Safety, Immunogenicity and Pharmacokinetics of SYN004 in Patients With Solid Tumors

Study Design:

In this open-label, dose escalation study, subjects will receive a single IV loading dose of
SYN004 on Day 1 of the first treatment week, followed by up to 7 fixed weekly doses of
SYN004. Subjects will be assigned to loading and fixed doses by dose group.

Each dose group will comprise 3 subjects and may be expanded to 6 subjects. Subjects will
enter dose groups in the order in which they are enrolled. There will be no intra-subject
dose adjustments.

Only 1 subject in a cohort may receive the loading dose of SYN004 on any given day; at least
1 day must elapse before the next subject in the cohort receives the loading dose.

Study SYN004-001 Dose Matrix. Three initial subjects will be enrolled followed by an
additional three if specified by protocol. Dose levels are specified below.

Group 1: Loading dose: 100 mg/m2; Weekly Dose: 62.5 mg/m2. Group 2: Loading dose: 200 mg/m2;
Weekly Dose: 125 mg/m2. Group 3: Loading dose: 400 mg/m2; Weekly Dose: 250 mg/m2.

After each dose of IV SYN004, subjects will be observed in the clinic for 12 hours. After the
loading dose, subjects will undergo safety evaluations on Days 2, 3 and 5. Safety evaluation
will also be performed on Day 1 (pre-treatment) and Day 3 of each fixed dose treatment week.

Dose-limiting toxicities (DLTs) are defined as any Grade ≥3 AE assessed by the investigator
or Medical Monitor, with agreement of the Safety Review Board (SRB), as related to SYN004.
Subjects with DLTs will be withdrawn from treatment. If 2 or more subjects in a dose group
experience DLTs, or one subject in a dose group experiences a Grade ≥3 infusion reaction, all
subjects in that dose group will be withdrawn from treatment.

Subjects in the dose groups are considered evaluable for dose escalation decisions if they
receive at least 4 doses of SYN004, or discontinue SYN004 because of a DLT.

Subjects who withdraw or are terminated per protocol before receiving 4 doses of SYN004 will
be replaced.

For subjects who receive at least 4 doses of SYN004, End of Study CT scans for RECIST
(version 1.1) evaluation will be performed six (6) days following the final SYN004 treatment.

There will be a 28-day safety monitoring period following the final dose of SYN004 for all
subjects in the study. All subjects will attend an End-of-Study Visit 28 days after the final
dose of SYN004.

Subjects who complete Cycles 1 and 2, who have evidence of improvement per RECIST 1.1 (i.e.,
findings of complete or partial response per RECIST 1.1) and meet the other eligibility
criteria will be offered up to 3 additional treatment cycles (i.e., up to 12 additional
weekly doses) of SYN004 in the SYN004-001 Extension Study. During the Extension Study,
subjects will receive the same fixed dose of SYN004 they received in Cycles 1 and 2.

Dose escalation will proceed according to a standard 3+3 study design.

Inclusion Criteria:

Note: No waivers of the study inclusion or exclusion criteria will be granted.

1. Diagnosis of a solid tumor for which the accepted standard of care includesa licensed
anti-EGFR therapy;

2. Tumor progression in patients with RAS wild type metastatic colorectal cancer
irrespective of their exposure to licensed anti-EGFR therapy including anti-EGFR
antibodies; OR Tumor progression in patients with metastatic colorectal cancer
refractory to cetuximab or panitumumab or other anti-EGFR antibodies OR Tumor
progression in patients with EGFR-mutated non-small cell lung cancer (NSCLC) who have
refused therapy.

OR Tumor progression or recurrence in patients with squamous cell carcinoma of the
head and neck irrespective of their exposure to licensed anti-EGFR therapy including
anti-EGFR antibodies.

