Ramucirumab and Paclitaxel or FOLFIRI in Advanced Small Bowel Cancers

SWOG Cancer Research Network

Status and phase

Enrolling

Phase 2

Conditions

Stage IV Small Intestinal Adenocarcinoma AJCC v8

Stage III Small Intestinal Adenocarcinoma AJCC v8

Metastatic Small Intestinal Adenocarcinoma

Stage IIIB Small Intestinal Adenocarcinoma AJCC v8

Stage IIIA Small Intestinal Adenocarcinoma AJCC v8

Treatments

Drug: Irinotecan

Drug: Paclitaxel

Biological: Ramucirumab

Drug: Leucovorin Calcium

Drug: Leucovorin

Drug: Fluorouracil

Drug: Irinotecan Hydrochloride

Study type

Interventional

Funder types

NETWORK

NIH

Identifiers

NCT04205968

NCI-2019-04213 (Registry Identifier)

U10CA180888 (U.S. NIH Grant/Contract)

S1922 (Other Identifier)

Details and patient eligibility

About

This phase II trial studies how well ramucirumab and paclitaxel or the FOLFIRI regimen (leucovorin calcium, fluorouracil, and irinotecan hydrochloride) work in treating patients with small bowel cancers that have spread extensively to other anatomic sites (advanced) or are no longer responding to treatment (refractory). Ramucirumab is a monoclonal antibody that attaches to and inhibits a molecule called VEGFR-2. This may restrain new blood vessel formation therefore reducing nutrient supply to tumor which may interfere with tumor cell growth and expansion. Drugs used in chemotherapy, such as paclitaxel, leucovorin calcium, fluorouracil, and irinotecan hydrochloride work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving Ramucirumab plus paclitaxel or FOLFIRI, may be helpful in treating advanced or refractory small bowel cancers and may help patients live longer.

Full description

PRIMARY OBJECTIVES:

I. To evaluate whether progression-free survival (PFS) meets an efficacy threshold in patients with previously treated advanced small bowel adenocarcinoma who receive treatment with ramucirumab and paclitaxel or FOLFIRI.

II. If the stated threshold is met in both arms, to choose the better regimen with respect to progression free survival (PFS).

SECONDARY OBJECTIVES:

I. To assess overall response rate (ORR) [complete and partial, confirmed and unconfirmed] in the subset of patients with measurable disease treated with ramucirumab and paclitaxel or FOLFIRI in this patient population.

II. To assess overall survival (OS) in patients treated with ramucirumab and paclitaxel or FOLFIRI in this patient population.

III. To evaluate safety and toxicity associated with combination ramucirumab and paclitaxel treatment or FOLFIRI therapy in this patient population.

TRANSLATIONAL OBJECTIVES:

I. To explore the correlation of maximum decrease in CEA levels and time to maximum decrease in CEA levels with PFS, OS, and ORR.

II. To bank tissue and blood samples for other future correlative studies from patients enrolled on the study.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive ramucirumab intravenously (IV) over 30-60 minutes on days 1 and 15, and paclitaxel IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive irinotecan IV over 90 minutes on days 1 and 15, leucovorin IV over 2 hours on days 1 and 15, and fluorouracil IV bolus on days 1 and 15. Patients also receive fluorouracil IV over 46-48 hours on days 1-3 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients completing study treatment are followed up every 8 weeks until disease progression. Once the disease has progressed, patients are followed up every 6 months for up to 3 years post registration.

Enrollment

94 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

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
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
Patients must have measurable or non-measurable disease. All scans needed for assessment of measurable disease must be performed within 28 days prior to registration. Non-measurable disease must be assessed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form
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
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 Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 2 sensory neuropathy is defined as "moderate symptoms; limiting instrumental activities of daily living (ADLs)"
Patients must have a complete medical history and physical exam within 28 days prior to registration
Patients must have a Zubrod performance status of 0 or 1
Absolute neutrophil count (ANC) >= 1,500/mcL (must be obtained within 28 days prior to registration)
Platelets >= 100,000/mcL (must be obtained within 28 days prior to registration)
A total bilirubin =< 1.5 x institutional limit normal (IULN) (must be obtained within 28 days prior to registration)
Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x IULN (or 5.0 x IULN if liver metastases are present) (must be obtained within 28 days prior to registration)
Serum creatinine =< 1.5 x IULN OR calculated creatinine clearance >= 40 mL/min (must have been obtained within 28 days prior to registration)
Patient must have urinary protein =< 1+ on dipstick or routine urinalysis (UA) within 28 days prior to registration. If dipstick or routine analysis is >= 2+, a 24 - hour urine collections for protein must demonstrate < 1000 mg of protein in 24 hours
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
Patients must not have known dihydropyrimidine dehydrogenase deficiency
Patients must be offered the opportunity to participate in specimen banking
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

Exclusion criteria

Patients must not have received prior treatment with irinotecan, taxane, or ramucirumab for small bowel adenocarcinoma
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
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
Patients must not be receiving chronic antiplatelet therapy, including dipyridamole or clopidogrel, or similar agents
Patient must not have a known bleeding diathesis
Patient must not have uncontrolled or poorly-controlled hypertension (> 160 mmHg systolic or > 100 mg HG diastolic for > 4 weeks) despite standard medical management
Patient tumors must not have known deficient mismatch repair (dMMR) or microsatellite instability high (MSI-H)
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
Patients must not have an active infection requiring systemic therapy
Patient must not have liver dysfunctions manifested by either (1) Child-Pugh B (or worse) 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
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
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
Patients must not have a prior history of gastrointestinal (GI) perforation/fistula or other risk factors for perforation within 120 days prior to registration
Patients must not have experienced any grade 3-4 GI bleeding within 90 days prior to registration
Patient must not have experienced any serious or non-healing wound, ulcer, or bone fracture within 28 days prior to registration

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

94 participants in 2 patient groups

Arm I (ramucirumab, paclitaxel)

Experimental group

Description:

Patients receive ramucirumab IV over 30-60 minutes on days 1 and 15, and paclitaxel IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Treatment: