUGA or ECHO < 50%;

15. Known hypersensitivity to any of the study drug components or excipients (e.g. doxorubicin, PEG or GSH);

16. Evidence of any other medical conditions (such as psychiatric illness, infectious diseases, physical examination or laboratory findings) that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment-related complications.