Phase II Trial of Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients With Cholangiocarcinoma (PrE0204)
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|ClinicalTrials.gov Identifier: NCT02181634|
Recruitment Status : Completed
First Posted : July 4, 2014
Results First Posted : May 29, 2018
Last Update Posted : October 3, 2018
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Patients with advanced or metastatic cholangiocarcinoma (CCA) who are not eligible for curative surgery, transplantation, or ablative therapies will receive nab-paclitaxel and gemcitabine chemotherapy.
The purpose of this study is to evaluate the effectiveness and safety of the combination of nab-paclitaxel and gemcitabine. The effectiveness will be determined by improvement in the length of time during and after treatment, that the CCA does not get worse.
|Condition or disease||Intervention/treatment||Phase|
|Cholangiocarcinoma||Drug: Nab-Paclitaxel and Gemcitabine||Phase 2|
Advanced cholangiocarcinomas (CCAs) are aggressive tumors with median survival time after diagnosis of less than 12 months, and five-year overall survival (OS) of ~5% with systemic chemotherapy. Currently available systemic therapies for CCA are largely ineffective, thus the rationale for the proposed research is to investigate targeted delivery of chemotherapy.
The goal of this study is to evaluate the efficacy of gemcitabine plus nab-paclitaxel in patients with advanced CCA. This is based on the premise that nab-paclitaxel binds to SPARC (secreted protein acidic and rich in cysteine) through its interaction with albumin, leading to an increase in intra-tumoral concentration of gemcitabine through decreased deoxycytidine deaminase (CDA) enzyme. We hope to improve on the OS of patients with advanced CCA through the use of the synergistic combination of nab-paclitaxel and gemcitabine to specifically target the SPARC protein in the peri-tumoral stroma. We aim to provide critical data to further develop pharmacologic strategies to target the desmoplastic stroma in order to increase chemotherapy responsiveness of CCAs.
We will also examine whether circulating tumor cell (CTC) levels with targeted gene expression analysis and stromal SPARC levels correlate with patient outcome and thus serve as prognostic biomarkers. We will evaluate the role of Human Equilibrative Nucleoside Transporter 1 (hENT1), CDA and tumor fibrosis as additional prognostic and predictive biomarkers in CCA. This clinical trial hopes to improve on the poor prognosis of patients with advanced CCA by establishing the activity of a platinum-free doublet, nab-paclitaxel plus gemcitabine that has shown clear clinical benefit in pancreatic cancer which has close biological parallels to CCA.
A maximum of 70 patients will be enrolled to attain 67 eligible/evaluable patients. Stage I will enroll 37 patients. If 21 or more patients are alive and progression-free at 6 months, the study will proceed to Stage II and an additional 33 patients will be enrolled.
Procurement of archived tissue, if available, from a previous diagnostic biopsy is mandatory for enrollment. If not available, this will not preclude participation in the trial, nor will additional biopsies be performed for research purposes only.
Optional blood samples will be requested.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||74 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Multi-Institutional, Single Arm, Two-Stage Phase II Trial of Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients With Advanced or Metastatic Cholangiocarcinoma|
|Actual Study Start Date :||December 9, 2014|
|Actual Primary Completion Date :||September 24, 2016|
|Actual Study Completion Date :||October 1, 2017|
Experimental: Nab-Paclitaxel and Gemcitabine
Nab-Paclitaxel 125 mg/m² IV and Gemcitabine 1000 mg/m² on days 1, 8 and 15 every 28 days until progression or unacceptable toxicity.
Drug: Nab-Paclitaxel and Gemcitabine
Nab-Paclitaxel will be administered first, at a dose of 125 mg/m² IV over a period of 30 minutes; gemcitabine will be administered second, at a dose of 1000 mg/m² over a period of 30 minutes.
- Progression-Free Survival (PFS) Rate at 6 Months (Proportion of Participants Alive and Progression-Free at 6 Months) [ Time Frame: Assessed at 6 months ]
Progression-free survival is defined as the time from the date of first study treatment to either the date of documented disease progression or death from any cause, whichever occurred first. Progression-free survival rate at 6 months is defined as the proportion of patients who were disease progression-free and alive at 6 months.
