Cediranib Maleate and Combination Chemotherapy in Treating Patients With Advanced Biliary Cancers

Phase 2

Terminated

• Conditions: Localized Unresectable Adult Primary Liver Cancer; Periampullary Adenocarcinoma; Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Recurrent Extrahepatic Bile Duct Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer; Recurrent Adult Primary Liver Cancer
• Interventions: Drug: cediranib maleate; Drug: oxaliplatin; Drug: leucovorin calcium; Drug: fluorouracil

• Registration Number: NCT01229111
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase II trial is studying how well giving cediranib maleate together with combination chemotherapy works in treating patients with advanced biliary cancers. Cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving cediranib maleate together with combination chemotherapy may kill more tumor cells.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the response rate to AZD2171 (cediranib maleate) and modified folinic acid-fluorouracil-oxaliplatin-6 regimen (FOLFOX 6) in subjects with advanced biliary cancers.

SECONDARY OBJECTIVES:

I. To determine overall assessment of toxicity of AZD2171 and modified FOLFOX6. II. To determine the progression-free survival of subjects with advanced biliary cancers treated with AZD2171 and modified FOLFOX6.

III. To determine overall survival of subjects with advanced biliary cancers treated with AZD2171 and modified FOLFOX6.

OUTLINE:

Patients receive cediranib maleate orally (PO) once daily (QD) on days 1-14 and modified FOLFOX6 comprising oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Study Timeline

• Study Start: 2010-10
• Study First Submitted: 2010-10-26
• Study First Submitted QC: 2010-10-26
• Study First Posted: 2010-10-27
• Primary Completion: 2014-03
• Study Completion: 2014-03
• Status Verified: 2017-02
• Results First Submitted: 2017-02-10
• Results First Submitted QC: 2017-02-10
• Last Update Submitted: 2017-02-10
• Results First Posted: 2017-03-29
• Last Update Posted: 2017-03-29

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 14

Inclusion Criteria

• Patients with histopathological or cytopathological diagnosis of advanced biliary carcinoma (gallbladder cancer, cholangiocarcinoma, ampullary cancer) not amenable to conventional surgical approach are eligible

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan

• No patients with untreated brain metastases

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)

• Life expectancy of greater than 12 weeks

• White blood cell (WBC)/leukocytes ≥ 3,000/μL

• Absolute neutrophil count ≥ 1,500/μL

• Platelets ≥ 100,000/μL

• Hemoglobin ≥ 9 g/dL

• Total bilirubin ≤ 3 mg/dL

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤ 2.5 times institutional upper limit of normal

• Creatinine within normal institutional limits OR calculated creatinine clearance ≥ 60 mL/min

• No patients with proteinuria not meeting the criteria below; urine sample must be tested by urine protein:creatinine (UPC) ratio or by urinalysis method within 1 week of starting study treatment; depending upon the testing method used, the following criteria must be met:

  • UPC ratio must be < 1.0; if UPC ratio is ≥ 1.0, a 24-hour urine specimen must be collected and must demonstrate < 1 g of protein
  • Urinalysis must indicate 0-1+ protein; if urinalysis reading is ≥ 2+, a 24-hour urine specimen must be collected and must demonstrate < 1 g of protein

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use adequate contraception (hormonal or barrier method of birth control; abstinence) before and during study treatment

  • Acceptable contraception includes abstinence, oral contraceptives, intra-uterine device (IUD), diaphragm, Norplant, approved hormone injections, condoms, or documentation of medical sterilization

• Patients with evidence of heart disease must be New York Heart Association (NYHA) Class I or II

  • NYHA Class II patients controlled with treatment are considered at increased risk for compromised left ventricular ejection fraction (LVEF) and will undergo increased cardiac monitoring

• No patients with other active invasive cancers except nonmelanoma skin cancer or carcinoma in-situ of the cervix

  • History of prior cancer is allowed as long as there has been no evidence of disease within the past 5 years

• No patients with mean corrected QT interval (QTc) > 480 msec (with Bazett's correction) in screening electrocardiogram or history of familial long QT syndrome

• No patients with uncontrolled hypertension defined as systolic blood pressure (BP) ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg, with or without anti-hypertensive medication or history of hypertensive crisis or hypertensive encephalopathy