OR Patients with locally advanced or metastatic colorectal carcinoma who have

1. relapsed after standard of care treatment,

2. proved refractory to standard of care treatment

3. refused standard of care treatment

4. been found to be medically unsuitable for standard of care treatment

3. Completion of written informed consent procedure;

4. Male or female subjects over 17 years of age

5. Life expectancy of at least 3 months;

6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2;

7. At least one measureable non-irradiated site of disease according to Response
Evaluation Criteria in Solid Tumors (RECIST) version 1.1;

8. Adequate bone marrow function, with absolute neutrophil count (ANC) >1,500/mm3,
platelet count >100,000/mm3, and hemoglobin > 10 g/mm3;

9. Adequate liver function, with bilirubin <1.5 x the upper limit of the normal range
(ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 x the
ULN;

10. Adequate renal function, with serum creatinine <1.5 mg/dL;

11. Adequate cardiac function, with left ventricular ejection fraction (LVEF) ≥50%, normal
electrocardiogram, and absence of significant cardiac disease;

12. In women of childbearing potential (defined as women of reproductive capacity who are
pre-menopausal or within 12 months of cessation of menses): negative serum pregnancy
test and use of an acceptable non-hormonal method of contraception;

13. Ability to communicate with the investigator, and understand and comply with the
requirements of the protocol;

14. Agrees to notify the investigator when deviating from the protocol requirements with
regard to concomitant medications;

15. Agrees to stay in contact with the study site for the duration of the study and to
provide updated contact information as necessary, and has no current plans to move
from the study area for the duration of the study.

Exclusion Criteria:

1. Participation in a study of an investigational agent or use of an investigational
device at the time of screening or within 4 weeks of enrollment;

2. Receipt of treatment with a monoclonal antibody (mAb) within 4 weeks of enrollment or
not recovered from an adverse event (i.e., event is >Grade 1 or subject has not
returned to baseline) due to treatment with a mAb administered >4 weeks before
enrollment;

3. Receipt of chemotherapy, targeted small molecule therapy, or radiation therapy within
2 weeks prior to enrollment, or not recovered from an adverse event (i.e., event is
>Grade 1 or subject has not returned to baseline) due to a previously-administered
agent;

4. Major surgical procedure or significant traumatic injury within 4 weeks prior to
screening;

5. Diagnosis of an additional malignancy that is progressing and requires treatment;
exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, and in situ cervical cancer that has undergone potentially curative therapy;

6. Active autoimmune disease requiring systemic treatment within the past 3 months, or a
documented history of severe autoimmune disease, or a syndrome that requires systemic
steroids or immunosuppressive agents (subjects with vitiligo or resolved childhood
asthma/atopy are allowed);

7. Diagnosis of an immune deficiency;

8. Receipt of systemic steroids or any form of immunosuppressive therapy within 7 days
prior to enrollment, with the following exceptions:

1. Stable doses of topical, ocular, intranasal or inhaled corticosteroids

2. Doses of systemic steroids that, in the opinion of the investigator, are
pysiologic replacement doses

3. Systemic steroids as prophylactic treatment for subjects with allergy to contrast
media

4. Non-absorbed intra-articular steroid injections

5. Systemic corticosteroids required for control of infusion reactions or AEs if
doses have been tapered to <10 mg prednisone or equivalent for 2 weeks prior to
the first study treatment

9. Evidence of interstitial lung disease or active, non-infectious pneumonitis;

10. Active infection requiring systemic therapy;

11. History of cerebrovascular accident, transient ischemic attack, or subarachnoid
hemorrhage within 6 months prior to screening;

12. Active hepatitis B (i.e., hepatitis B surface antigen [HBsAg] positive) or hepatitis C
(i.e., hepatitis C virus [HCV] ribonucleic acid [RNA; qualitative] is detected);

13. Serious non-healing wound, ulcer, or bone fracture;

14. Any severe or uncontrolled medical condition or other condition that could affect
participation in the study;

15. Any current medical, psychiatric, occupational, or substance abuse problems that, in
the opinion of the investigator, will make it unlikely that the subject will comply
with the protocol.