Clinical Trials /

Ramucirumab and Paclitaxel or FOLFIRI in Advanced Small Bowel Cancers

NCT04205968

Description:

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.

Related Conditions:
  • Small Intestinal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: S1922
  • SECONDARY ID: NCI-2019-04213
  • SECONDARY ID: S1922
  • SECONDARY ID: S1922
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT04205968

Conditions

  • 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

Interventions

DrugSynonymsArms
Fluorouracil5 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-2-9757Arm II (irinotecan, leucovorin, fluorouracil)
IrinotecanArm II (irinotecan, leucovorin, fluorouracil)
Irinotecan HydrochlorideCampto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, Irinotecan Hydrochloride Trihydrate, Irinotecan Monohydrochloride Trihydrate, U-101440EArm II (irinotecan, leucovorin, fluorouracil)
LeucovorinFolinic acidArm II (irinotecan, leucovorin, fluorouracil)
Leucovorin CalciumAdinepar, 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, WellcovorinArm II (irinotecan, leucovorin, fluorouracil)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm I (ramucirumab, paclitaxel)
RamucirumabAnti-VEGFR-2 Fully Human Monoclonal Antibody IMC-1121B, Cyramza, IMC-1121B, LY3009806, Monoclonal Antibody HGS-ETR2Arm I (ramucirumab, paclitaxel)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (ramucirumab, paclitaxel)ExperimentalPatients 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.
  • Paclitaxel
  • Ramucirumab
Arm II (irinotecan, leucovorin, fluorouracil)ExperimentalPatients 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.
  • Fluorouracil
  • Irinotecan
  • Irinotecan Hydrochloride
  • Leucovorin
  • Leucovorin Calcium

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure:Overall survival (OS)
Time Frame:From date of registration to date of death due to any cause, assessed up to 3 years
Safety Issue:
Description: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.
Measure:Overall response rate
Time Frame:Up to 3 years after registration
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1. Will be compared across treatment arms via chi-square tests.
Measure:Incidence of adverse events
Time Frame:Up to 3 years after registration
Safety Issue:
Description:Will be compared across treatment arms via chi-square tests.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Southwest Oncology Group

Last Updated

May 1, 2020