PrE0204: Phase II Trial of Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients With Cholangiocarcinoma

• Sponsor: PrECOG, LLC. (Other)
• Overall Status: Completed
• CT.gov ID: NCT02181634
• Collaborator: Celgene Corporation (Industry)
• Enrollment: 74
• Locations: 25
• Arm: 1
• Actual Duration (Months): 33.7
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Detailed Description

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 Design

• Study Type: Interventional
• Actual Enrollment: 74 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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: Dec 9, 2014
• Actual Primary Completion Date: Sep 24, 2016
• Actual Study Completion Date: Oct 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
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.; Other Names: Abraxane® Cytotoxic Antimicrotubular Gemzar® Pyrimidine Antimetabolite

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) Rate at 6 Months (Proportion of Participants Alive and Progression-Free at 6 Months) [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.

Secondary Outcome Measures

1. Overall Survival (OS) [Every 3-6 months for up to 3 years]

   OS is defined as the time from enrollment until death or last patient contact.

2. Progression-free Survival (PFS) [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.

3. Time To Progression (TTP) [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.

4. Overall Response Rate (ORR) [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.

5. Disease Control Rate (DCR) [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.

6. Association Between PFS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline [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.

7. Association Between OS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline [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.

Other Outcome Measures

1. Change in Circulating Tumor Cells (CTCs) [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.

2. Stromal SPARC Expression [Baseline]

   Correlate stromal SPARC (high versus low) expression by immunohistochemistry (IHC) with median PFS, OS, TTP, ORR and DCR.

3. Fibrosis Expression [Baseline]

   Correlate fibrosis (low, intermediate and high) by trichrome staining with median PFS, OS, TTP, ORR and DCR.

4. CDA Expression [Baseline]

   Correlate CDA (high versus low) expression by IHC with median PFS, OS, TTP, ORR and DCR.

5. hENT Expression [Baseline]

   Correlate hENT1 (high versus low) expression by IHC with median PFS, OS, TTP, ORR and DCR.

6. Banking Biospecimens for Future Assessment [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Colorado Cancer Research Program	Denver	Colorado	United States	80222
2	Northwestern University	Chicago	Illinois	United States	60611
3	Advocate Christ Medical Center	Oak Lawn	Illinois	United States	60453
4	Siouxland Hematology-Oncology Associates	Sioux City	Iowa	United States	51101
5	Ochsner Medical Center	New Orleans	Louisiana	United States	70121
6	Tufts Medical Center	Boston	Massachusetts	United States	02111
7	University Massachusetts Memorial Medical Center	Worcester	Massachusetts	United States	01655
8	St. Joseph Mercy Health System	Ann Arbor	Michigan	United States	48106-0995
9	University of Michigan Health System	Ann Arbor	Michigan	United States	48109
10	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
11	Metro Minnesota CCOP	Saint Louis Park	Minnesota	United States	55416
12	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08901
13	Montefiore Medical Center	Bronx	New York	United States	10461
14	Mount Sinai Hospital	New York	New York	United States	10029
15	University of Rochester Medical Center	Rochester	New York	United States	14642
16	University of Pennsylvania, Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
17	University of Pennsylvania; Abramson Cancer Center at Presbyterian Medical Center	Philadelphia	Pennsylvania	United States	19104
18	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
19	University of Tennessee Medical Center	Knoxville	Tennessee	United States	37920
20	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
21	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
22	Gundersen Health System	La Crosse	Wisconsin	United States	54601
23	University of Wisconsin-Madison	Madison	Wisconsin	United States	53792
24	Aurora Cancer Care	Wauwatosa	Wisconsin	United States	53226
25	Medical University of Vienna	Vienna		Austria	1090

Sponsors and Collaborators

• PrECOG, LLC.
• Celgene Corporation

Investigators

• Study Chair: Vaibhav Sahai, MD, University of Michigan Health System in Ann Arbor, MI

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: PrECOG, LLC.
• ClinicalTrials.gov Identifier: NCT02181634
• Other Study ID Numbers: PrE0204; AX-CL-OTHER-PrECOG-004080; 2015-002066-24
• First Posted: Jul 4, 2014
• Last Update Posted: Oct 3, 2018
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by PrECOG, LLC.: Advanced Cholangiocarcinoma; Metastatic Cholangiocarcinoma; CCA; Bile Duct Cancer; Nab-Paclitaxel; Abraxane®; Gemcitabine; Gemzar®
• Additional relevant MeSH terms: Cholangiocarcinoma; Gemcitabine; Paclitaxel; Antimetabolites

Study Results

Participant Flow

Arm/Group Title	Nab-Paclitaxel and Gemcitabine
Arm/Group Description	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. 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.
Period Title: Overall Study
STARTED	74
Eligible and Treated	73
COMPLETED	2
NOT COMPLETED	72

Baseline Characteristics

Arm/Group Title	Nab-Paclitaxel and Gemcitabine
Arm/Group Description	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. 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.
Overall Participants	73
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	43 58.9%
Male	30 41.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.4%
Not Hispanic or Latino	71 97.3%
Unknown or Not Reported	1 1.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 1.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 4.1%
White	67 91.8%
More than one race	0 0%
Unknown or Not Reported	2 2.7%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) Rate at 6 Months (Proportion of Participants Alive and Progression-Free at 6 Months)
Description	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.
Time Frame	Assessed at 6 months

Outcome Measure Data

Analysis Population Description

Eligible and treated

Arm/Group Title	Nab-Paclitaxel and Gemcitabine
Arm/Group Description	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. 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.
Measure Participants	73
Number (95% Confidence Interval) [proportion of participants]	0.605 0.8%

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from enrollment until death or last patient contact.
Time Frame	Every 3-6 months for up to 3 years

Outcome Measure Data

Analysis Population Description

Eligible and treated

Arm/Group Title	Nab-Paclitaxel and Gemcitabine
Arm/Group Description	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. 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.
Measure Participants	73
Median (95% Confidence Interval) [months]	11.2

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	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 Frame	Every 3-6 months for up to 3 years

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Nab-Paclitaxel and Gemcitabine
Arm/Group Description	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. 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.
Measure Participants	73
Median (95% Confidence Interval) [months]	7.7

4. Secondary Outcome

Title	Time To Progression (TTP)
Description	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.
Time Frame	Every 3-6 months for up to 3 years

Outcome Measure Data

Analysis Population Description

Eligible and treated

Arm/Group Title	Nab-Paclitaxel and Gemcitabine
Arm/Group Description	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. 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.
Measure Participants	73
Median (95% Confidence Interval) [months]	7.7

5. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	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.
Time Frame	Every 3-6 months for up to 3 years

Outcome Measure Data

Analysis Population Description

Eligible and treated

Arm/Group Title	Nab-Paclitaxel and Gemcitabine
Arm/Group Description	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. 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.
Measure Participants	73
Number (95% Confidence Interval) [proportion of participants]	0.301 0.4%

6. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	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.
Time Frame	Every 3-6 months for up to 3 years

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Nab-Paclitaxel and Gemcitabine
Arm/Group Description	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. 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.
Measure Participants	73
Number (95% Confidence Interval) [proportion of participants]	0.658 0.9%

7. Secondary Outcome

Title	Association Between PFS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline
Description	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.
Time Frame	CA 19-9 was evaluated every 8 weeks until progression or for up to 3 years and off-treatment

Outcome Measure Data

Analysis Population Description

Eligible and treated patients with CA 19-9 data available

Arm/Group Title	Nab-Paclitaxel and Gemcitabine
Arm/Group Description	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. 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.
Measure Participants	35
CA 19-9 decline >=50%	7.7
CA 19-9 decline <50%	1.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nab-Paclitaxel and Gemcitabine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.099
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.02
	Confidence Interval	(2-Sided) 95%; 0.86 to 4.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Association Between OS and Maximum Change in Carbohydrate Antigen (CA) 19-9 From Baseline
Description	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.
Time Frame	CA 19-9 was evaluated every 8 weeks until progression or for up to 3 years and off-treatment

Outcome Measure Data

Analysis Population Description

Eligible and treated patients with CA 19-9 data available

Arm/Group Title	Nab-Paclitaxel and Gemcitabine
Arm/Group Description	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. 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.
Measure Participants	35
CA 19-9 decline >=50%	14.6
CA 19-9 decline <50%	10.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nab-Paclitaxel and Gemcitabine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.54
	Confidence Interval	(2-Sided) 95%; 0.64 to 3.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Other Pre-specified Outcome

Title	Change in Circulating Tumor Cells (CTCs)
Description	Correlate change in CTCs to median PFS, OS, TTP, ORR and DCR.
Time Frame	Prior to Cycle 1, Day 1; Cycle 1 Day 8; Cycle 3, Day 1 and at Off Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Stromal SPARC Expression
Description	Correlate stromal SPARC (high versus low) expression by immunohistochemistry (IHC) with median PFS, OS, TTP, ORR and DCR.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Fibrosis Expression
Description	Correlate fibrosis (low, intermediate and high) by trichrome staining with median PFS, OS, TTP, ORR and DCR.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	CDA Expression
Description	Correlate CDA (high versus low) expression by IHC with median PFS, OS, TTP, ORR and DCR.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Other Pre-specified Outcome

Title	hENT Expression
Description	Correlate hENT1 (high versus low) expression by IHC with median PFS, OS, TTP, ORR and DCR.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Other Pre-specified Outcome

Title	Banking Biospecimens for Future Assessment
Description	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.
Time Frame	Prior to Cycle 1, Day 1; Cycle 1, Day 8; Cycle 3, Day 1 and at Off Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Assessed every week for the first 2 cycles, then every two cycles (every 8 weeks) and 30 days after the last dose of therapy
Arm/Group Title	Nab-Paclitaxel and Gemcitabine
Arm/Group Description	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. 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.
All Cause Mortality
	Nab-Paclitaxel and Gemcitabine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Nab-Paclitaxel and Gemcitabine
	Affected / at Risk (%)	# Events
Total	42/74 (56.8%)
Blood and lymphatic system disorders
Anemia	1/74 (1.4%)
Febrile neutropenia	2/74 (2.7%)
Haemolytic uraemic syndrome	3/74 (4.1%)
Neutropenia	1/74 (1.4%)
Cardiac disorders
Atrial fibrillation	2/74 (2.7%)
Cardiac failure	1/74 (1.4%)
Cardiac failure congestive	1/74 (1.4%)
Pericardial effusion	1/74 (1.4%)
Tachycardia	1/74 (1.4%)
Gastrointestinal disorders
Abdominal pain	3/74 (4.1%)
Ascites	2/74 (2.7%)
Constipation	1/74 (1.4%)
Diarrhea	3/74 (4.1%)
Gastrointestinal haemorrhage	1/74 (1.4%)
General disorders
Disease progression	2/74 (2.7%)
Fatigue	1/74 (1.4%)
Generalised oedema	2/74 (2.7%)
Multi-organ failure	2/74 (2.7%)
Oedema peripheral	1/74 (1.4%)
Pyrexia	5/74 (6.8%)
Hepatobiliary disorders
Bile duct obstruction	1/74 (1.4%)
Bile duct stenosis	2/74 (2.7%)
Biliary fistula	1/74 (1.4%)
Cholangitis	3/74 (4.1%)
Cholecystitis	1/74 (1.4%)
Cholestasis	1/74 (1.4%)
Hyperbilirubinaemia	3/74 (4.1%)
Infections and infestations
Abscess	1/74 (1.4%)
Biliary tract infection	1/74 (1.4%)
Clostridium difficile infection	1/74 (1.4%)
Device related infection	2/74 (2.7%)
Diverticulitis	1/74 (1.4%)
Emphysematous cholecystitis	1/74 (1.4%)
Infection	1/74 (1.4%)
Lung infection	1/74 (1.4%)
Neutropenic sepsis	1/74 (1.4%)
Pneumonia	1/74 (1.4%)
Sepsis	4/74 (5.4%)
Injury, poisoning and procedural complications
Humerus fracture	1/74 (1.4%)
Post procedural haemorrhage	1/74 (1.4%)
Investigations
Neutrophil count decreased	1/74 (1.4%)
