Talimogene Laherparepvec, Chemotherapy and Radiation Therapy Before Surgery in Treating Patients With Locally Advanced or Metastatic Rectal Cancer

PRIMARY OBJECTIVES:

I. To determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of
talimogene laherparepvec in combination with capecitabine and radiation in rectal cancer.

SECONDARY OBJECTIVES:

I. To establish safety and feasibility of the combination including complications from
surgical resection II. To determine the neoadjuvant rectal (NAR) score of talimogene
laherparepvec with chemotherapy and radiation.

EXPLORATORY OBJECTIVES:

I. To correlate genomic information including RAS, RAF mutation status with response, disease
free survival (DFS) and/or overall survival (OS).

II. To determine immunomodulatory changes following talimogene laherparepvec, chemotherapy
and radiation treatment including proportions of immune cell infiltrates in serially
collected peripheral blood and/or frozen tumor samples (pre-, on treatment, and at post
progression).

III. To identify magnetic resonance imaging (MRI)-based features including MRI
circumferential margin (mrCRM) at baseline or post-therapy mrCRM, MRI tumor regression grade
(mrTRG) to define determinants of response, DFS and OS.

IV. To determine the disease free survival (DFS) and overall survival (OS) of talimogene
laherparepvec with chemotherapy and radiation in patients undergoing curative resection.

V. To determine the pathological complete response (pCR) rate of talimogene laherparepvec
with chemotherapy and radiation.

OUTLINE: This is a dose-escalation study of talimogene laherparepvec.

Patients receive talimogene laherparepvec intralesionally via endoscopy on weeks 1, 4, 6, and
8. Patients receive 5-fluorouracil intravenously (IV) by bolus and over 46 hours, leucovorin
IV bolus, and oxaliplatin IV over 2 hours on weeks 2 and 4. Patients also receive
capecitabine orally (PO) twice daily (BID) followed by radiation therapy for 28 fractions on
days 1-5 of weeks 8-13. Patients undergo resection surgery on weeks 21-25.

After completion of study treatment, patients are followed up for 30 days and up to 5 years
thereafter.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed A) low lying (i.e. =< 6
cm from the anal verge) rectal adenocarcinoma eligible for concurrent chemoradiation
therapy to rectal tumor, B) if the treatment is palliative in the metastatic setting,
no additional requirements for tumor size or nodal involvement is needed; C) if the
treatment is in the neoadjuvant setting, the tumor must ALSO be high-risk locally
advanced rectal cancer defined as T3-4, N+, and/or at risk for a positive radial
margin (as determined by the surgeon)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Absolute neutrophil count (ANC) >= 1.5 x 10^9 /L

- Hemoglobin >= 9 g/dL

- Platelets >= 100,000 x 10^9 /L

- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except patients
with Gilbert's syndrome, who can have total bilirubin < 3 mg/DL)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
institutional ULN

- Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault
formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min

- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
time (PTT) =< 1.5 x institutional unless the subject is on anticoagulant therapy (if
the subject is receiving anticoagulant therapy, PT, and activated partial
thromboplastin time [aPTT] must be within therapeutic range of intended use of
anticoagulants)

- Patients must have signed informed consent indicating that they are aware of the
investigational nature of the study, and are aware that participation is voluntary;
patients must be made aware of their other treatment options

- Talimogene laherparepvec, as well as other therapeutic agents used in this trial
including radiation and capecitabine, may cause fetal harm when administered to a
pregnant woman; women of childbearing potential (WOCBP) is defined as any female who
has experienced menarche and who has not undergone surgical sterilization
(hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is
defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of
other biological or physiological causes; WOCBP and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry, during the study participation, and for four months after the last dose of the
drug; WOCBP must have a negative serum pregnancy test within 72 hours prior to
enrollment and agree to use effective contraception throughout the treatment period
and for 4 months after the last dose of study 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

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had radiotherapy within < 4 weeks are ineligible

- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) except alopecia are ineligible

- Use of other investigational, chemotherapeutic or targeted drugs within 28 days (or
five half-lives, whichever is shorter; with a minimum of 14 days from the last dose)
preceding the first dose of talimogene laherparepvec and during the study are
ineligible

