A Study of LY2090314 and Chemotherapy in Participants With Metastatic Pancreatic Cancer

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01632306
• Collaborator: Mayo Clinic (Other)
• Enrollment: 13
• Locations: 2
• Arms: 3
• Duration (Months): 27
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Purpose of this phase I/II study is to test how well LY2090314 works in combination with different chemotherapies in treating participants with metastatic pancreatic cancer.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer	Drug: LY2090314; Drug: FOLFOX; Drug: Gemcitabine; Drug: Nab-paclitaxel	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of LY2090314 and Chemotherapy in Metastatic Pancreatic Cancer Patients With Metastases Amenable to Biopsy
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LY2090314 + Gemcitabine LY2090314 given intravenously (IV) on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), 8 and 15 in 28 day cycle in combination with 1000 milligram/square meter (mg/m^2) gemcitabine given IV on days 1, 8 and 15. Cohort closed to new enrollment per protocol addendum.	Drug: LY2090314; LY2090314 administered IV; Drug: Gemcitabine; Gemcitabine administered IV; Other Names: Gemzar LY188011
Experimental: LY2090314 + FOLFOX LY2090314 given IV on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), and 15 in 28 day cycle in combination with FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin) given IV, on days 1 and 15 in 28 day cycle.	Drug: LY2090314; LY2090314 administered IV; Drug: FOLFOX; FOLFOX administered IV; Other Names: FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin)
Experimental: LY2090314 + Gemcitabine + Nab-paclitaxel LY2090314 given IV on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), 8 and 15 in 28 day cycle in combination with 1000 mg/m^2 gemcitabine + 125 mg/m^2 nab-paclitaxel given IV on days 1, 8 and 15 in 28-day cycle. New cohort opened per protocol amendment.	Drug: LY2090314; LY2090314 administered IV; Drug: Gemcitabine; Gemcitabine administered IV; Other Names: Gemzar LY188011 ; Drug: Nab-paclitaxel; Nab-paclitaxel administered IV

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to 4 Hours Post-Treatment on Day 0 in Glycogen Synthase Phosphorylation [Baseline, 4 Hours Post-Treatment on Day 0]

   Change in the phosphorylation level of glycogen synthase, a glycogen synthase kinase-3 beta (GSK-3beta) inhibitor, from baseline to 4 hours post-treatment on day 0 using tumor tissue and blood specimens.

Secondary Outcome Measures

1. Overall Survival (OS) [Baseline to Date of Death Due to any Cause Up to 21 Months]

2. Percentage of Participants Who Survived at 6 Months [Baseline to Date of Death to any cause Up to 6 Months]

3. Progression Free Survival (PFS) [Baseline to Disease Progression Up to 18 Months]

   PFS was as the time from enrollment to the earliest documented evidence of disease progression or death,whatever comes first.

4. Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)] [Baseline Up to 6 Months]

   Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1) criteria. CR was defined as the disappearance of all target and non-target lesions and all target and non-target lymph nodes were non-pathological or normal in size [<10 millimeter (mm) short axis]. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions taking as reference the baseline sum diameters. ORR calculated as: (sum of the number of participants with PRs and CRs) divided by (number of evaluable participants) multiplied by 100. A CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Metastatic pancreatic cancer with metastases amenable to biopsy

• Willingness to provide tissue and blood samples for research purposes

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1

Exclusion Criteria:

• History of islet cell, acinar cell, or cystadenocarcinomas

• Prior cytotoxic chemotherapy for metastatic disease, except prior gemcitabine or FOLFIRINOX (5FU + leucovorin + irinotecan + oxaliplatin)

• Radiation therapy, immunotherapy or biologic therapy <28 days prior to study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic of Jacksonville	Jacksonville	Florida	United States	32224
2	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Eli Lilly and Company
• Mayo Clinic

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01632306
• Other Study ID Numbers: 14453; I2H-MC-JWYD; NCT01671202
• First Posted: Jul 2, 2012
• Last Update Posted: Jan 15, 2019
• Last Verified: Jan 1, 2019

• Additional relevant MeSH terms: Pancreatic Neoplasms; Leucovorin; Gemcitabine; Paclitaxel; Fluorouracil; Oxaliplatin

