APX005M With Concurrent Chemoradiation for Resectable Esophageal and Gastroesophageal Junction Cancers

PRIMARY OBJECTIVES:

I. To establish the safety and feasibility of combining APX005M with standard-of-care
chemoradiation (external beam radiation in daily fractions, with concurrent weekly low-dose
carboplatin/paclitaxel) in the neoadjuvant setting for patients with resectable esophageal
and gastroesophageal junction (GEJ) cancers.

SECONDARY OBJECTIVES:

I. To assess the efficacy of this novel combination, as measured by the pathologic complete
response (pCR) rate.

OUTLINE:

Patients receive APX005M intravenously (IV) over 60 minutes during weeks 1, 4, 7, and 10,
radiation therapy once daily (QD) for 5 days per week during weeks 3-8, and paclitaxel IV
over 60 minutes and carboplatin IV over 60 minutes once weekly (days 1, 8, 15, 22, and 29)
during weeks 3-8 in the absence of disease progression or unacceptable toxicity. Patients
then undergo surgery 1-7 weeks after last dose of APX005M.

After completion of study treatment, patients are followed up at 1, 3, and 6 months.

Inclusion Criteria:

1. Age ≥ 18 years of age

2. Histologically proven squamous cell carcinoma, adenocarcinoma or undifferentiated
carcinoma of the esophagus or GE junction.

3. Surgically resectable (T1-3 Nx by endoscopic ultrasound). Excluded are:

1. Very early stage tumors (T1N0)

2. Cervical esophageal tumors

3. Tumors invading the tracheobronchial tree or associated with tracheoesophageal
fistula

4. Any evidence of distant metastases (as determined by endoscopic ultrasound (EUS)
or CT/PET)

5. Cervical, supraclavicular, or other nodal disease that is either not included in
the radiation field or is not able to be resected at the time of esophagectomy

4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

5. Adequate hematological, renal, and hepatic parameters defined as follows:

1. Absolute Neutrophil Count (ANC) ≥1.5 × 109/L in absence of growth factor support

2. Platelet count ≥150 × 109/L

3. Hemoglobin >9 g/dL

4. Serum creatinine ≤1.5 mg/dL, or calculated (using the formula of Cockcroft and
Gault) or measured creatinine clearance ≥30 mL/min

5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper
limit of normal (ULN)

6. Total bilirubin ≤1.5x ULN

6. Women of child bearing potential (WOCBP) must have a negative serum pregnancy test
within the 7 days prior to investigational product administration and a negative urine
pregnancy test within the 3 days prior to the first investigational product
administration, or a negative serum pregnancy test within the 3 days prior to the
first investigational product administration

7. WOCBP and male subjects who are sexually active with WOCBP must agree to use 2 highly
effective methods of contraception (including a physical barrier) during the study and
for 30 days following the last dose of investigational product

8. Ability to understand a written informed consent document, and the willingness to sign
it

Exclusion Criteria:

1. Any history of or current hematologic malignancy

2. History of a second primary cancer is allowed in the event the cancer is curatively
resected and there is no evidence of recurrence/metastatic disease x 1 year. Subjects
who have a history of cervical or breast carcinoma in situ, localized prostate cancer,
adequately treated basal cell or squamous cell carcinoma of the skin, or superficial
bladder tumors [Ta, Tis & T1] are also allowed

3. Major surgery within 4 weeks of first dose of investigational product

4. Prior or concurrent treatment with any anticancer agent for the same cancer diagnosis

5. Prior exposure to any immuno-oncology agents, including CD40/PD-1/PD-L1/CTLA-4
inhibitors (if any ambiguity, should be discussed with study principal investigator)

6. History of bone marrow transplantation

7. Uncontrolled diabetes or hypertension

8. History of autoimmune disorders with the exception of vitiligo or autoimmune thyroid
disorders

9. Chronic steroid dependency (prednisone equivalent > 10 mg/day). Any steroid use should
be discontinued at least 2 weeks prior to initiation of study treatment.

10. History of sensitivity or allergy to monoclonal antibodies (mAbs) or immunoglobulin G
(IgG)

11. History of severe hypersensitivity reaction to Cremaphor EL.

12. Pre-existing > grade 2 peripheral sensory neuropathy.

13. Congestive heart failure (New York Heart Association Class III to IV), symptomatic
ischemia, conduction abnormalities uncontrolled by conventional intervention, or
myocardial infarction within 6 months before first dose

14. History of any arterial thromboembolic event within 3 months prior to first dose of
investigational product

15. Active coagulopathy

16. Active known clinically serious infections (> Grade 2 National Cancer Institute (NCI)-
CTCAE version 4.03)

17. Known human immunodeficiency virus (HIV) infection

18. Subjects of reproductive potential who do not use effective methods of birth control

19. Pregnant or actively breastfeeding women

20. Any clinically significant psychiatric, social, or medical condition that, in the
opinion of the Investigator, could increase subject's risk, interfere with protocol
adherence, or affect a subject's ability to give informed consent.