Metabolism and nutrition disorders
Hyponatraemia	1/74 (1.4%)
Hypovolaemia	1/74 (1.4%)
Nervous system disorders
Encephalopathy	1/74 (1.4%)
Facial nerve disorder	1/74 (1.4%)
Haemorrhage intracranial	1/74 (1.4%)
Headache	1/74 (1.4%)
Hepatic encephalopathy	1/74 (1.4%)
Syncope	1/74 (1.4%)
Renal and urinary disorders
Acute kidney injury	2/74 (2.7%)
Renal failure	1/74 (1.4%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/74 (1.4%)
Dyspnoea	1/74 (1.4%)
Pneumonitis	1/74 (1.4%)
Pulmonary embolism	1/74 (1.4%)
Respiratory failure	2/74 (2.7%)
Skin and subcutaneous tissue disorders
Rash macular	1/74 (1.4%)
Rash maculo-papular	1/74 (1.4%)
Vascular disorders
Deep vein thrombosis	3/74 (4.1%)
Embolism	3/74 (4.1%)
Hypertension	1/74 (1.4%)
Hypotension	1/74 (1.4%)
Thrombosis	1/74 (1.4%)
Other (Not Including Serious) Adverse Events
	Nab-Paclitaxel and Gemcitabine
	Affected / at Risk (%)	# Events
Total	72/74 (97.3%)
Blood and lymphatic system disorders
Anemia	31/74 (41.9%)
Neutropenia	26/74 (35.1%)
Eye disorders
Vision blurred	5/74 (6.8%)
Gastrointestinal disorders
Abdominal distension	5/74 (6.8%)
Abdominal pain	12/74 (16.2%)
Ascites	5/74 (6.8%)
Constipation	34/74 (45.9%)
Decreased appetite	28/74 (37.8%)
Diarrhea	35/74 (47.3%)
Dry mouth	4/74 (5.4%)
Nausea	34/74 (45.9%)
Stomatitis	8/74 (10.8%)
Vomiting	18/74 (24.3%)
General disorders
Asthenia	5/74 (6.8%)
Chills	11/74 (14.9%)
Fatigue	53/74 (71.6%)
Influenza like illness	4/74 (5.4%)
Oedema peripheral	31/74 (41.9%)
Pain	7/74 (9.5%)
Pyrexia	18/74 (24.3%)
Infections and infestations
Mucosal inflammation	4/74 (5.4%)
Sepsis	4/74 (5.4%)
Investigations
Alanine aminotransferase increased	18/74 (24.3%)
Aspartate aminotransferase increased	18/74 (24.3%)
Blood alkaline phosphatase increased	17/74 (23%)
Blood bilirubin increased	7/74 (9.5%)
Hyperbilirubinemia	7/74 (9.5%)
Hypoalbuminemia	9/74 (12.2%)
Hypocalcemia	4/74 (5.4%)
Leukopenia	5/74 (6.8%)
Neutrophil count decreased	14/74 (18.9%)
Platelet count decreased	11/74 (14.9%)
Thrombocytopenia	16/74 (21.6%)
Weight decreased	22/74 (29.7%)
Weight increased	5/74 (6.8%)
White blood cell count decreased	10/74 (13.5%)
Metabolism and nutrition disorders
Dehydration	7/74 (9.5%)
Hypokalaemia	7/74 (9.5%)
Hyponatremia	8/74 (10.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	13/74 (17.6%)
Back pain	6/74 (8.1%)
Bone pain	4/74 (5.4%)
Muscular weakness	14/74 (18.9%)
Musculoskeletal pain	5/74 (6.8%)
Myalgia	8/74 (10.8%)
Pain in extremity	9/74 (12.2%)
Nervous system disorders
Dizziness	11/74 (14.9%)
Dysgeusia	17/74 (23%)
Headache	6/74 (8.1%)
Neuropathy peripheral	28/74 (37.8%)
Peripheral sensory neuropathy	9/74 (12.2%)
Tremor	4/74 (5.4%)
Psychiatric disorders
Insomnia	12/74 (16.2%)
Renal and urinary disorders
Acute kidney injury	5/74 (6.8%)
Respiratory, thoracic and mediastinal disorders
Cough	11/74 (14.9%)
Dyspnea	22/74 (29.7%)
Epistaxis	11/74 (14.9%)
Pleural effusion	4/74 (5.4%)
Skin and subcutaneous tissue disorders
Alopecia	39/74 (52.7%)
Nail discolouration	5/74 (6.8%)
Pruritus	5/74 (6.8%)
Rash	9/74 (12.2%)
Rash maculo-papular	7/74 (9.5%)
Vascular disorders
Deep vein thrombosis	5/74 (6.8%)
Embolism	4/74 (5.4%)
Hot flashes	6/74 (8.1%)
Hypertension	10/74 (13.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.