Study Results

Participant Flow

Arm/Group Title	LY2090314 + Gemcitabine	LY2090314 + FOLFOX	LY2090314 + Gemcitabine + Nab-paclitaxel
Arm/Group Description	LY2090314 given intravenously (IV) on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), 8 and 15 in 28 day cycle in combination with 1000 milligram/square meter (mg/m²) gemcitabine given IV on days 1, 8 and 15. Cohort closed to new enrollment per protocol addendum.	LY2090314 given IV on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), and 15 in 28 day cycle in combination with FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin) given IV, on days 1 and 15 in 28 day cycle.	LY2090314 given IV on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), 8 and 15 in 28 day cycle in combination with 1000 mg/m² gemcitabine + 125 mg/m² nab-paclitaxel given IV on days 1, 8 and 15 in 28-day cycle. New cohort opened per protocol amendment.
Period Title: Overall Study
STARTED	3	10	0
Received at Least One Dose of Study Drug	3	10	0
COMPLETED	2	10	0
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	LY2090314 + Gemcitabine	LY2090314 + FOLFOX	Total
Arm/Group Description	LY2090314 given intravenously (IV) on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), 8 and 15 in 28 day cycle in combination with 1000 milligram/square meter (mg/m²) gemcitabine given IV on days 1, 8 and 15. Cohort closed to new enrollment per protocol addendum.	LY2090314 given IV on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), and 15 in 28 day cycle in combination with FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin) given IV, on days 1 and 15 in 28 day cycle.	Total of all reporting groups
Overall Participants	3	10	13
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.7 (8.5)	64.0 (4.9)	63.2 (5.7)
Sex: Female, Male (Count of Participants)
Female	1 33.3%	4 40%	5 38.5%
Male	2 66.7%	6 60%	8 61.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	3 100%	8 80%	11 84.6%
Unknown or Not Reported	0 0%	2 20%	2 15.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	3 100%	9 90%	12 92.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 10%	1 7.7%
Region of Enrollment (participants) [Number]
United States	3 100%	10 100%	13 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to 4 Hours Post-Treatment on Day 0 in Glycogen Synthase Phosphorylation
Description	Change in the phosphorylation level of glycogen synthase, a glycogen synthase kinase-3 beta (GSK-3beta) inhibitor, from baseline to 4 hours post-treatment on day 0 using tumor tissue and blood specimens.
Time Frame	Baseline, 4 Hours Post-Treatment on Day 0

Outcome Measure Data

Analysis Population Description

Zero participants analyzed. GSK3β phosphorylation levels were not determined, and the primary endpoint was not examined as there wasn't viable tumor tissue for analysis.

Arm/Group Title	LY2090314 + Gemcitabine	LY2090314 + FOLFOX
Arm/Group Description	LY2090314 given intravenously (IV) on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), 8 and 15 in 28 day cycle in combination with 1000 milligram/square meter (mg/m²) gemcitabine given IV on days 1, 8 and 15. Cohort closed to new enrollment per protocol addendum.	LY2090314 given IV on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), and 15 in 28 day cycle in combination with FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin) given IV, on days 1 and 15 in 28 day cycle.
Measure Participants	0	0

2. Secondary Outcome

Title	Overall Survival (OS)
Time Frame	Baseline to Date of Death Due to any Cause Up to 21 Months

Outcome Measure Data

Analysis Population Description

All the participants that received at least one dose of study drug.

Arm/Group Title	LY2090314 + Gemcitabine	LY2090314 + FOLFOX
Arm/Group Description	LY2090314 given intravenously (IV) on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), 8 and 15 in 28 day cycle in combination with 1000 milligram/square meter (mg/m²) gemcitabine given IV on days 1, 8 and 15. Cohort closed to new enrollment per protocol addendum.	LY2090314 given IV on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), and 15 in 28 day cycle in combination with FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin) given IV, on days 1 and 15 in 28 day cycle.
Measure Participants	3	10
Median (95% Confidence Interval) [Months]	1.8	7.7

3. Secondary Outcome

Title	Percentage of Participants Who Survived at 6 Months
Time Frame	Baseline to Date of Death to any cause Up to 6 Months

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug.

Arm/Group Title	LY2090314 + Gemcitabine	LY2090314 + FOLFOX
Arm/Group Description	LY2090314 given intravenously (IV) on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), 8 and 15 in 28 day cycle in combination with 1000 milligram/square meter (mg/m²) gemcitabine given IV on days 1, 8 and 15. Cohort closed to new enrollment per protocol addendum.	LY2090314 given IV on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), and 15 in 28 day cycle in combination with FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin) given IV, on days 1 and 15 in 28 day cycle.
Measure Participants	3	10
Number (90% Confidence Interval) [Percentage of participants]	0 0%	50.0 500%

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was as the time from enrollment to the earliest documented evidence of disease progression or death,whatever comes first.
Time Frame	Baseline to Disease Progression Up to 18 Months

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug.

