AMP-224, a PD-1 Inhibitor, With Stereotactic Body Radiation Therapy in Metastatic Colorectal Cancer

Background:

- Colorectal cancer remains the second leading cause of cancer death in western countries
with a median survival of approximately 24 months despite recent advances in systemic
treatment.

- Several preclinical studies have documented an increase in peripheral antitumor immunity
following radiation, a phenomenon known as the abscopal effect. Tumor PDL1 expression
has also been shown to be induced by radiation, which can suppress the anti-tumor immune
response. Inhibition of programmed cell death-1 (PD-1)/programmed death ligand-1(PDL-1)
axis has been shown to improve anti-tumor immunity by blocking the tumor-mediated
suppression of cytotoxic T cells.

- AMP-224, a B7-DC Fc fusion protein, binds to PD-1, an inhibitory receptor that is
present on the cell surface of exhausted, activated, effector, and memory T cells. AMP-
224 has a unique mechanism of action in that it binds specifically to PD-1HI T cells
(chronically stimulated / exhausted T cells) but not to PD-1LO cells which represent the
normal activated T cells population

- The aim of the study is to evaluate whether the anti-tumor immunity of anti-PD1 therapy
(with AMP-224) can be enhanced by radiation therapy.

Objectives:

- To assess safety, tolerability and feasibility of AMP-224 in combination with stereotactic
body radiation therapy (SBRT) in patients with metastatic colorectal cancer.

Eligibility:

- Histologically confirmed metastatic colorectal cancer.

- Patient must have progressed on or been intolerant of prior oxaliplatin- and irinotecan
containing regimen and have metastatic lesions that are not amenable to curative
resection.

- Patient must have one focus of metastatic disease in the liver that is amenable to SBRT.

- Patient must have at least one measurable metastatic lesion by Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1 criteria outside the radiation field.

- Patients must be willing to undergo mandatory pre and post treatment tumor biopsy.

Design:

- This is a pilot study whereby all patients will receive SBRT to one liver lesion and
concomitant AMP-224. A single treatment of low dose/cyclophosphamide will be
administered in conjunction with the SBRT therapy prior to the first AMP-224 treatment.

- Hypofractionated radiation will be administered to a metastatic disease site at a dose
and schedule of 8Gy for 1 or 3 days in dose levels (DL)1 or 2 respectively. The day of
first administration of AMP-224 will be designated as Day 1. In DL1 the SBRT will be
administered on Day 0. In DL2 the SBRT will be administered from D-2 to D0. The study
will begin with DL1 and escalate to DL2 once all subjects enrolled at DL1 have remained
on study for 4 weeks, which is the DLT period.

- AMP-224 therapy will be given as an intravenous infusion beginning on Day 1 and then
every 14 days for a total of 6 treatments only. Optional continuation of treatment q2-
weekly until progressive disease (PD) will be considered in responding patients.

- Cyclophosphamide 200 mg/m(2) intravenous will be given on Day 0, prior to the first dose
of AMP-224.

- Correlative studies: Peripheral blood will be collected (pre-dose) on days 1, 29, 57 and
93 for immune studies (including immunogenicity, circulating PD plasma samples, immune
monitoring for phenotyping and peripheral blood mononuclear cells (PBMC) for T-cell
activation). Tumor biopsies (formalin-fixed paraffin-embedded (FFPE) + Frozen) of an
irradiated and non-irradiated liver lesion will be collected on day 1 and day 29, which
will be analyzed by immunohistochemistry for tumor-infiltrating lymphocytes in addition
to ribonucleic acid (RNA) analysis.

- Pharmacokinetic (PK) samples will be collected on Days 1, 15, 29, 43, 57, 71 in addition
to up to 5 post treatment dates (if feasible).

-Inclusion Criteria

1. Patients must have histopathological confirmation of Colorectal Carcinoma (CRC) by the
Laboratory of Pathology of the National Cancer Institute (NCI) prior to entering this
study.

