Phase III Study of ABI-007(Albumin-bound Paclitaxel) Plus Gemcitabine Versus Gemcitabine in Metastatic Adenocarcinoma of the Pancreas

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Celgene Corporation

ClinicalTrials.gov Identifier:

NCT00844649

First received: February 13, 2009

Last updated: April 15, 2016

Last verified: April 2016

History of Changes

Results First Received: October 21, 2013

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Metastatic Pancreatic Cancer
Interventions:	Drug: Albumin-bound paclitaxel (ABI-007) Drug: Gemcitabine

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants were randomized in a 1:1 ratio and the randomization was stratified by geographic region (Australia versus Eastern Europe versus Western Europe versus North America), Karnofsky performance status (70 to 80 versus 90 to 100), and by the presence of liver metastases (yes versus no)

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
38 participants were randomized but not treated due to the participants request to withdraw after the randomization results became known. 1 participant was randomized to Gemcitabine and was treated with Albumin-bound paclitaxel ABI-007/Gemcitabine in error and analyzed as treated and included in the intent to treat population (ITT)

Reporting Groups

	Description
Albumin-bound Paclitaxel (ABI-007)/Gemcitabine (Gem)	Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest
Gemcitabine (Gem)	Gemcitabine 1000 mg/m^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)

Participant Flow: Overall Study

	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine (Gem)	Gemcitabine (Gem)
STARTED	431 ^[1]	430 ^[1]
Treated Population	421 ^[2]	402 ^[2]
COMPLETED	26 ^[3]	12 ^[3]
NOT COMPLETED	405	418
Progressive Disease	196	245
Adverse Event	128	73
Physician Decision	25	18
Protocol Violation	10	6
Withdrawal by Subject	28	39
Unspecified	7	10
Withdrew prior to starting treatment	11	27

[1]	Started = Intent to Treat Population and includes all randomized participants
[2]	Treated population = all randomized patients who received at least one dose of study drug
[3]	Completed = participants remaining on treatment at the time of the data cut off 17 Sept 2012

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
For the Karnofsky Performance Status (KPS) baseline characteristic, some of the participants did not have a baseline KPS recorded by the clinical site.

Reporting Groups

	Description
Albumin-bound Paclitaxel (ABI-007)/Gemcitabine	ABI-007 125 mg/m^2 administered in combination with gemcitabine 1000 mg/m^2 weekly for 3 weeks followed by one week of rest. Albumin-bound paclitaxel (ABI-007)/Gemcitabine : ABI-007 125 mg/m^2 administered in combination with Gemcitabine 1000 mg/m^2 weekly for 3 weeks, Days 1, 8, and 15 followed by one week of rest
Gemcitabine	Gemcitabine, 1000 mg/m^2 administered weekly for 7 weeks followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks followed by a week of rest (Cycle 2 onward). Gemcitabine : Gemcitabine, 1000 mg/m2 administered weekly for 7 weeks, Day 1 through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks, Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward).
Total	Total of all reporting groups

Description

Albumin-bound Paclitaxel (ABI-007)/Gemcitabine

ABI-007 125 mg/m^2 administered in combination with gemcitabine 1000 mg/m^2 weekly for 3 weeks followed by one week of rest.

Albumin-bound paclitaxel (ABI-007)/Gemcitabine : ABI-007 125 mg/m^2 administered in combination with Gemcitabine 1000 mg/m^2 weekly for 3 weeks, Days 1, 8, and 15 followed by one week of rest

Gemcitabine

Gemcitabine, 1000 mg/m^2 administered weekly for 7 weeks followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks followed by a week of rest (Cycle 2 onward).

Gemcitabine : Gemcitabine, 1000 mg/m2 administered weekly for 7 weeks, Day 1 through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks, Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward).

Total

Total of all reporting groups

Baseline Measures

	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine	Gemcitabine	Total
Number of Participants [units: participants]	431	430	861
Age [units: years] Mean (Standard Deviation)	61.4 (10.70)	63.0 (9.27)	62.2 (10.04)
Gender [units: participants]
Female	186	173	359
Male	245	257	502
Race (NIH/OMB) [units: participants]
American Indian or Alaska Native	0	0	0
Asian	8	9	17
Native Hawaiian or Other Pacific Islander	1	0	1
Black or African American	16	16	32
White	378	375	753
More than one race	25	26	51
Unknown or Not Reported	3	4	7
Karnofsky Performance Status (KPS) ^[1] [units: participants]
100% = normal, no complaints, no signs of disease	69	69	138
90% = normal activity, few symptoms of disease	179	199	378
80% = normal activity, some symptoms of disease	149	128	277
70% = caring for self, unable to work	30	33	63
60% = needs help, can manage most tasks	2	0	2
50% = needs help often and medical care	0	0	0
40% = disabled; requires special care & assistance	0	0	0
30% = severely disabled; death is imminent	0	0	0
20% = hospitalized; requires supportive treatment	0	0	0
10% = Moribund, fatal processes progressing fast	0	0	0
0% = Dead	0	0	0
Pancreatic Primary Tumor Location ^[2] [units: participants]
Head	191	180	371
Body	132	136	268
Tail	105	110	215
Unknown = not specified	3	4	7
Number of Baseline Lesions (Target + Non-Target) ^[3] [units: participants]
1	1	0	1
2	32	25	57
3	7	7	14
4	37	43	80
5	8	8	16
>5	276	262	538

