Ramucirumab Plus Irinotecan for Previously Treated Advanced Gastric or Gastro-esophageal Junction Adenocarcinoma

Therapuetic Areas:Oncology
Age Range:18 - Any
Start Date:November 1, 2017
End Date:September 30, 2020
Contact:Haeseong Park, M.D., MPH
Phone:(314) 747-7401

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Ramucirumab Plus Irinotecan in Patients With Previously Treated Advanced Gastric or Gastro-esophageal Junction Adenocarcinoma

The investigators hypothesize that this combination regimen of irinotecan plus ramucirumab
administered as second line treatment will be tolerated and lead to improved outcomes similar
to paclitaxel plus ramucirumab in patients with advanced gastric and gastro-esophageal
junction (GEJ) cancers. This study proposes a phase II clinical trial with irinotecan plus
ramucirumab for treatment of patients with metastatic gastric and GEJ adenocarcinoma who have
progressed after first line chemotherapy. To the knowledge of the investigators, this regimen
has not been previously administered to this patient population, so safety and tolerability
will be monitored and reported.

Inclusion Criteria:

- Histopathologically or cytologically confirmed diagnosis of gastric or
gastroesophageal junction (GEJ) adenocarcinoma that is metastatic or locally advanced
and unresectable.

- Measurable disease defined as lesions that can be accurately measured in at least one
dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan (or MRI at the
discretion of the principal investigator (PI)), as ≥ 20 mm by chest x-ray, or ≥ 10 mm
with calipers by clinical exam.

- Experienced documented objective radiographic or clinical disease progression during
first-line therapy or within 4 months after the last dose of first-line therapy with
any platinum/fluoropyrimidine doublet with or without anthracycline (epirubicin or
doxorubicin) or taxane (docetaxel) for unresectable or metastatic disease.

- At least 18 years of age.

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

- Normal bone marrow and organ function as defined below:

- Absolute neutrophil count (ANC) ≥ 1,500/µL

- Hemoglobin ≥ 9.0 g/dL (5.58 mmol/L)

- Platelets ≥ 100,000/µL

- Total bilirubin ≤ 1.5 mg/dL (25.65 µmol/L)

- AST(SGOT)/ALT(SGPT) ≤ 3.0 x institutional upper limit of normal (IULN) (or ≤ 5.0
x IULN in the setting of liver metastases)

- Creatinine ≤ 1.5 x IULN OR creatinine clearance ≥ 40 mL/min/1.73 m2 for patients
with creatinine levels > 1.5 x IULN (that is, if serum creatinine is > 1.5 x
IULN, a 24-hour urine collection to calculate creatinine clearance must be

- Urinary protein ≤ 1+ on dipstick or routine urinalysis (UA); if dipstick or
routine UA is ≥ 2+, a 24-hour urine collection for protein must demonstrate <
1000 mg of protein in 24 hours

- Adequate coagulation function as defined by INR ≤ 1.5 and PTT ≤ 5 seconds above
the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin
must be switched to low molecular weight heparin and have achieved stable
coagulation profile prior to first dose of protocol therapy.

- All clinically significant toxic effects (except peripheral neuropathy) of prior
locoregional therapy, surgery, or other anticancer therapy have resolved to ≤
Common Terminology Criteria for Adverse Events (CTCAE) grade 1.

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control, abstinence) prior to study entry
and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she must inform her
treating physician immediately. Women of childbearing potential must have a
negative serum pregnancy test within 7 days of study entry.

- Ability to understand and willingness to sign an IRB approved written informed
consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

- Squamous cell or undifferentiated gastric cancer.

- Received any chemotherapy (including irinotecan) other than platinum and
fluoropyrimidine with or without anthracycline or taxane for advanced gastric or GEJ

- Received previous systemic chemotherapy with a cumulative dose of > 900 mg/m^2 of
epirubicin or > 400 mg/m^2 of doxorubicin.

- Received any previously systemic therapy (including investigational agents) targeting
VEGF or the VEGFR signaling pathways. Other previous targeted therapies are permitted
if stopped at least 28 days prior to start of treatment.

- A history of other malignancy ≤ 3 years previous with the exception of basal cell or
squamous cell carcinoma of the skin which were treated with local resection only or
carcinoma in situ of the cervix or other solid tumors treated curatively and without
evidence of recurrence.

- Currently receiving any other investigational agents.

- History or evidence of known brain metastases or carcinomatous meningitis. Patients
with known brain metastases must 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.

- A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to monoclonal antibody treatment, any components used in the
ramucirumab DP preparation, irinotecan, or other agents used in the study.

- Any grade 3-4 GI bleeding within 3 months prior to enrollment.

- History of gastrointestinal perforation and/or fistulae within 6 months prior to

- History of deep vein thrombosis, pulmonary embolism, or any other significant
thromboembolism (venous port of catheter thrombosis or superficial venous thrombosis
are not considered "significant") during the 3 months prior to enrollment.

- History of any arterial thromboembolic event, including but not limited to myocardial
infarction, transient ischemic attack, cerebrovascular accident, or unstable angina
within 6 months prior to enrollment.

- Diagnosis of symptomatic congestive heart failure (NYHA II-IV) or symptomatic or
poorly controlled cardiac arrhythmia.

- Uncontrolled or poorly controlled hypertension (> 160 mmHg systolic or > 100 mmHg
diastolic for > 4 weeks) despite standard medical management.

- Presence of serious or nonhealing wound, ulcer, or bone fracture within 28 days prior
to enrollment.

- Major surgery within 28 days prior to first dose of protocol therapy.

- Minor surgery/subcutaneous venous access device placement within 7 days prior to first
dose of protocol therapy.

- Receiving chronic antiplatelet therapy, including aspirin, nonsteroidal
anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others),
dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose
325 mg/day) is permitted.

- The patient has elective or planned major surgery to be performed during the course of
the clinical trial.

- Bowel obstruction, history or presence of inflammatory enteropathy or extensive
intestinal resection (hemicolectomy or extensive small intestine resection with
chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.

- Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a
history of hepatic encephalopathy or clinically meaningful ascites resulting from
cirrhosis (i.e. ascites from cirrhosis requiring diuretics or paracentesis).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, metabolic disorders or other nonmalignant organ or systemic disease or
secondary effects of cancer that induce a high medical risk and make assessment of
survival uncertain, or psychiatric illness/social situations that would limit
compliance with study requirements.

- Pregnant and/or breastfeeding.

- Known HIV-positivity on combination antiretroviral therapy because of the potential
for pharmacokinetic interactions with ramucirumab and irinotecan. In addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.
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