Adult Primary Cholangiocellular Carcinoma, Advanced Adult Primary Liver Cancer, Cholangiocarcinoma of the Extrahepatic Bile Duct, Cholangiocarcinoma of the Gallbladder, Localized Unresectable Adult Primary Liver Cancer, Periampullary Adenocarcinoma, Recurrent Adult Primary Liver Cancer, Recurrent Extrahepatic Bile Duct Cancer, Recurrent Gallbladder Cancer, Unresectable Extrahepatic Bile Duct Cancer, Unresectable Gallbladder Cancer
Conditions
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.
Interventions
DRUGcediranib maleate
Given PO
DRUGoxaliplatin
Given IV
DRUGleucovorin calcium
Given IV
DRUGfluorouracil
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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 |
| Identification of Factors That Predict Survival | Up to three years | Factors that predict survival will be identified by Cox model or extended Cox model. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from hospitals in Cleveland and Columbus, Ohio from October 2010 through February 2013.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Cediranib Maleate and Modified FOLFOX) 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.
cediranib maleate: Given PO
oxaliplatin: Given IV
leucovorin calcium: Given IV
fluorouracil: Given IV | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | Treatment (Cediranib Maleate and Modified FOLFOX) |
|---|---|
| Age, Customized 30-39 years | 1 participants |
| Age, Customized 40-49 years | 1 participants |
| Age, Customized 50-59 years | 3 participants |
| Age, Customized 60-69 years | 8 participants |
| Age, Customized 70-79 years | 1 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 11 / 13 |
Outcome results
Primary
The Response Rate of Patients Evaluated Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
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.
Time frame: Up to 3 years
Population: Patients that were evaluable
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Cediranib Maleate and Modified FOLFOX) | The Response Rate of Patients Evaluated Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Partial Response (PR) | 4 participants |
| Treatment (Cediranib Maleate and Modified FOLFOX) | The Response Rate of Patients Evaluated Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Stable Disease (SD) | 6 participants |
| Treatment (Cediranib Maleate and Modified FOLFOX) | The Response Rate of Patients Evaluated Using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Progressive Disease (PD) | 1 participants |
Secondary
Estimation of Overall Survival
Time of overall response
Time frame: Up to 3 years
Population: Patients that received treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Cediranib Maleate and Modified FOLFOX) | Estimation of Overall Survival | 19.2 Months |
Secondary
Identification of Factors That Predict Survival
Factors that predict survival will be identified by Cox model or extended Cox model.
Time frame: Up to three years
Population: Statistically, due to the small sample size, analysis could not be done
Secondary
Progression Free Survival
Time in months that evaluable subjects survived progression free
Time frame: Up to 3 years
Population: Patients that were evaluable for response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Cediranib Maleate and Modified FOLFOX) | Progression Free Survival | 14.4 Months |
Secondary
Tabulation of the Toxicity Profile of the Combination Therapy
Number of patients that experienced \>/= grade 3 treatment related toxicities (definite, probable, possible).
Time frame: Up to 3 years
Population: All patients that received treatment drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Cediranib Maleate and Modified FOLFOX) | Tabulation of the Toxicity Profile of the Combination Therapy | 11 participants |