Recombinant Human Arginase 1 (rhArg1) in Patients With Advanced Arginine Auxotrophic Solid Tumors

This is a phase 1, multiple sites, open label and non-randomized study to evaluate the safety
of PEG-BCT-100. Patient enrollment and sample size will follow a classical 3 + 3
dose-escalation design. The study will enroll a maximum of 36 patients. Cohorts of 3 patients
will receive an initial single dose of PEG-BCT-100 beginning at 0.5 mg/kg. Single dose safety
parameters including hematology and chemistry laboratory profiles will be monitored for 3
weeks. Patients not demonstrating a dose-limiting toxicity (DLT) following the single dose
may then receive two additional doses of PEG-BCT-100 at the same dose level on Day 22 and Day
29. After these 2 additional doses, patients will undergo a full tumor and safety assessment
after Day 29. Patients whose cancer is stable or responding may then receive weekly doses of
PEG-BCT- 100 until disease progression. Dose escalations are planned for the next cohorts of
3 patients, which will be enrolled after Day 22 of the previous cohort, assuming that no
single dose DLTs were reported. Each cohort of 3 patients may begin weekly administration if
there is no DLTs by Day 22, and if the previous and lower dose cohort has successfully passed
Week 4 of the study (doses on Days 1, and 22 + one week).

As of the beginning of 2018, an additional 22 patients will include only malignant melanoma
patients. All newly enrolled patients will be enrolled at the dose level of Cohort Four (2.7
mg/kg) of PEG-BCT-100.

Inclusion Criteria:

- Confirmed diagnosis of Stage IIIb/IV malignant melanoma or castration resistant
adenocarcinoma of prostate (CRPC).

- Advanced cancer not candidate for treatment with modality or agents that are approved
or have established efficacy. Candidates who cannot tolerate standard treatment or
whose cancers have progressed on current standard of care.

- Males or females 18 years-old and above.

- Ability to understand and willingness to provide written informed consent;

- Karnofsky performance status (see Appendix 13.3) of 80% or above and expected survival
of more than 12 weeks.

- Negative urine pregnancy test, if female, and willingness to use an effective method
of contraception during the entire study period whether the patient is male or female.

Exclusion Criteria:

- Has received cancer treatment, e.g. chemotherapy, targeted biologic or enzymes, either
approved or investigational, within 4 weeks prior to the start of the PEG-BCT-100;

- Advancing liver failure indicated by uncontrolled ascites, pleural effusions, or
encephalopathy.

- Child-Pugh score of B and C (see Appendix 13.4).

- Significant hepatic, renal or bone marrow dysfunction indicated by: total bilirubin
>2.0 mg/dL, evidence of bile duct obstruction, serum albumin <2.5 g/dL, serum ALT or
AST >2.5 x upper limit of normal, serum creatinine ≥1.5 mg/dL, ANC ≥1.5 x 109/L,
platelets <100 x 109/L, or INR >2.0.

- Significant cardiac or pulmonary disease defined by New York Heart Association (NYHA)
Class III or IV (see Appendix 13.5), left ventricular ejection fraction (LVEF) lower
than institutional normal limits by echo or MUGA, history of myocardial infarction
within the past 6 months, significant unstable arrhythmia or evidence of ischemia on
ECG.

- Pregnant or nursing women. NOTE: Women of child-bearing potential and men must agree
to use adequate contraception (hormonal or barrier method of birth control or
abstinence) prior to study entry and for the duration of study participation. Should a
woman become pregnant or suspect she is pregnant while participating in this study,
she should inform her treating physician immediately.

- Significant active infection including HIV requiring oral or parenteral anti-infective
therapies.

- Use of investigational drug(s) within 4 weeks of enrollment.

- Prior treatment with arginine depleting agent.