2. Patients must have progressed on or been intolerant of prior oxaliplatin and
irinotecan containing chemotherapeutic regimen and have disease that is not amenable
to potentially curative resection. Patients who have a known KRAS wild type tumor must
have progressed or been intolerant to cetuximab or panitumumab-based chemotherapy.

3. Patients must have one focus of metastatic disease in the liver that is amenable to
stereotactic body radiation therapy (SBRT) in the opinion of radiation oncology.

4. All patients enrolled will be required to have measurable disease by Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria outside the radiation field.

5. Study patients must have disease that is amenable to pre and post treatment biopsy and
be willing to undergo this.

6. Age greater than or equal 18 years

7. Life expectancy of greater than 3 months

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

9. Patients must have acceptable organ and marrow function as defined below:

- leukocytes less than or equal to 3,000/mcL

- absolute neutrophil count less than or equal 1,500/mcL

- platelets less than or equal 100,000/mcL

- total bilirubin greater than or equal 1.5X institution upper limit of normal

- Patients are eligible with alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) measuring up to 5 x ULN given the presence of liver
metastasis.

- creatinine greater than 1.5X institution upper limit of normal

Or

-creatinine clearance less than or equal 45 mL/min/1.73 m(2), as calculated below, for
patients with creatinine levels above institutional normal

10. Patients must have recovered from any acute toxicity related to prior therapy,
including surgery. Toxicity should be less than or equal to grade 1 or returned to
baseline.

11. Patients must not have other invasive malignancies within the past 3 years (with the
exception of non-melanoma skin cancers, localized prostate cancer, carcinoma in situ
of the cervix and non-invasive bladder cancer that has had successful curative
treatment).

12. Patient must be able to understand and willing to sign a written informed consent
document.

Exclusion Criteria

1. Prior immune checkpoint inhibition with anti-programmed cell death-1 (PD1)/programmed
death ligand-1(PD-L1) or anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) therapy or
other specific T cell targeting agents.

2. Patients who have had chemotherapy (or so-called targeted systemic therapy), large
field radiotherapy, or major surgery must wait 4 weeks after completing treatment
prior to entering the study.

3. Patients with known brain metastases will be excluded from this clinical trial because
of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

4. Uncontrolled intercurrent illness including, but not limited to, hypertension
(systolic blood pressure (BP) greater than 160, diastolic BP greater than 100),
ongoing or active systemic infection, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, uncontrolled diabetes or psychiatric
illness/social situations that would limit compliance with study requirements.

5. Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy
are excluded from this study due to the possibility of pharmacokinetic interactions
between antiretroviral medications and the investigational agent.

6. History of chronic autoimmune disease (e.g., systemic lupus erythematosus or Wegener's
granulomatosis, Addison's disease, multiple sclerosis, Graves disease, Hashimoto's
thyroiditis, hypophysitis, etc.) with symptomatic disease within the 3 years before
randomization. Note: Active vitiligo or a history of vitiligo will not be a basis for
exclusion. In addition, a past history of certain autoimmunity eg rheumatoid arthritis
or thyroiditis may be allowed per principal investigator (PI) discretion provided it
has been quiescent for a minimum of three years.

7. Active or history of inflammatory bowel disease (colitis, Crohn's), irritable bowel
disease, celiac disease, or other serious, chronic, gastrointestinal conditions
associated with diarrhea.

8. Dementia or significantly altered mental status that would prohibit the understanding
or rendering of Information and Consent and compliance with the requirements of the
protocol.

9. Currently receiving immunosuppressive doses of steroids or other immunosuppressive
medications (inhaled and topical steroids are permitted)

10. History of sarcoidosis syndrome

11. History of hypersensitivity reaction to human or mouse antibody products.

12. Pregnancy and breast feeding are exclusion factors. The effects of AMP-224 on the
developing human fetus are unknown. Enrolled patients must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry, the duration of study participation and 3 months after the end of the
treatment. Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately.

13. Patients with unhealed surgical wounds for more than 30 days.

14. Patients with known sensitivity or allergy to any components of AMP-224.