[1]	The Karnofsky Performance Status Scale (KPS) was designed to measure the level of participant activity and medical care requirements. A general measure of participant independence and has been widely used as a general assessment of participants with cancer. The Karnofsky score runs from 100 to 0, where 100 is "perfect" health and 0 is death. The primary purpose of its development was to allow physicians to evaluate a participant's ability to survive chemotherapy for cancer. Two participants from the Albumin bound paclitaxel arm and one from the Gemcitabine arm did not have KPS performed.
[2]	Main location or area of the pancreas where the disease is detected at diagnosis. Unknown location refers to disease area not being specified.
[3]	Target lesions are those measurable at baseline and are generally the largest lesions, most reliably measured and most representative of the participants sites of disease. Non target lesions are all of the sites of disease present at baseline not classified as target lesions. They include bone and cystic lesions and pleural/pericardial effusion/ascites. The Independent Radiology Reviewers (IRR) only evaluated scans for those with baseline and follow-up scans.

Outcome Measures

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1. Primary:

Overall Survival (OS) [ Time Frame: From randomization to death; until the data cut off 17 Sept 2012. The maximum time in follow up was 37 months. ]

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2. Secondary:

Progression-free Survival (PFS) by Independent Radiological Review (IRR) [ Time Frame: Randomization until disease progression or death from any cause; Until the data cut off of 17 Sept 2012. The maximum time in follow up was 37 months. ]

Show Outcome Measure 2

3. Secondary:

Percentage of Participants Who Achieved an Objective Confirmed Overall Response by Independent Radiological Review (IRR) [ Time Frame: Assessment every 4 weeks after initial response; Day 1 to data cut off of 17 Sept 2013; maximum time on study 37 months ]

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4. Other Pre-specified:

Participants With Treatment Emergent Adverse Events (AE) [ Time Frame: Study drug initiation through 30 days after the last dose of study drug or EOS, whichever is later; Up to 696 days ]

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5. Other Pre-specified:

Number of Participants With Dose Reductions [ Time Frame: Maximum time on treatment was 666 days ]

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6. Other Pre-specified:

Number of Participants With Dose Interruptions [ Time Frame: Maximum time on treatment was 666 days ]

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7. Other Pre-specified:

Number of Participants With Dose Delays/Doses Not Given [ Time Frame: Up to 666 days ]

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Serious Adverse Events

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Other Adverse Events

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Time Frame	Day 1 up to 30 days after the last dose (a maximum of 666 days)
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5

Reporting Groups

	Description
Albumin-bound Paclitaxel (ABI-007)/Gemcitabine	Albumin-bound paclitaxel (ABI-007)/Gemcitabine: ABI-007 125 mg/m^2 administered intravenously (IV) in combination with Gemcitabine 1000 mg/m^2 IV weekly for 3 weeks on Days 1, 8, and 15 followed by one week of rest
Gemcitabine	Gemcitabine 1000 mg/m^2 administered IV weekly for 7 weeks through Day 43 followed by a week of rest (Cycle 1), followed by cycles of weekly administration for 3 weeks on Days 1, 8, and 15 followed by a week of rest (Cycle 2 onward)

