A Phase I/II Study of Pexa-Vec Oncolytic Virus in Combination With Immune Checkpoint Inhibition in Refractory Colorectal Cancer

Background:

- Immune-based approaches in colorectal cancer have unfortunately with the notable
exception of immune checkpoint inhibition in microsatellite instable (MSI-hi) disease
been largely unsuccessful. The reasons for this are unclear but no doubt relate to the
fact that in advanced disease colorectal cancer appears to be less immunogenic, as
evidenced by the lack of infiltrating lymphocytes with advancing T stage

- Pexa-Vec (JX-594) is a thymidine kinase gene-inactivated oncolytic vaccinia virus
engineered for the expression of transgenes encoding human granulocyte- macrophage
colony-stimulating factor (GM-CSF) and beta-galactosidase. Apart from the direct
oncolytic activity, oncolytic viruses such as Pexa-Vec have been shown to mediate tumor
cell death via the induction of innate and adaptive immune responses

- Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the
surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated
downregulation of T-cell activation. Durvalumab is a human monoclonal antibody directed
against PD-L1.

- The aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec
oncolytic viral therapy can be enhanced by immune checkpoint inhibition.

Objective:

-To determine the safety, tolerability and feasibility of Pexa-Vec oncolytic virus in
combination with immune checkpoint inhibition in patients with refractory metastatic
colorectal cancer.

Eligibility:

- Histologically confirmed metastatic colorectal cancer.

- Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and
irinotecan-containing, fluorouracil-based, 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, been intolerant of or refused cetuximab or
panitumumabbased chemotherapy.

- Patients tumors must be documented to be microsatellite-stable (MSS) either by genetic
analysis or immunohistochemistry OR microsatellite-high with documented disease
progression following anti-PD1/PDL1 therapy.

- Patients must have at least one focus of metastatic disease that is amenable to pre- and
ontreatment biopsy.

- Willingness to undergo mandatory tumor biopsy.

Design:

- The proposed study is Phase I/II study of Pexa-Vec oncolytic virus at two dose levels in
combination with immune checkpoint inhibition in patients with metastatic colorectal
cancer.

- Patients with advanced microsatellite-stable colorectal cancer (or MSI-hi disease that
is refractory to PD-1 monotherapy) will receive Pexa-Vec, administered IV at a dose of
either 3 x 108 plaque forming units (pfu) (DL1) or 109 pfu (DL2) every 2 weeks for 4
doses, in 4 separate arms A1, A2, B1, and B2. The first administration will be on Day
(minus) 12, followed by administration on Days 2, 16 and 30 (i.e. 4 doses in total).

- Arms A1 and A2: In addition to the oncolytic virus patients will also receive
durvalumab at a flat dose of 1500 mg as an intravenous infusion beginning on Day 1
followed by q28days until off-treatment criteria are met.

- Arms B1 and B2: In addition to the oncolytic virus patients will also receive
tremelimumab 75 mg and durvalumab 1500 mg as intravenous infusions beginning on Day
1 followed by q28days for 4 doses with subsequent continuation of the durvalumab
alone until off-treatment criteria are met.

- Pexa-Vec will commence on Day (minus) 12 to facilitate tumor biopsies following
oncolytic virus alone. All patients will undergo a baseline tumor biopsy and a post
treatment biopsy. The timing of the post-treatment biopsy will depend on assignment. The
assignment will be balanced with an equal number assigned to each timing group. Patients
will be assigned to receive the second biopsy on Day 1 (i.e. after one dose of Pexa-Vec
alone) or Day 29 (i.e. after the combination of immune checkpoint inhibition and
Pexa-Vec). (Specific dates of biopsy will have a window of 72 hrs. to allow for
logistical issues; however, the biopsy will not be performed within 48 hrs. after
Pexa-Vec administration).

- Accrual ceiling will be set at 35 to allow for patients replaceable for reasons other
than toxicity.

- Patients will be restaged every 8 weeks +/- 3 days

- INCLUSION CRITERIA:

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

- Patients must have progressed on, been intolerant of or refused prior oxaliplatin- and
irinotecan-containing, fluorouracil-based, 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, been intolerant of or refused cetuximab or
panitumumab-based chemotherapy.

- Patients tumors must be documented to be microsatellite-stable (MSS) either by genetic
analysis or immunohistochemistry OR microsatellite-high with documented disease
progression following anti-PD1/PDL1 therapy.

- Patients must have at least one focus of metastatic disease that is amenable to pre-
and on-treatment biopsy and be willing to undergo this. Ideally the biopsied lesion
should not be one of the target measurable lesions, although this can be up to the
discretion of the investigators.

- All patients enrolled will be required to have measurable disease by RECIST 1.1
criteria.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of Pexa-Vec in combination with tremelimumab and/or
durvalumab in patients <18 years of age, children are excluded from this study, but
will be eligible for future pediatric trials.

- ECOG performance status 0-1

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

- Leukocytes greater than or equal to 3,000/mcL

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

- Platelets greater than or equal to 100,000/mcL

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

- Hb > 9g/dl

- AST (SGOT)/ALT (SGPT) less than or equal to 2.5 x institutional upper limit of
normal unless liver metastases are present, in which case it must be less than or
equal to 5x ULN

- Creatinine <1.5X institution upper limit of normal, OR

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

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

- The effects of Pexa-Vec, durvalumab and tremelimumab on the developing human fetus are
unknown. For this reason, women of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence) prior
to study entry, for the duration of study participation and up to 180 days after the
last dose of durvalumab + tremelimumab combination therapy or 90 days after the last
dose of durvalumab monotherapy, whichever is the longer time period. 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.

- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:

- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).

- Women greater than or equal to 50 years of age would be considered
post-menopausal if they have been amenorrheic for 12 months or more following
cessation of all exogenous hormonal treatments, had radiation-induced menopause
with last menses >1 year ago, had chemotherapy-induced menopause with last menses
>1 year ago, or underwent surgical sterilization (bilateral oophorectomy,
bilateral salpingectomy or hysterectomy. Subject is willing and able to comply
with the protocol for the duration of the study including undergoing treatment
and scheduled visits and examinations including follow up.

- Body weight >35kg

EXCLUSION CRITERIA:

- Patients who have had anti-cancer therapy (chemotherapy, immunotherapy, endocrine
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies
or other investigation agents), large field radiotherapy, or major surgery must wait 4
weeks after completing treatment prior to entering the study.

- No prior exposure to immune-mediated therapy including, but not limited to, other anti
CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2 (anti-PD-L2)
antibodies, including therapeutic anticancer vaccines. The exception to this is those
whose tumors are MSI-hi and are refractory to anti-PD1 monotherapy.

- Involvement in the planning and/or conduct of the study

- Previous IP assignment in the present study

- Patients who are receiving any other investigational agents.

- Inability to suspend treatment with anti-hypertensive medication (including but not
limited to: diuretics, beta-blockers, angiotensin converting enzyme [ACE] inhibitors,
aldosterone antagonists, etc.) for 48 hours pre and post each Pexa-Vec administration.

- Patients with severe hypertension who in the opinion of the investigator cannot
withhold antihypertensive medication for 48 hours pre and post Pexa-Vec
administration.

- Any unresolved toxicity NCI CTCAE Grade greater than or equal to 2 from previous
anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values
defined in the inclusion criteria

- Patients with Grade greater than or equal to 2 neuropathy will be evaluated on a
case-by-case basis

- 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.

- Uncontrolled intercurrent illness including, but not limited to, hypertension
(systolic BP > 160, diastolic BP > 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. For patients with a history of cardiovascular
disease, cardiology consultation. Echocardiogram, troponin and creatinine clearance
must be obtained prior to enrollment. NOTE: Patients with active cardiac disease (e.g.
myocarditis and myocardial infarction) within 12 months of study entry are excluded
from study participation.

- 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. HIV positive patients not receiving
antiretroviral therapy are excluded due to the possibility that Durvalumab or
Tremelimumab may worsen their condition and the likelihood that the underlying
condition may obscure the attribution of adverse events.

- Known significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or
immune-suppressive medication including high-dose corticosteroids (defined as greater
than or equal to 20 mg/day prednisone or equivalent which is ongoing at the time of
enrollment and/or was taken for more than 4 weeks within the preceding 2 months of
enrollment)

- 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
enrollment. Note: Active vitiligo or a history of vitiligo will not be a basis for
exclusion. In addition, a past history of certain autoimmunity e.g. rheumatoid
arthritis or thyroiditis may be allowed per PI discretion provided it has been
quiescent for a minimum of three years. The following are exceptions to this
criterion:

1. Patients with vitiligo or alopecia

2. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on
hormone replacement

3. Any chronic skin condition that does not require systemic therapy

4. Patients without active disease in the last 5 years may be included

5. Patients with celiac disease controlled by diet alone

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

- History of active primary immunodeficiency

- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing (if clinically
indicated), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis
C. Patients with a past or resolved HBV infection (defined as the presence of
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction
is negative for HCV RNA.

- Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

- Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra
articular injection)

- Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of
prednisone or its equivalent

- Steroids as premedication for hypersensitivity reactions (e.g. CT scan
premedication)

- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
Note:

Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30
days after the last dose of IP.

- Female patients who are breastfeeding. Because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
Pexa-Vec, breastfeeding should be discontinued if the mother is treated with Pexa-Vec.
These potential risks may also apply to other agents used in this study.

- Known allergy or hypersensitivity to IP

- Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.

- History of sarcoidosis syndrome

- Mean QT interval corrected for heart rate (QTc) greater than or equal to 470 ms
calculated from 3 electrocardiograms (ECGs) using Fredericia s Correction

- Patients with a history of Interstitial lung disease or pneumonitis

- Subjects with uncontrolled seizures

- History of leptomeningeal carcinomatosis

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

- Patients with unhealed surgical wounds for more than 30 days

- Ongoing severe inflammatory skin condition (as determined by the Investigator)
requiring medical treatment

- History of severe eczema (as determined by the Investigator) requiring medical
treatment

- Patients with tumor(s) invading a major vascular structure (e.g. carotid artery) or
other key anatomical structure (e.g. pulmonary airway) in the event of post treatment
tumor swelling and/or necrosis (hepatic and portal vein involvement allowed)

- Patients with liver tumors in a location that would potentially result in significant
clinical adverse effects in the opinion of investigator if post-treatment tumor
swelling were to occur, including at the site of the common bile duct

- Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural
effusions. Mild ascites that does not preclude safe tumor biopsy as protocol specified
is allowed at the discretion of the treating physician.

- Medical conditions, per the investigator s judgment, that predispose the patient to
untoward medical risk in the event of volume loading (e.g. intravenous [IV] fluid
bolus infusion), tachycardia, or hypotension during or following treatment with
Pexa-Vec

- Any prior or planned organ transplant (e.g. liver transplant)

- Patients who experienced a severe systemic reaction or side-effect as a result of a
previous vaccination with vaccinia

- Pulse oximetry O2 saturation <90% at rest on room air