- Patients who have previously been treated with talimogene laherparepvec, any other
oncolytic virus or pelvic radiation are ineligible

- Patients with known active central nervous system (CNS) metastases are ineligible;
subjects with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging for at least four weeks prior to
the first dose of trial treatment and any neurologic symptoms have returned to
baseline), have no evidence of new or enlarging brain metastases

- Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy
to talimogene laherparepvec or any of its components, capecitabine, fluorouracil
(5-FU) and / or oxaliplatin are ineligible

- Patients with a history or evidence of active autoimmune disease (e.g., pneumonitis,
glomerulonephritis, vasculitis, or other); or history of active autoimmune disease
that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive
drugs or biological agents used for treatment of autoimmune diseases) within 2 months
of enrollment are ineligible; (replacement therapy [e.g., thyroxine for
hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy
for adrenal or pituitary insufficiency] is not considered a form of systemic treatment
for autoimmune disease)

- Patients with evidence of clinically significant immunosuppression such as the
following are ineligible:

- Primary immunodeficiency state such as severe combined immunodeficiency disease

- Concurrent opportunistic infection

- Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid
doses > 10 mg/day of prednisone or equivalent within 2 months prior to enrollment

- Patients with active herpetic skin lesions or prior complications of herpetic
infection (e.g., herpetic keratitis or encephalitis) are ineligible

- Patients with viral infections requiring intermittent or chronic systemic (intravenous
or oral) treatment with an antiherpetic drug (e.g., acyclovir), other than
intermittent topical use are ineligible

- Patients with other viral infections are ineligible:

- Known to have acute or chronic active hepatitis B or hepatitis C infection

- Known to have human immunodeficiency virus (HIV) infection

- Prior therapy with viral-based tumor vaccine

- Received live vaccine within 28 days prior to enrollment

- Subject who is unwilling to minimize exposure with his/her blood or other body fluids
to individuals who are at higher risks for herpes simplex virus (HSV)-1 induced
complications such as immunosuppressed individuals, individuals known to have HIV
infection, pregnant women, or children under the age of 1 year, during talimogene
laherparepvec treatment and through 30 days after the last dose of talimogene
laherparepvec are ineligible

- Patients with uncontrolled intercurrent illness including, but not limited to, active,
non-colorectal malignancies requiring systemic therapy, ongoing or active infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements are ineligible

- Although no effects on embryo-fetal development have been observed in animal studies,
adequate and well-controlled studies with talimogene laherparepvec have not been
conducted in pregnant women; in addition, given the high risk of detrimental effects
of other study agents including capecitabine, 5-FU, oxaliplatin and radiation on
embryo-fetal development, the study treatment must be excluded in the following
patients:

- Female subject is pregnant or breast-feeding, or planning to become pregnant
during study treatment and through 4 months after the last dose of talimogene
laherparepvec

- Female subject of childbearing potential who is unwilling to use acceptable
method(s) of effective contraception during study treatment and through 4 months
after the last dose of talimogene laherparepvec

- Sexually active subjects and their partners unwilling to use male or female latex
condom to avoid potential viral transmission during sexual contact while on
treatment and within 30 days after treatment with talimogene laherparepvec

- Patients that unable to swallow oral medications are ineligible

- Patients with a major surgical procedure, open biopsy, or significant traumatic injury
within 28 days prior to initiation of therapy, or anticipation of need for major
surgical procedure during the course of the study other than that defined by protocol
are ineligible

- If patients require anticoagulation while on protocol, they should be switched from
warfarin to another alternative anticoagulant such as low molecular weight heparin or
oral direct factor Xa inhibitors as deemed appropriate by the treating physician for
the duration they are on capecitabine (must be switched at least 1 week prior to
starting capecitabine) to avoid drug-drug interaction of warfarin with capecitabine

- Patients with a known dihydropyrimidine dehydrogenase (DPD) deficiency are ineligible

- Patients who are unable to get MRIs due to any reason including pacemakers or
automatic implantable cardioverter-defibrillator (AICD) are ineligible