Inclusion 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:

1. 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, which per the
multi-disciplinary team decision do not require immediate radiotherapy or
surgery.. Brain metastases may be stable, progressive, symptomatic or
asymptomatic brain metastasis/es. Stable or decreasing dosage of steroids (e.g.
dexamethasone) for 7 days prior to baseline MRI or non-enzyme inducing
anti-epileptic drugs is allowed.

Or -

2. 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 dosage of steroids
(e.g. dexamethasone) for 7 days prior to baseline MRI 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, which per the multi-disciplinary
team decision do not require immediate radiotherapy or surgery, can be included to this
escalation phase as well

- Breast cancer brain metastases expansion phase:

1. 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. Brain metastases may be stable, progressive,
symptomatic or asymptomatic brain metastasis/es. Stable or decreasing dosage of
steroids (e.g. dexamethasone) for 7 days prior to baseline MRI or non-enzyme inducing
anti-epileptic drugs is allowed.

Or -

2. Patients with pathologically confirmed diagnosis of advanced breast cancer with 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:

1. 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. 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 use of
non-enzyme inducing anti-epileptic drugs are allowed.

Or

2. 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:

1. 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. 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 use of
non-enzyme inducing anti-epileptic drugs are allowed.

Or

2. Patients with pathologically confirmed diagnosis of advanced melanoma with newly
diagnosed, untreated, brain metastases, which per multi-disciplinary team decision do
not require immediate radiotherapy or surgery.

Recurrent malignant glioma study arm of the expansion phase:

1. 7 patients with histologically proven glioma grade IV, which is progressive following
first line treatment with surgery or biopsy followed by fractionated radiotherapy
with concurrent temozolomide-containing chemotherapy.

and

2. 7 patients with histologically confirmed malignant (WHO grade III and IV) glioma or
histologically confirmed low-grade (WHO grade II) glioma with radiographic evidence
of malignant transformation by MRI, that are refractory to standard therapy, or for
whom no standard therapy exists or do not require immediate standard therapy per the
multi-disciplinary team decision. Patients in both groups should have stable or
decreasing dosage of steroids (e.g. dexamethasone) for a minimum of 7 days prior to
baseline MRI. Non-enzyme inducing anti-epileptic drugs are allowed

Exclusion Criteria.

- 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 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 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:

• 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. Left Ventricle Ejection
Fraction (LVEF) by MUGA or ECHO < 55% for patients receiving 2B3-101 in
combination with trastuzumab. For patients receiving single agent 2B3-101
treatment. Left Ventricle Ejection Fraction (LVEF) by MUGA or ECHO < 50%.

15. Known hypersensitivity to any of the study drugs 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.