Ramucirumab and Paclitaxel or FOLFIRI in Advanced Small Bowel Cancers

• ClinicalTrials.gov Identifier: NCT04205968
• Recruitment Status: Recruiting
• First Posted: December 20, 2019
• Last Update Posted: May 3, 2023
• Sponsor: SWOG Cancer Research Network
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): SWOG Cancer Research Network

Tracking Information

• First Submitted Date: December 18, 2019
• First Posted Date: December 20, 2019
• Last Update Posted Date: May 3, 2023
• Actual Study Start Date: June 1, 2020
• Estimated Primary Completion Date: June 15, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 18, 2019)

Progression free survival (PFS) [ Time Frame: From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years ]

PFS will be assessed in all eligible and evaluable (received at least one dose of protocol therapy) patients using the Kaplan-Meier method, with statistical differences in event rates between treatment arms assessed via stratified Cox regression model.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 18, 2019)

• Overall survival (OS) [ Time Frame: From date of registration to date of death due to any cause, assessed up to 3 years ]
  Probabilities of OS will be estimated using the method of Kaplan-Meier, with statistical differences in event rates between treatment arms assessed via stratified Cox regression model.
• Overall response rate [ Time Frame: Up to 3 years after registration ]
  Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1. Will be compared across treatment arms via chi-square tests.
• Incidence of adverse events [ Time Frame: Up to 3 years after registration ]
  Will be compared across treatment arms via chi-square tests.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: December 18, 2019)

CEA level [ Time Frame: Up to 3 years after registration ]

CEA levels will be measured at the beginning of the first cycle and every 8 weeks during the study. Maximum decrease in CEA levels from treatment onset and time to maximum decrease in CEA will be summarized in descriptive analyses. Decrease in CEA levels will be defined as high (>= 50% change) versus low (< 50% change).

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Ramucirumab and Paclitaxel or FOLFIRI in Advanced Small Bowel Cancers
• Official Title: Randomized Phase II Selection Study of Ramucirumab and Paclitaxel Versus FOLFIRI in Refractory Small Bowel Adenocarcinoma
• Brief Summary: 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.

Detailed 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Metastatic Small Intestinal Adenocarcinoma
• Stage III Small Intestinal Adenocarcinoma AJCC v8
• Stage IIIA Small Intestinal Adenocarcinoma AJCC v8
• Stage IIIB Small Intestinal Adenocarcinoma AJCC v8
• Stage IV Small Intestinal Adenocarcinoma AJCC v8

Intervention

• Drug: Fluorouracil
  Given IV bolus or IV
  Other Names:

  • 5 Fluorouracil
  • 5 Fluorouracilum
  • 5 FU
  • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
  • 5-Fluorouracil
  • 5-Fluracil
  • 5-FU
  • 5FU
  • AccuSite
  • Carac
  • Fluoro Uracil
  • Fluouracil
  • Flurablastin
  • Fluracedyl
  • Fluracil
  • Fluril
  • Fluroblastin
  • Ribofluor
  • Ro 2-9757
  • Ro-2-9757
• Drug: Irinotecan
  Given IV
• Drug: Irinotecan Hydrochloride
  Given IV
  Other Names:

  • Campto
  • Camptosar
  • Camptothecin 11
  • Camptothecin-11
  • CPT 11
  • CPT-11
  • Irinomedac
  • Irinotecan Hydrochloride Trihydrate
  • Irinotecan Monohydrochloride Trihydrate
  • U-101440E
• Drug: Leucovorin
  Given IV
  Other Name: Folinic acid
• Drug: Leucovorin Calcium
  Given IV
  Other Names:

  • Adinepar
  • Calcifolin
  • Calcium (6S)-Folinate
  • Calcium Folinate
  • Calcium Leucovorin
  • Calfolex
  • Calinat
  • Cehafolin
  • Citofolin
  • Citrec
  • Citrovorum Factor
  • Cromatonbic Folinico
  • Dalisol
  • Disintox
  • Divical
  • Ecofol
  • Emovis
  • Factor, Citrovorum
  • Flynoken A
  • Folaren
  • Folaxin
  • FOLI-cell
  • Foliben
  • Folidan
  • Folidar
  • Folinac
  • Folinate Calcium
  • folinic acid
  • Folinic Acid Calcium Salt Pentahydrate
  • Folinoral
  • Folinvit
  • Foliplus
  • Folix
  • Imo
  • Lederfolat
  • Lederfolin
  • Leucosar
  • leucovorin
  • Rescufolin
  • Rescuvolin
  • Tonofolin
  • Wellcovorin
• Drug: Paclitaxel
  Given IV
  Other Names:

  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol
  • Taxol Konzentrat
• Biological: Ramucirumab
  Given IV
  Other Names:

  • Anti-VEGFR-2 Fully Human Monoclonal Antibody IMC-1121B
  • Cyramza
  • IMC-1121B
  • LY3009806
  • Monoclonal Antibody HGS-ETR2

Study Arms

• Experimental: Arm I (ramucirumab, paclitaxel)
  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.
  Interventions:

  • Drug: Paclitaxel
  • Biological: Ramucirumab
• Experimental: Arm II (irinotecan, leucovorin, fluorouracil)
  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.
  Interventions:

  • Drug: Fluorouracil
  • Drug: Irinotecan
  • Drug: Irinotecan Hydrochloride
  • Drug: Leucovorin
  • Drug: Leucovorin Calcium

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 18, 2019): 94
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 16, 2025
• Estimated Primary Completion Date: June 15, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Christy Klepetko; 210/614-8808 ext 9312; cklepetko@swog.org

Contact: Dana Sparks; 210/614-8808 ext 1004; dsparks@swog.org

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04205968
• Other Study ID Numbers: S1922; NCI-2019-04213 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); S1922 ( Other Identifier: SWOG ); S1922 ( Other Identifier: CTEP ); U10CA180888 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: SWOG Cancer Research Network
• Original Responsible Party: Same as current
• Current Study Sponsor: SWOG Cancer Research Network
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Michael J Overman; SWOG Cancer Research Network

• PRS Account: SWOG Cancer Research Network
• Verification Date: May 2023