  • Patients with initial BP elevations are eligible once their BP is controlled to above parameters

• No patients with uncontrolled intercurrent illness including, but not limited to:

  • Hypertension (> 140/90 mm Hg)
  • Chronic or active infection requiring chronic suppressive antibiotics
  • History of or symptomatic congestive heart failure requiring chronic medical therapy
  • NYHA class III or IV heart disease
  • Unstable angina pectoris within 180 days prior to starting study treatment
  • Myocardial infarction within 180 days prior to study treatment
  • Gastroduodenal ulcer(s) determined by endoscopy to be active within 180 days prior to study treatment
  • Serious or non-healing wound, skin ulcers, or bone fracture
  • Any significant bleeding that is not related to the primary tumor within 180 days prior to study treatment
  • Known bleeding diathesis or coagulopathy
  • Paresthesias, peripheral sensory neuropathy > gr. 1 per Common Terminology Criteria for Adverse Events (CTCAE) v.4, or peripheral motor neuropathy ≥ gr. 2 per CTCAE v.4
  • Psychiatric illness/social situations that would limit compliance with study requirements

• No patients with history of transient ischemic attack (TIA) or cerebrovascular accident (CVA) within 180 days prior to study treatment, symptomatic peripheral ischemia; history of arterial thrombotic event within 180 days prior to study treatment; gastrointestinal (GI) perforation within 180 days prior to study treatment

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

• Patients who are chemotherapy naive unless chemotherapy was given as adjuvant post-surgical treatment and at least 6 months have elapsed since adjuvant chemotherapy

• No patients who have had major surgical procedures, open biopsies, or significant traumatic injury within 28 days prior to study treatment

• Chemotherapy for prior cancer is permitted

• Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or PK of AZD2171 will be determined following review of their case by the Principal Investigator

  • Efforts should be made to switch patients with brain metastases who are taking enzyme-inducing anticonvulsant agents to other medications

• Patients may not be receiving any other investigational agents nor have participated in an investigational trial within the past 30 days

• Patients may not be receiving any medication that may markedly affect renal function (e.g., vancomycin, amphotericin, pentamidine)

• Patients may not be receiving therapeutic doses of Coumadin or equivalent

• No patients requiring drugs with proarrhythmic potential

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (cediranib maleate and modified FOLFOX)	cediranib maleate	Patients receive cediranib maleate PO QD on days 1-14 and modified FOLFOX6 comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on day 1.
Treatment (cediranib maleate and modified FOLFOX)	leucovorin calcium	Patients receive cediranib maleate PO QD on days 1-14 and modified FOLFOX6 comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on day 1.
Treatment (cediranib maleate and modified FOLFOX)	oxaliplatin	Patients receive cediranib maleate PO QD on days 1-14 and modified FOLFOX6 comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on day 1.
Treatment (cediranib maleate and modified FOLFOX)	fluorouracil	Patients receive cediranib maleate PO QD on days 1-14 and modified FOLFOX6 comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on day 1.

Primary Outcome Measures

Name	Time	Method
The Response Rate of Patients Evaluated Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	Up to 3 years	The number of patients with a Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions); Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival	Up to 3 years	Time in months that evaluable subjects survived progression free
Estimation of Overall Survival	Up to 3 years	Time of overall response
Tabulation of the Toxicity Profile of the Combination Therapy	Up to 3 years	Number of patients that experienced \>/= grade 3 treatment related toxicities (definite, probable, possible).
Identification of Factors That Predict Survival	Up to three years	Factors that predict survival will be identified by Cox model or extended Cox model.

Trial Locations

Locations (7)

Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center; 🇺🇸 Columbus, Ohio, United States

Lake University Ireland Cancer Center; 🇺🇸 Mentor, Ohio, United States

UHHS-Chagrin Highlands Medical Center; 🇺🇸 Orange Village, Ohio, United States

UH-Seidman Cancer Center at Saint John Medical Center; 🇺🇸 Westlake, Ohio, United States

Seidman Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center; 🇺🇸 Cleveland, Ohio, United States

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center; 🇺🇸 Cleveland, Ohio, United States

Ireland Cancer Center Landerbrook Health Center; 🇺🇸 Mayfield Heights, Ohio, United States