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the diameter/axes of target lesions, taking as reference the smallest sum on study, or unequivocal progression of existing non-target lesions, or the appearance of new lesions.
- Overall Survival (OS) [ Time Frame: Every 3-6 months for up to 3 years ]OS is defined as the time from enrollment until death or last patient contact.
- Progression-free Survival (PFS) [ Time Frame: Every 3-6 months for up to 3 years ]Progression-free survival is defined as the time from the date of first study treatment to either the date of documented disease progression or death from any cause, whichever occurred first.
- Time To Progression (TTP) [ Time Frame: Every 3-6 months for up to 3 years ]TTP was defined as the time from date of first dose of study therapy to date of removal from study for progression. Patients who have not experienced progression were censored at the date of last disease evaluation. Progression is evaluated using Solid Tumor Response Criteria (RECIST) Version 1.1. Progression is defined as at least a 20% increase in the sum of the diameters/axes of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm over the nadir. The appearance of new lesions or unequivocal progression of existing non-target lesions also constitutes disease progression.
- Overall Response Rate (ORR) [ Time Frame: Every 3-6 months for up to 3 years ]Overall response rate is defined as the proportion of patients with complete response or partial response per RECIST version 1.1. Complete response is defined as disappearance of all lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters/axes of target lesions and the persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker levels above the normal limits. A confirmation assessment performed >=4 weeks after the criteria for response is met is required.
- Disease Control Rate (DCR) [ Time Frame: Every 3-6 months for up to 3 years ]Disease control rate is the proportion of patients achieved complete response, partial response or stable disease per RECIST version 1.1. Complete response is defined as disappearance of all lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters/axes of target lesions and the persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker levels above the normal limits. Stable disease is defined as neither sufficient shrinkage to qualify for complete or partial response nor sufficient increase to qualify for progression. A confirmation assessment performed >=4 weeks after the criteria for response is met is required.
- Association Between PFS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline [ Time Frame: CA 19-9 was evaluated every 8 weeks until progression or for up to 3 years and off-treatment ]Patients were dichotomized into maximum CA 19-9 decline >=50% and maximum CA 19-9 decline <50%. Cox proportional hazards model was used to evaluate the association between PFS and maximum change in CA 19-9.
- Association Between OS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline [ Time Frame: CA 19-9 was evaluated every 8 weeks until progression or for up to 3 years and off-treatment ]Patients were dichotomized into maximum CA 19-9 decline >=50% and maximum CA 19-9 decline <50%. Cox proportional hazards model was used to evaluate the association between OS and maximum change in CA 19-9.
- Change in Circulating Tumor Cells (CTCs) [ Time Frame: Prior to Cycle 1, Day 1; Cycle 1 Day 8; Cycle 3, Day 1 and at Off Treatment ]Correlate change in CTCs to median PFS, OS, TTP, ORR and DCR.
- Stromal SPARC Expression [ Time Frame: Baseline ]Correlate stromal SPARC (high versus low) expression by immunohistochemistry (IHC) with median PFS, OS, TTP, ORR and DCR.
- Fibrosis Expression [ Time Frame: Baseline ]Correlate fibrosis (low, intermediate and high) by trichrome staining with median PFS, OS, TTP, ORR and DCR.
- CDA Expression [ Time Frame: Baseline ]Correlate CDA (high versus low) expression by IHC with median PFS, OS, TTP, ORR and DCR.
- hENT Expression [ Time Frame: Baseline ]Correlate hENT1 (high versus low) expression by IHC with median PFS, OS, TTP, ORR and DCR.
- Banking Biospecimens for Future Assessment [ Time Frame: Prior to Cycle 1, Day 1; Cycle 1, Day 8; Cycle 3, Day 1 and at Off Treatment ]Optional specimen banking of patient blood specimens (including serum, plasma and buffy coat) as well as fixed left-over tissue specimens when available from all enrolled patients in this trial for possible future molecular, pharmacogenomic, and/or proteomic testing.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Must have histologically-confirmed diagnosis of cholangiocarcinoma Stage II, III, or IV CCA (intra-hepatic, extra-hepatic and perihilar) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed histology are not allowed.
