Randomized Phase II Study of Ramucirumab and Paclitaxel versus FOLFIRI in Refractory Small Bowel Adenocarcinoma

Disease Related Criteria

a. Patients must have histologically or cytologically confirmed small bowel adenocarcinoma. Ampullary adenocarcinomas are not eligible. Patients must have metastatic disease or locally advanced unresectable disease.

b. Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to registration. Patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to registration.

c. Patients must have measurable or non-measurable disease. a diagnostic quality CT scan or MRI, performed within 28 days prior to registration, which demonstrates measurable disease, as defined in Section 10.1 Scans must include imaging of the chest, abdomen and pelvis, with the exception of patients with head/neck cancer, who must have imaging of the chest, abdomen, pelvis and neck. If there is clinical suspicion for bone metastases at the time of enrollment (in the judgement of the treating investigator) bone scan should be performed. Bone scans done within 42 days prior to registration may be used to establish baseline condition at registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form.

Prior/Concurrent Therapy Criteria


a. Patients must have progressed on prior therapy with a fluoropyrimidine and/or oxaliplatin, given either for metastatic / locally advanced disease or as adjuvant therapy completed within the previous 12 months.

b. Patients must not have received prior treatment with irinotecan, taxane, or ramucirumab for small bowel adenocarcinoma.

c. Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to registration and all toxicity must be resolved to Grade 1 (with the exception of Grade 2 neuropathy) prior to registration. In CTCAE version 5.0 Grade 2 sensory neuropathy is defined as “moderate symptoms; limiting instrumental activities of daily living (ADLs)”

d. Patients must not have had major surgery within 28 days prior to registration, or minor surgery within 7 days prior to registration, and must not be planned for elective major surgery to be performed during protocol treatment.

e. Patients must not be currently enrolled in or have discontinued within the last 28 days a clinical trial involving an investigational product or non-approved use of a drug, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Patients participating in surveys or observational studies are eligible to participate in this study.

f. Patients must not be receiving chronic antiplatelet therapy, including dipyridamole or clopidogrel, or similar agents.

Clinical/Laboratory Criteria

a. Patients must have a complete medical history and physical exam within 28 days prior to registration.

b. Patients must be at least 18 years of age.

c. Patients must have a Zubrod Performance Status of 0 or 1 (see Section 10.4)

d. Patients must have adequate bone marrow function as evidenced by all of the following: ANC greater than or equal to 1,500/mcL and platelets greater than or equal to 100,000/mcL. These results must be obtained within 28 days prior to registration.

e. Patient must have adequate hepatic function as evidenced by a total bilirubin less than or equal 1.5 x institutional limit normal (IULN), and SGOT (AST) and SGPT (ALT) less than or equal 3.0 x IULN (or 5.0 x IULN if liver metastases are present). These results must be obtained within 28 days prior to registration.

f. Patient must not have a known bleeding diathesis

g. Patients must have adequate renal function as evidenced by ONE of the following: serum creatinine less than 1.5 x IULN OR calculated creatinine clearance greater than 40 mL/min. This serum creatinine result must have been obtained within 28 days prior to registration.


h. A urine sample tested for proteinuria by either the dipstick method or a urine protein creatinine (UPC) ratio (see Section 8.3, Table 2 for dipstick protein reading information):
1. the dipstick method must indicate 0-1+ protein. If dipstick reading is greater than or equal to 2+, a 24-hour urine must be done and it must demonstrate less than 1.0 g of protein per 24 hours.
2. A urine protein creatinine (UPC) ratio must be less than 1.0. If the UPC ratio is greater than or equal to 1.0 a 24-hour urine must be done and it must demonstrate less than 1.0 g of protein per 24 hours.

i. Patient must not have uncontrolled or poorly-controlled hypertension (greater than 160 mmHg systolic or greater than 100 mm HG diastolic for greater than 4 weeks) despite standard medical management.

j. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

k. Patient tumors must not have known deficient mismatch repair (dMMR) or microsatellite instability high (MSI-H).

l. Patients must not be pregnant or nursing and must have had a negative pregnancy test within 4 weeks of starting treatment. Women/men of reproductive potential must have agreed to use an effective contraceptive method. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.

m. Patients must not have an active infection requiring systemic therapy.

n. Patient must not have liver dysfunctions manifested by either (1) Child-Pugh B (or worse) (see Appendix 18.2) or (2) cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.

o. Patients must not have known dihydropyrimidine dehydrogenase deficiency.

p. Patients must not have a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significant”) during the 90 days prior to registration.

q. Patients must not have experienced any arterial thrombotic event (including but not limited to myocardial infarction, unstable angina, stable angina markedly limiting ordinary physical activity, cerebrovascular accident, or transient ischemic attack) within 120 days prior to registration.

r. Patients must not have a prior history of GI perforation/fistula or other risk factors for perforation within 120 days prior to registration.

s. Patients must not have experienced any Grade 3-4 GI bleeding within 90 days prior to registration.

t. Patient must not have experienced any serious or non-healing wound, ulcer, or bone fracture within 28 days prior to registration.

Specimen Submission Criteria

a. Patients must be offered the opportunity to participate in specimen banking as outlined in Section 15.1.

Regulatory Criteria

a. Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.

b. As a part of the OPEN registration process (see Section 13.3 for OPEN access instructions) the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.