Resectable Cholangiocarcinoma, Stage IB Intrahepatic Cholangiocarcinoma AJCC v8, Stage IIIA Intrahepatic Cholangiocarcinoma AJCC v8, Stage IIIB Intrahepatic Cholangiocarcinoma AJCC v8, Stage III Intrahepatic Cholangiocarcinoma AJCC v8, Stage II Intrahepatic Cholangiocarcinoma AJCC v8
Conditions
Brief summary
This phase II trial studies how well gemcitabine, cisplatin, and nab-paclitaxel work before surgery in treating participants with high-risk bile duct cancer in the liver (intrahepatic cholangiocarcinoma). Drugs used in chemotherapy, such as nab-paclitaxel, cisplatin, and gemcitabine, 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 combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.
Detailed description
PRIMARY OBJECTIVE: To assess the feasibility of therapeutic approach that includes neoadjuvant chemotherapy including gemcitabine hydrochloride (gemcitabine), cisplatin, and nab-paclitaxel for high-risk but technically resectable intrahepatic cholangiocarcinoma and is completed with surgical resection. SECONDARY OBJECTIVES: I. To assess the radiological response rate to neoadjuvant systemic chemotherapy according to the Response Evaluation Criteria in Solid Tumors (RECIST). II. To determine the R0 resection rate. III. To determine patient recurrence-free survival (RFS). IV. To identify patient overall survival (OS) rate. OUTLINE: Participants receive nab-paclitaxel intravenously (IV) over 30 minutes, cisplatin IV over 60 minutes, and gemcitabine IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Participants with stable disease (SD), partial response (PR), or complete response (CR) then undergo standard of care hepatectomy with portal lymphadenectomy. After completion of study treatment, participants are followed up every 4 months for 3 years.
Interventions
DRUGCisplatin
Given IV
DRUGGemcitabine
Given IV
DRUGNab-paclitaxel
Given IV
Sponsors
Celgene
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Emory University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of intrahepatic cholangiocarcinoma. * High-quality cross-sectional imaging by computerized tomography (CT) or magnetic resonant imaging (MRI) performed within 6 weeks prior to enrollment and showed a resectable, but high-risk, intrahepatic cholangiocarcinoma (IHCCA) confined to the liver, bile duct, and/or regional lymph nodes. Tumors will be considered high-risk if the high-quality, contrast-enhanced CT and/or MRI +/- positron emission tomography (PET) scan showed: (must meet at least one of the criteria below) 1. T-stage ≥ Ib (Ib-IV) 2. Solitary lesion \> 5 cm 3. Multifocal tumors or satellite lesions present confined to the same lobe of the liver as the dominant lesion but still technically resectable 4. Presence of major vascular invasion but still technically resectable 5. Suspicious or involved regional lymph nodes (N1) * No distant extrahepatic disease (M0) * Able to give informed consent. * Able to adhere to study visit schedule and other protocol requirements. * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. * Absolute neutrophil count (ANC) ≥ 1,500 cells/μL * Platelet count ≥ 100,000 cells/μL * Hemoglobin ≥ 9 g/dL * Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN * Albumin ≥ 3 g/dL * Creatinine ≤ 1.5 x ULN * Non-pregnant and non-lactating. * Women of child-bearing potential (defined as a sexually mature woman who \[1\] has not undergone hysterectomy \[the surgical removal of the uterus\] or bilateral oophorectomy \[the surgical removal of both ovaries\] or (2) has not been naturally postmenopausal for at least 24 consecutive months \[i.e., has had menses at any time during the preceding 24 consecutive months\]) must commit to true abstinence from heterosexual contact or agree to use, and be able to comply with, effective contraception without interruption for 28 days prior to starting gemcitabine/cisplatin/nab-paclitaxel (including dose interruptions) until treatment with gemcitabine/cisplatin/nab-paclitaxel is complete. * Male subjects must practice true abstinence or agree to use a condom during sexual contact with a female of childbearing potential or a pregnant female while on treatment (including during dose interruptions) with gemcitabine/cisplatin/nab-paclitaxel and for 6 months following gemcitabine/cisplatin/nab-paclitaxel discontinuation, even if he has undergone a successful vasectomy.