- Must have radiographically measurable disease in at least one site not previously treated with radiation, chemoembolization, radioembolization, or other local ablative procedures; a new area of tumor progression within or adjacent to a previously-treated lesion, if clearly measurable by a Radiologist, is acceptable.
- May have received prior radiation, chemoembolization, radioembolization, or other local ablative therapies, or hepatic resection if completed ≥ 4 weeks prior to registration AND if patient has recovered to ≤ grade 1 toxicity. NOTE: Measurable disease (as required above) must still be present.
- May have received prior radiation for bone or brain metastases if patient is now asymptomatic and has completed all radiation and steroid therapy (if applicable) ≥ 2 weeks prior to registration.
- Age ≥ 18 years.
- Child-Pugh score of A or B with ≤ 7 points.
- Eastern Cooperative Oncology Group performance status of 0-1.
- Willing to provide archived tissue, if available, from a previous diagnostic biopsy.
- Must be able to tolerate CT and/or MRI with contrast.
Adequate organ function obtained ≤ 2 weeks prior to registration:
- Absolute Neutrophil Count ≥ 1500/mm³
- Hemoglobin ˃9.0 g/dL
- Platelets ˃100,000/mm³
- Serum Creatinine ≤ 1.5x Upper Limit Normal (ULN)
- Creatinine Clearance ≥ 50 mL/min
- Albumin ≥ 2.8 g/dL
- Total Bilirubin ≤ 1.5 mg/dL or ≤ 1.5x ULN
- Aspartate Aminotransaminase (AST)/Alanine Aminotransaminase (ALT) ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases)
- International Normalized Ratio (INR) <1.5x the ULN [INR ≥ 1.5 is allowed if anticoagulation is used.]
- Women must not be pregnant or breastfeeding since nab-paclitaxel and/or gemcitabine may harm the fetus or child.
- Must not have received prior systemic cytotoxic chemotherapy or targeted therapy for this cancer.
- Must not be receiving treatment with other investigational agents.
- Must not have a pre-existing >grade 2 peripheral neuropathy.
- Must not be receiving immunosuppressive medications, including systemic corticosteroids, aside from the following exceptions: used for adrenal replacement, appetite stimulation, therapy for asthma, bronchitis exacerbation (≤ 2 weeks), anti-emesis, or pre-medication for procedures (i.e. CT scan).
- No known Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) seropositivity.
- Must not have undergone liver transplantation.
- Must not have serious non-healing wound, ulcer, bone fracture, or abscess.
- Must not have undergone a major surgical procedure <4 weeks prior to registration.
- Must not have possible histories of pneumonitis or pneumonitis risk factors.
- Must not have an active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ.
- Must have no ongoing or active, uncontrolled infections.
- Must have no evidence of significant, uncontrolled concomitant diseases including, but not limited to: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, myocardial infarction within preceding 12 months, uncontrolled peripheral vascular disease, cerebrovascular accident within preceding 12 months, pulmonary disease impairing functional status or requiring oxygen, connective tissue disease including lupus.
- Must not have any history of allergic reaction(s) attributed to compounds of similar composition to nab-paclitaxel or gemcitabine.
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): NCT02181634
|Study Chair:||Vaibhav Sahai, MD||University of Michigan Health System in Ann Arbor, MI|
|Responsible Party:||PrECOG, LLC.|
|Other Study ID Numbers:||
AX-CL-OTHER-PrECOG-004080 ( Other Grant/Funding Number: Celgene )
2015-002066-24 ( EudraCT Number )
|First Posted:||July 4, 2014 Key Record Dates|
|Results First Posted:||May 29, 2018|
|Last Update Posted:||October 3, 2018|
|Last Verified:||September 2018|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||No|
|Plan Description:||Data is proprietary|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
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Neoplasms by Histologic Type
Antineoplastic Agents, Phytogenic
Molecular Mechanisms of Pharmacological Action