Arm/Group Title	LY2090314 + Gemcitabine	LY2090314 + FOLFOX
Arm/Group Description	LY2090314 given intravenously (IV) on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), 8 and 15 in 28 day cycle in combination with 1000 milligram/square meter (mg/m²) gemcitabine given IV on days 1, 8 and 15. Cohort closed to new enrollment per protocol addendum.	LY2090314 given IV on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), and 15 in 28 day cycle in combination with FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin) given IV, on days 1 and 15 in 28 day cycle.
Measure Participants	3	10
Median (95% Confidence Interval) [Months]	1.8	3.4

5. Secondary Outcome

Title	Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)]
Description	Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1) criteria. CR was defined as the disappearance of all target and non-target lesions and all target and non-target lymph nodes were non-pathological or normal in size [<10 millimeter (mm) short axis]. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions taking as reference the baseline sum diameters. ORR calculated as: (sum of the number of participants with PRs and CRs) divided by (number of evaluable participants) multiplied by 100. A CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart.
Time Frame	Baseline Up to 6 Months

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug.

Arm/Group Title	LY2090314 + Gemcitabine	LY2090314 + FOLFOX
Arm/Group Description	LY2090314 given intravenously (IV) on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), 8 and 15 in 28 day cycle in combination with 1000 milligram/square meter (mg/m²) gemcitabine given IV on days 1, 8 and 15. Cohort closed to new enrollment per protocol addendum.	LY2090314 given IV on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), and 15 in 28 day cycle in combination with FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin) given IV, on days 1 and 15 in 28 day cycle.
Measure Participants	3	10
Number (95% Confidence Interval) [Percentage of Participants]	0 0%	10.0 100%