Exclusion criteria
* Peripheral neuropathy of grade 2 or greater by Common Terminology Criteria for Adverse Events (CTCAE) 4.0. In CTCAE version 4.0 grade 2 sensory neuropathy is defined as moderate symptoms; limiting instrumental activities of daily living (ADLs). * Concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study such as unstable angina, myocardial infarction within 6 months, unstable symptomatic arrhythmia, symptomatic congestive heart failure, uncontrolled diabetes, serious active, uncontrolled infection after inadequate biliary drainage if tumor obstructing bile duct, or psychiatric illness/social situations. * Pregnancy (positive pregnancy test) or lactation. * Known central nervous system (CNS) disease, except for treated brain metastasis. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator \[LINAC\], or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded. * Previous (within the past 5 years) or concurrent presence of other cancer, except non-melanoma skin cancer and in situ carcinomas. * History of allergy or hypersensitivity to any of the study drugs. * Current abuse of alcohol or illicit drugs. * Inability or unwillingness to sign the informed consent form.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Completed All Preoperative and Operative Therapy | Up to 12 weeks after study start | Completion of all therapy rate will be recorded. |
| Number of Participants With Adverse Events | Up to 3 years after study start | Will be monitored using method of Thall, Simon and Estey, and will be tabulated by the maximum reported Common Terminology Criteria for Adverse Events (CTCAE) grade. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Radiological Response Rate Defined as the Percentage of Patients Who Will Have Complete Response (CR), Partial Response (PR) or Stable Disease (SD) After the Neoadjuvant Therapy | Up to 12 weeks after study start | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Recurrence-free Survival (RFS) | From the date of surgery up to 3 years | RFS is defined as the time between the date of surgery and the date of disease recurrence or death, whichever occurred first. If a patient did not have an event (i.e. disease recurrence or death) by the time of final analysis, patient will be censored at the last disease evaluation time. |
| Number of Participants With Overall Survival | From date of neoadjuvant treatment start up to 3 years | OS is defined as the time from date of neoadjuvant treatment start to the date of death from any cause or to the date of last follow-up if patients are alive. If a patient is alive by the time of final analysis, the patient will be censored at the last follow-up date. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gemcitabine, Cisplatin, Nab-paclitaxel Participants receive nab-paclitaxel IV over 30 minutes, cisplatin IV over 60 minutes, and gemcitabine IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Participants with stable disease (SD), partial response (PR), or complete response (CR) then undergo standard of care hepatectomy with portal lymphadenectomy.
Cisplatin: Given IV
Gemcitabine: Given IV
Nab-paclitaxel: Given IV | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Gemcitabine, Cisplatin, Nab-paclitaxel |
|---|---|
| Age, Continuous | 61.17 years STANDARD_DEVIATION 9.57 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 7 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment Benaroya Research Institute at Virginia Mason | 3 Participants |
| Region of Enrollment Emory University | 11 Participants |
| Region of Enrollment Mayo Clinic-Rochester | 4 Participants |
| Region of Enrollment MD Anderson | 12 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 30 |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 14 / 30 |
Outcome results
Primary
Number of Participants Who Completed All Preoperative and Operative Therapy
Completion of all therapy rate will be recorded.
Time frame: Up to 12 weeks after study start
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants Who Completed All Preoperative and Operative Therapy | 22 Participants |
Primary
Number of Participants With Adverse Events
Will be monitored using method of Thall, Simon and Estey, and will be tabulated by the maximum reported Common Terminology Criteria for Adverse Events (CTCAE) grade.
Time frame: Up to 3 years after study start
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Gastrointestinal disorders | 11 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | General disorders and administration site conditions | 11 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Respiratory, thoracic and mediastinal disorders | 4 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Skin and subcutaneous tissue disorders | 13 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Vascular disorders | 1 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Any adverse event | 26 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Blood and lymphatic system disorders | 13 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Ear and labyrinth disorders | 2 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Endocrine disorders | 1 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Investigations | 15 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Metabolism and nutrition disorders | 4 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Nervous system disorders | 9 participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Adverse Events | Renal and urinary disorders | 1 participants |
Secondary
Number of Participants With Overall Survival
OS is defined as the time from date of neoadjuvant treatment start to the date of death from any cause or to the date of last follow-up if patients are alive. If a patient is alive by the time of final analysis, the patient will be censored at the last follow-up date.
Time frame: From date of neoadjuvant treatment start up to 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gemcitabine, Cisplatin, Nab-paclitaxel | Number of Participants With Overall Survival | 30 Participants |
Secondary
Radiological Response Rate Defined as the Percentage of Patients Who Will Have Complete Response (CR), Partial Response (PR) or Stable Disease (SD) After the Neoadjuvant Therapy
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 12 weeks after study start
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gemcitabine, Cisplatin, Nab-paclitaxel | Radiological Response Rate Defined as the Percentage of Patients Who Will Have Complete Response (CR), Partial Response (PR) or Stable Disease (SD) After the Neoadjuvant Therapy | PD | 3 Participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Radiological Response Rate Defined as the Percentage of Patients Who Will Have Complete Response (CR), Partial Response (PR) or Stable Disease (SD) After the Neoadjuvant Therapy | PR | 7 Participants |
| Gemcitabine, Cisplatin, Nab-paclitaxel | Radiological Response Rate Defined as the Percentage of Patients Who Will Have Complete Response (CR), Partial Response (PR) or Stable Disease (SD) After the Neoadjuvant Therapy | SD | 20 Participants |
Secondary
Recurrence-free Survival (RFS)
RFS is defined as the time between the date of surgery and the date of disease recurrence or death, whichever occurred first. If a patient did not have an event (i.e. disease recurrence or death) by the time of final analysis, patient will be censored at the last disease evaluation time.
Time frame: From the date of surgery up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gemcitabine, Cisplatin, Nab-paclitaxel | Recurrence-free Survival (RFS) | 23.7 months |