Other Adverse Events

	Albumin-bound Paclitaxel (ABI-007)/Gemcitabine	Gemcitabine
Total, other (not including serious) adverse events
# participants affected / at risk	412/421 (97.86%)	392/402 (97.51%)
Blood and lymphatic system disorders
Anaemia ^{† 1}
# participants affected / at risk	175/421 (41.57%)	131/402 (32.59%)
Neutropenia ^{† 1}
# participants affected / at risk	172/421 (40.86%)	122/402 (30.35%)
Thrombocytopenia ^{† 1}
# participants affected / at risk	127/421 (30.17%)	115/402 (28.61%)
Leukopenia ^{† 1}
# participants affected / at risk	58/421 (13.78%)	39/402 (9.70%)
Gastrointestinal disorders
Nausea ^{† 1}
# participants affected / at risk	223/421 (52.97%)	189/402 (47.01%)
Diarrhoea ^{† 1}
# participants affected / at risk	182/421 (43.23%)	94/402 (23.38%)
Vomiting ^{† 1}
# participants affected / at risk	145/421 (34.44%)	107/402 (26.62%)
Constipation ^{† 1}
# participants affected / at risk	122/421 (28.98%)	111/402 (27.61%)
Abdominal Pain ^{† 1}
# participants affected / at risk	92/421 (21.85%)	87/402 (21.64%)
Abdominal pain upper ^{† 1}
# participants affected / at risk	42/421 (9.98%)	28/402 (6.97%)
Dyspepsia ^{† 1}
# participants affected / at risk	34/421 (8.08%)	28/402 (6.97%)
Stomatitis ^{† 1}
# participants affected / at risk	31/421 (7.36%)	14/402 (3.48%)
Abdominal distension ^{† 1}
# participants affected / at risk	16/421 (3.80%)	29/402 (7.21%)
Ascites ^{† 1}
# participants affected / at risk	15/421 (3.56%)	26/402 (6.47%)
General disorders
Fatigue ^{† 1}
# participants affected / at risk	247/421 (58.67%)	183/402 (45.52%)
Oedema peripheral ^{† 1}
# participants affected / at risk	194/421 (46.08%)	123/402 (30.60%)
Pyrexia ^{† 1}
# participants affected / at risk	160/421 (38.00%)	111/402 (27.61%)
Asthenia ^{† 1}
# participants affected / at risk	77/421 (18.29%)	51/402 (12.69%)
Chills ^{† 1}
# participants affected / at risk	48/421 (11.40%)	34/402 (8.46%)
Mucosal inflammation ^{† 1}
# participants affected / at risk	42/421 (9.98%)	16/402 (3.98%)
Pain ^{† 1}
# participants affected / at risk	24/421 (5.70%)	8/402 (1.99%)
Infections and infestations
Urinary tract infection ^{† 1}
# participants affected / at risk	37/421 (8.79%)	14/402 (3.48%)
Oral candidiasis ^{† 1}
# participants affected / at risk	33/421 (7.84%)	15/402 (3.73%)
Cellulitis ^{† 1}
# participants affected / at risk	25/421 (5.94%)	16/402 (3.98%)
Investigations
Weight decreased ^{† 1}
# participants affected / at risk	57/421 (13.54%)	47/402 (11.69%)
Alanine aminotransferase increased ^{† 1}
# participants affected / at risk	45/421 (10.69%)	36/402 (8.96%)
Haemoglobin decreased ^{† 1}
# participants affected / at risk	41/421 (9.74%)	29/402 (7.21%)
Aspartate aminotransferase increased ^{† 1}
# participants affected / at risk	38/421 (9.03%)	35/402 (8.71%)
Platelet count decreased ^{† 1}
# participants affected / at risk	33/421 (7.84%)	25/402 (6.22%)
Neutrophil count decreased ^{† 1}
# participants affected / at risk	26/421 (6.18%)	19/402 (4.73%)
Blood alkaline phosphatase increased ^{† 1}
# participants affected / at risk	21/421 (4.99%)	30/402 (7.46%)
Metabolism and nutrition disorders
Decreased appetite ^{† 1}
# participants affected / at risk	149/421 (35.39%)	104/402 (25.87%)
Dehydration ^{† 1}
# participants affected / at risk	75/421 (17.81%)	33/402 (8.21%)
Hypokalemia ^{† 1}
# participants affected / at risk	50/421 (11.88%)	28/402 (6.97%)
Hypoalbuminaemia ^{† 1}
# participants affected / at risk	25/421 (5.94%)	18/402 (4.48%)
Hyperglycaemia ^{† 1}
# participants affected / at risk	22/421 (5.23%)	18/402 (4.48%)
Musculoskeletal and connective tissue disorders
Pain in extremity ^{† 1}
# participants affected / at risk	48/421 (11.40%)	24/402 (5.97%)
Arthralgia ^{† 1}
# participants affected / at risk	46/421 (10.93%)	13/402 (3.23%)
Myalgia ^{† 1}
# participants affected / at risk	44/421 (10.45%)	15/402 (3.73%)
Back Pain ^{† 1}
# participants affected / at risk	41/421 (9.74%)	40/402 (9.95%)
Bone pain ^{† 1}
# participants affected / at risk	24/421 (5.70%)	8/402 (1.99%)
Nervous system disorders
Neuropathy peripheral ^{† 1}
# participants affected / at risk	116/421 (27.55%)	11/402 (2.74%)
Peripheral sensory neuropathy ^{† 1}
# participants affected / at risk	107/421 (25.42%)	17/402 (4.23%)
Dysgeusia ^{† 1}
# participants affected / at risk	68/421 (16.15%)	33/402 (8.21%)
Headache ^{† 1}
# participants affected / at risk	60/421 (14.25%)	38/402 (9.45%)
Dizziness ^{† 1}
# participants affected / at risk	47/421 (11.16%)	34/402 (8.46%)
Psychiatric disorders
Insomnia ^{† 1}
# participants affected / at risk	64/421 (15.20%)	46/402 (11.44%)
Depression ^{† 1}
# participants affected / at risk	50/421 (11.88%)	24/402 (5.97%)
Anxiety ^{† 1}
# participants affected / at risk	35/421 (8.31%)	43/402 (10.70%)
Respiratory, thoracic and mediastinal disorders
Cough ^{† 1}
# participants affected / at risk	72/421 (17.10%)	30/402 (7.46%)
Dyspnoea ^{† 1}
# participants affected / at risk	71/421 (16.86%)	61/402 (15.17%)
Epistaxis ^{† 1}
# participants affected / at risk	64/421 (15.20%)	14/402 (3.48%)
Dyspnoea exertional ^{† 1}
# participants affected / at risk	24/421 (5.70%)	13/402 (3.23%)
Skin and subcutaneous tissue disorders
Alopecia ^{† 1}
# participants affected / at risk	212/421 (50.36%)	21/402 (5.22%)
Rash ^{† 1}
# participants affected / at risk	117/421 (27.79%)	39/402 (9.70%)
Pruritis ^{† 1}
# participants affected / at risk	34/421 (8.08%)	20/402 (4.98%)
Dry Skin ^{† 1}
# participants affected / at risk	24/421 (5.70%)	9/402 (2.24%)
Erythema ^{† 1}
# participants affected / at risk	24/421 (5.70%)	13/402 (3.23%)
Vascular disorders
Hypotension ^{† 1}
# participants affected / at risk	38/421 (9.03%)	26/402 (6.47%)
Deep vein thrombosis ^{† 1}
# participants affected / at risk	30/421 (7.13%)	22/402 (5.47%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 15.0

Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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More Information

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Certain Agreements:

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

There IS 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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Authorship/contents of any publication is determined by site and provides sponsor a publication prior to submission. Sponsor has 60 days to review and avoid editorial changes but may request site delete confidential data. If publication contains patentable matter, site agrees to delay publication for 60 days. If study is part of multicenter protocol, site agrees not to independently publish. If multicenter publication is not forthcoming in 18 months after study end, site may proceed accordingly.

Results Point of Contact:

Name/Title: Anne McClain
Organization: Celgene Corporation
phone: 1-888-260-1599
e-mail: clinicaltrialdisclosure@celgene.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ramanathan RK, Goldstein D, Korn RL, Arena F, Moore M, Siena S, Teixeira L, Tabernero J, Van Laethem JL, Liu H, McGovern D, Lu B, Von Hoff DD. Positron emission tomography response evaluation from a randomized phase III trial of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas. Ann Oncol. 2016 Apr;27(4):648-53. doi: 10.1093/annonc/mdw020. Epub 2016 Jan 22.

Goldstein D, Von Hoff DD, Moore M, Greeno E, Tortora G, Ramanathan RK, Macarulla T, Liu H, Pilot R, Ferrara S, Lu B. Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT). Eur J Cancer. 2016 Jan;52:85-91. doi: 10.1016/j.ejca.2015.10.017. Epub 2015 Dec 1.

Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. doi: 10.1056/NEJMoa1304369. Epub 2013 Oct 16.

McCleary-Wheeler AL, McWilliams R, Fernandez-Zapico ME. Aberrant signaling pathways in pancreatic cancer: a two compartment view. Mol Carcinog. 2012 Jan;51(1):25-39. doi: 10.1002/mc.20827.

Responsible Party:	Celgene Corporation
ClinicalTrials.gov Identifier:	NCT00844649 History of Changes
Other Study ID Numbers:	CA046
Study First Received:	February 13, 2009
Results First Received:	October 21, 2013
Last Updated:	April 15, 2016
Health Authority:	United States: Food and Drug Administration Russia: Ministry of Health of the Russian Federation Ukraine: Ministry of Health Italy: The Italian Medicines Agency Canada: Health Canada Austria: Agency for Health and Food Safety Belgium: Federal Agency for Medicinal Products and Health Products France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) Germany: Federal Institute for Drugs and Medical Devices Spain: Spanish Agency of Medicines Australia: Department of Health and Ageing Therapeutic Goods Administration

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