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Ramucirumab and Paclitaxel or FOLFIRI in Advanced Small Bowel Cancers

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04205968
Recruitment Status : Recruiting
First Posted : December 20, 2019
Last Update Posted : August 14, 2023
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
SWOG Cancer Research Network

Study Description
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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.

Condition or disease Intervention/treatment Phase
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 Drug: Fluorouracil Drug: Irinotecan Drug: Irinotecan Hydrochloride Drug: Leucovorin Drug: Leucovorin Calcium Drug: Paclitaxel Biological: Ramucirumab Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 94 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase II Selection Study of Ramucirumab and Paclitaxel Versus FOLFIRI in Refractory Small Bowel Adenocarcinoma
Actual Study Start Date : June 1, 2020
Estimated Primary Completion Date : June 15, 2025
Estimated Study Completion Date : June 16, 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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.
 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
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.
 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


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Incidence of adverse events [ Time Frame: Up to 3 years after registration ]
    Will be compared across treatment arms via chi-square tests.


Other Outcome Measures:
  1. 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).


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04205968


Contacts
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Contact: Christy Klepetko 210/614-8808 ext 9312 cklepetko@swog.org
Contact: Dana Sparks 210/614-8808 ext 1004 dsparks@swog.org

Locations
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Sponsors and Collaborators
SWOG Cancer Research Network
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Michael J Overman SWOG Cancer Research Network
More Information
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Responsible Party: SWOG Cancer Research Network
ClinicalTrials.gov Identifier: 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 )
First Posted: December 20, 2019    Key Record Dates
Last Update Posted: August 14, 2023
Last Verified: August 2023

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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
Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Calcium, Dietary
Leucovorin
Folic Acid
Paclitaxel
Camptothecin
Fluorouracil
Irinotecan
Albumin-Bound Paclitaxel
Ramucirumab
Antineoplastic Agents, Immunological
 Antibodies
Immunoglobulins
Antibodies, Monoclonal
Lexatumumab
Calcium
Levoleucovorin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs
Calcium-Regulating Hormones and Agents