ExIST Study of LY2157299 (Galunisertib) in Rectal Cancer

This is a prospective Phase II study to test the efficacy of LY2157299 in combination with neoadjuvant chemoradiation in patients with rectal adenocarcinoma. This study will test the hypothesis that LY2157299 will improve effector T cell tumor infiltration and activity resulting in improved pathologic response rates. The investigators propose that this improved immune response will result in improved disease-free and overall survival.

The objectives are:

• Determine the rate of pathologic complete response in patients with locally advanced rectal adenocarcinoma treated with neoadjuvant chemoradiation and the investigational agent LY2157299
• Correlate immunoscore changes prior to therapy, during therapy, and at surgical resection with pathologic response and MRI parameters
• Immune monitoring to evaluate potential biomarkers of treatment success.

Eligible patients will have histologically confirmed rectal adenocarcinoma, AJCC Stage IIA IIIC or AJCC Stage IV appropriate for consideration of primary rectal tumor resection. Patients will undergo a forceps biopsy of the rectal mass as part of the diagnostic workup as well as undergo staging evaluation including an MRI with additional study sequences. Enrolled patients will receive a 14 day course of LY2157299 followed by a repeat biopsy and MRI with study sequences. In this trial the investigators plan to use the maximum tolerated dose of LY2157299 established in human clinical trials, 300mg delivered as 150mg P.O. BID. On day 15 patients will begin chemoradiation with either 5-FU (fluorouracil ) or capecitabine (Xeloda®). On day 29, patients will undergo another fourteen day course of LY2157299 concurrent with their ongoing chemoradiation.

Patients will undergo 50.4 to 54Gy of radiation in 1.8Gy daily fractions delivered Monday through Friday for a total of 28-30 fractions. The acceptable duration of chemoradiation, including treatment breaks or delays, is up to 8 weeks total. Six to ten weeks after completing their neoadjuvant therapy, patient will undergo a tumor specific mesorectal excision as per standard of care with evaluation of pathologic response rate. Patients will be followed for disease-free survival, progression free survival, local recurrence, and overall survival. A three patient safety lead-in will be performed, where a six week safety period following completion of radiation will be completed prior to enrolling subsequent patients.

Inclusion criteria

• Patients (male and female) with histologically confirmed rectal adenocarcinoma, AJCC Stage IIA-IIIC or AJCC Stage IV appropriate for consideration of primary rectal tumor resection.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Age 18 years or above.
• Laboratory values (performed within 28 days prior to enrollment) as follows:

• WBC ≥3.0 109/L
• Hgb ≥9g/dl (patients may be transfused to reach this level)
• Platelets ≥99 109 /L
• Creatinine ≤1.5X upper limit of laboratory normal
• AST/ALT ≤5 X upper limit of laboratory normal
• Total bilirubin ≤1.5X upper limit of laboratory normal
• BNP ≤ 3 times the baseline value and upper limit of laboratory normal
• Troponin I ≤ upper limit of laboratory normal
• hsCRP ≤ upper limit of laboratory normal
• Cystatin ≤ upper limit of laboratory normal
• PT/INR ≤1.5X upper limit of laboratory normal
• Pre-menopausal women must have a negative pregnancy test on the day treatment starts and must avoid becoming pregnant while on treatment and for 3 months following completion of therapy. Men must avoid fathering a child while on treatment and for 3 months following completion of therapy. This exclusion is required due to the toxicities that chemotherapy, radiation, and LY2157299 may have on the forming fetus, spermatogenesis or the nursing child. Also, because pregnancy may alter immune function it may limit the treatment efficacy. Women of childbearing potential must agree to use a medically approved contraceptive method during the treatment period and for 3 months following the last dose of LY2157299. Contraceptive methods may include an intrauterine device [IUD], birth control pills or barrier method. If condoms are used as a barrier method, a spermicidal agent should be added as a double barrier protection.
• No active bleeding.
• Ability to give informed consent and comply with the protocol. Patients with a history of psychiatric illness must be judged able to understand fully the investigational nature of the study and the risks associated with the therapy.

Exclusion criteria

• Active infection requiring systemic antibiotics.
• Active autoimmune disease as defined by the autoimmune disease assessment tool (see protocol)
• Diagnosis of a solid tumor malignancy (excluding non-melanoma skin cancer) within 3 years of enrollment.
• History of prior pelvic radiation.
• Aortic aneurysm (see protocol)
• Abnormal Echocardiogram (see protocol)
• Immunodeficiency, need for immunosuppressive medications, or need for chronic steroids.
• Participation in any investigational drug study within 28 days of enrollment.
• Pregnant or lactating women, as treatment involves risks to the embryo or fetus.
• Other medical or psychiatric conditions that in the opinion of the Principal Investigator would preclude safe participation in protocol.
• History of cardiac disease, including myocardial infarction within 6 months before study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension, major cardiac abnormalities, a predisposition for developing aneurysms including family history of aneurysms, Marfan syndrome, bicuspid aortic valve, or evidence of damage to the large vessels of the heart.
• Concomitant use of strong CYP3A4 inhibitors and inducers