Adverse Events

Adverse Event Reporting Description	All participants who received at least one dose of study drug.
Arm/Group Title	LY2090314 + Gemcitabine		LY2090314 + FOLFOX
Arm/Group Description	LY2090314 given intravenously (IV) on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), 8 and 15 in 28 day cycle in combination with 1000 milligram/square meter (mg/m²) gemcitabine given IV on days 1, 8 and 15. Cohort closed to new enrollment per protocol addendum.		LY2090314 given IV on days 1 (at cycle 1 LY2090314 given on day 0 instead of day 1), and 15 in 28 day cycle in combination with FOLFOX (leucovorin + 5-fluorouracil + oxaliplatin) given IV, on days 1 and 15 in 28 day cycle.
All Cause Mortality
	LY2090314 + Gemcitabine		LY2090314 + FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	LY2090314 + Gemcitabine		LY2090314 + FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		7/10 (70%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)	1	1/10 (10%)	1
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	1/10 (10%)	1
Ascites	1/3 (33.3%)	1	1/10 (10%)	1
Colitis	0/3 (0%)	0	1/10 (10%)	1
Diarrhea	1/3 (33.3%)	1	0/10 (0%)	0
Gastric fistula	1/3 (33.3%)	1	0/10 (0%)	0
Small intestinal obstruction	1/3 (33.3%)	1	0/10 (0%)	0
Upper gastrointestinal hemorrhage	0/3 (0%)	0	1/10 (10%)	1
General disorders
Failure to Thrive	0/3 (0%)	0	1/10 (10%)	1
Hepatobiliary disorders
Gallbladder obstruction	0/3 (0%)	0	1/10 (10%)	1
Infections and infestations
Clostridium difficle infection	0/3 (0%)	0	1/10 (10%)	1
Lung infection	0/3 (0%)	0	1/10 (10%)	1
Peritoneal infection	1/3 (33.3%)	1	0/10 (0%)	0
Sepsis	1/3 (33.3%)	1	0/10 (0%)	0
Skin infection	1/3 (33.3%)	1	0/10 (0%)	0
Investigations
Neutrophil count decreased	0/3 (0%)	0	2/10 (20%)	3
Platelet count decreased	0/3 (0%)	0	1/10 (10%)	1
Metabolism and nutrition disorders
Anorexia	0/3 (0%)	0	1/10 (10%)	1
Dehydration	1/3 (33.3%)	1	0/10 (0%)	0
Hypophosphatemia	0/3 (0%)	0	1/10 (10%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration	0/3 (0%)	0	1/10 (10%)	1
Vascular disorders
Hypotension	0/3 (0%)	0	1/10 (10%)	1
Thromboembolic event	0/3 (0%)	0	1/10 (10%)	3
Pulmonary embolism	0/3 (0%)	0	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	LY2090314 + Gemcitabine		LY2090314 + FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		10/10 (100%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)	1	2/10 (20%)	3
Endocrine disorders
Adrenal insufficiency	0/3 (0%)	0	1/10 (10%)	1
Eye disorders
Blurred vision	0/3 (0%)	0	1/10 (10%)	6
Gastrointestinal disorders
Abdominal pain	2/3 (66.7%)	2	8/10 (80%)	25
Ascites	0/3 (0%)	0	2/10 (20%)	4
Bloating	0/3 (0%)	0	1/10 (10%)	1
Colitis	0/3 (0%)	0	1/10 (10%)	2
Constipation	0/3 (0%)	0	3/10 (30%)	13
Diarrhea	1/3 (33.3%)	1	4/10 (40%)	14
Esophageal pain	0/3 (0%)	0	2/10 (20%)	2
Flatulence	0/3 (0%)	0	2/10 (20%)	8
Gastritis	0/3 (0%)	0	1/10 (10%)	2
Gastroesophageal reflux disease	0/3 (0%)	0	2/10 (20%)	9
Mucositis oral	0/3 (0%)	0	3/10 (30%)	9
Nausea	2/3 (66.7%)	2	6/10 (60%)	26
Vomiting	1/3 (33.3%)	1	1/10 (10%)	8
General disorders
Edema limbs	0/3 (0%)	0	1/10 (10%)	2
Edema trunk	0/3 (0%)	0	1/10 (10%)	1
Fatigue	0/3 (0%)	0	9/10 (90%)	30
Fever	1/3 (33.3%)	1	1/10 (10%)	4
night sweats	0/3 (0%)	0	1/10 (10%)	1
Pain	0/3 (0%)	0	2/10 (20%)	3
Immune system disorders
Allergic reaction	0/3 (0%)	0	1/10 (10%)	2
Infections and infestations
Mucosal infection	0/3 (0%)	0	1/10 (10%)	1
Investigations
Alanine aminotransferase	1/3 (33.3%)	1	4/10 (40%)	11
Alkaline phosphatase	0/3 (0%)	0	3/10 (30%)	7
Aspartate aminotransferase increased	1/3 (33.3%)	1	4/10 (40%)	8
Blood bilirubin increased	0/3 (0%)	0	1/10 (10%)	1
Cardiac troponin T increased	0/3 (0%)	0	1/10 (10%)	1
Creatinine increased	0/3 (0%)	0	1/10 (10%)	2
ECG QT corrected interval prolonged	1/3 (33.3%)	1	5/10 (50%)	5
Elevated lactic acid	0/3 (0%)	0	1/10 (10%)	1
Neutrophil count decreased	0/3 (0%)	0	3/10 (30%)	10
Platelet count decreased	0/3 (0%)	0	5/10 (50%)	23
White blood cell	0/3 (0%)	0	1/10 (10%)	6
Metabolism and nutrition disorders
Anorexia	1/3 (33.3%)	1	4/10 (40%)	14
Dehydration	0/3 (0%)	0	1/10 (10%)	1
Hyperglycemia	0/3 (0%)	0	1/10 (10%)	7
Hypoalbuminemia	1/3 (33.3%)	1	1/10 (10%)	1
Hypocalcemia	0/3 (0%)	0	2/10 (20%)	8
Hypoglycemia	0/3 (0%)	0	1/10 (10%)	2
Hypokalemia	0/3 (0%)	0	2/10 (20%)	5
Hypomagnesemia	0/3 (0%)	0	2/10 (20%)	8
Hyponatremia	0/3 (0%)	0	2/10 (20%)	3
Musculoskeletal and connective tissue disorders
Arthritis	0/3 (0%)	0	1/10 (10%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Death due to disease progression	1/3 (33.3%)	1	0/10 (0%)	0
Nervous system disorders
Akathisia	0/3 (0%)	0	1/10 (10%)	7
Cognitive disturbance	0/3 (0%)	0	1/10 (10%)	1
Dizziness	0/3 (0%)	0	1/10 (10%)	7
Dysgeusia	0/3 (0%)	0	2/10 (20%)	10
Headache	0/3 (0%)	0	1/10 (10%)	2
Dysgeusia	0/3 (0%)	0	1/10 (10%)	1
Headache	0/3 (0%)	0	1/10 (10%)	1
Peripheral motor neuropathy	0/3 (0%)	0	1/10 (10%)	7
Peripheral sensory neuropathy	0/3 (0%)	0	4/10 (40%)	21
Psychiatric disorders
Anxiety	0/3 (0%)	0	1/10 (10%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/3 (0%)	0	1/10 (10%)	6
Cough	0/3 (0%)	0	1/10 (10%)	5
Dyspnea	1/3 (33.3%)	1	2/10 (20%)	9
Sinus disorder	0/3 (0%)	0	1/10 (10%)	1
Skin and subcutaneous tissue disorders
Alopecia	0/3 (0%)	0	3/10 (30%)	6
Skin ulceration	0/3 (0%)	0	1/10 (10%)	1
Vascular disorders
Hypotension	0/3 (0%)	0	1/10 (10%)	1

Limitations/Caveats

Study was terminated due to slow enrollment. No participants were enrolled in arm LY2090314 + Gemcitabine + Nab-paclitaxel due to inability to enroll participants.

More Information

Certain Agreements

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

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.