Proton w/FOLFIRINOX-Losartan for Pancreatic Cancer

• ClinicalTrials.gov Identifier: NCT01821729
• Recruitment Status: Unknown
• First Posted: April 1, 2013
• Results First Posted: September 17, 2019
• Last Update Posted: September 25, 2020
• Sponsor: Massachusetts General Hospital
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Theodore Sunki Hong, Massachusetts General Hospital

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Pancreatic Cancer
• Interventions: Drug: FOLFIRINOX; Drug: Losartan; Radiation: Proton Beam Radiation
• Enrollment: 50

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Experimental Arm
Arm/Group Description	FOLFIRINOX, Losartan, Proton Beam Radiation Therapy FOLFIRINOX: Oxaliplatin via IV on Day 1 over 2 hours; Irinotecan via IV on Day 1 over 90 minutes, 5FU via IV on Day 1 over 2-4 minutes Losartan: Taken orally every day during Phase I for all 8 cycles Proton Beam Radiation: 30-45 minutes per day, daily Monday-Friday
Period Title: Overall Study
Started	50
Received Chemoradiotherapy	45
Underwent Attempted Surgery	42
Completed	49
Not Completed	1
Reason Not Completed
Withdrawal by Subject	1

Baseline Characteristics

Arm/Group Title		Experimental Arm
Arm/Group Description		FOLFIRINOX, Losartan, Proton Beam Radiation Therapy FOLFIRINOX: Oxaliplatin via IV on Day 1 over 2 hours; Irinotecan via IV on Day 1 over 90 minutes, 5FU via IV on Day 1 over 2-4 minutes Losartan: Taken orally every day during Phase I for all 8 cycles Proton Beam Radiation: 30-45 minutes per day, daily Monday-Friday
Overall Number of Baseline Participants		49
Baseline Analysis Population Description		Baseline characteristics are reported for all participants that started treatment. One participant withdrew consent prior to the start of study treatment.
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	49 participants
		63; (42 to 78)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	49 participants
	Female	23 46.9%
	Male	26 53.1%
Race and Ethnicity Not Collected [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	0 participants
		[1] Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	49 participants
		49 100.0%
ECOG PS [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	49 participants
	0	36 73.5%
	1	13 26.5%
		[1] Measure Description: Eastern Cooperative Oncology Group Performance Status: Lower scores indicate better functioning of daily activities of living. The score ranges from 0 to 5.
CA19-9 level [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	49 participants
	<35 U/mL (Normal)	9 18.4%
	≥ 35 U/mL (Elevated)	40 81.6%
		[1] Measure Description: Carbohydrate antigen (CA) 19-9 is a type of antigen released by pancreatic cancer cells. Elevated CA 19-9 is associated with tumor growth.
CEA level [1] [2]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	48 participants
	<3.4 ng/mL (Normal)	30 62.5%
	≥3.4 ng/mL (Elevated)	18 37.5%
		[1] Measure Description: Carcinoembryonic antigen is a bio-marker that is associated with some types of cancers. Elevated CEA levels can indicate the presence of a tumor.; [2] Measure Analysis Population Description: CEA levels were not available for one participant
Tumor site; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	49 participants
	Head	31 63.3%
	Body	14 28.6%
	Tail	4 8.2%
Tumor size; Median (Full Range); Unit of measure: Mm
	Number Analyzed	49 participants
		41; (18 to 68)
Vascular involvement [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	47 participants
	Arterial alone	15 31.9%
	Venous alone	11 23.4%
	Arterial + venous	21 44.7%
		[1] Measure Analysis Population Description: Two participants did not have vascular involvement

Outcome Measures

1. Primary Outcome

Title	Number of Participants With R0 Resection
Description	The number of participants that received treatment with proton radiation along with FOLFIRINOX-Losartan and then subsequently underwent attempted surgery and achieved R0 resection. R0 resection means that no cancer cells were seen microscopically at the resection margin.
Time Frame	At the time of surgery (approximately 4 months after the start of treatment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Arm
Arm/Group Description:	FOLFIRINOX, Losartan, Proton Beam Radiation Therapy FOLFIRINOX: Oxaliplatin via IV on Day 1 over 2 hours; Irinotecan via IV on Day 1 over 90 minutes, 5FU via IV on Day 1 over 2-4 minutes Losartan: Taken orally every day during Phase I for all 8 cycles Proton Beam Radiation: 30-45 minutes per day, daily Monday-Friday
Overall Number of Participants Analyzed	49
Measure Type: Count of Participants; Unit of Measure: Participants
	34 69.4%

2. Secondary Outcome

Title	Progression-Free Survival
Description	To determine the progression free survival of patients with locally advanced disease who receive FOLFIRINOX-Losartan and proton beam radiation therapy. Disease progression was assessed using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Progressive disease (PD): At least a 20% increase in the sum of the longest diameter (LD) of target lesion, taking as reference the smal lest sum LD recorded since the treatment started or the appearance of one or more new lesions (new lesions must be > slice thickness).
Time Frame	From the start of treatment until death or progression, median duration of 17.5 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Arm
Arm/Group Description:	FOLFIRINOX, Losartan, Proton Beam Radiation Therapy FOLFIRINOX: Oxaliplatin via IV on Day 1 over 2 hours; Irinotecan via IV on Day 1 over 90 minutes, 5FU via IV on Day 1 over 2-4 minutes Losartan: Taken orally every day during Phase I for all 8 cycles Proton Beam Radiation: 30-45 minutes per day, daily Monday-Friday
Overall Number of Participants Analyzed	49
Median (95% Confidence Interval); Unit of Measure: Months
	17.5; (13.9 to 22.7)

3. Secondary Outcome

Title	Overall Survival for FOLFIRINOX + Proton Beam Radiation
Description	To determine overall survival in patients treated with preoperative FOLFIRINOX and proton beam radiation therapy
Time Frame	2 years

Outcome Measure Data Not Reported

4. Secondary Outcome

Title	Overall Survival for FOLFIRINOX Without Proton Radiation
Description	To determine the overall survival of patients with locally advanced disease who receive FOLFIRINOX-Losartan without proton radiation (i.e. patients who demonstrate progression at restaging)
Time Frame	2 years

Outcome Measure Data Not Reported

5. Secondary Outcome

Title	Determine Toxicity FOLFIRINOX-Losartan
Description	To determine the toxicity of FOLFIRINOX-Losartan in patients with locally advanced pancreatic disease
Time Frame	2 years

Outcome Measure Data Not Reported

6. Secondary Outcome

Title	Determine Toxicity of FOLFIRINOX-Losartan and Proton Beam Radiation
Description	To determine the toxicity of FOLFIRINOX-Losartan and proton beam radiation in patients with locally advanced pancreatic cancer.
Time Frame	2 years

Outcome Measure Data Not Reported

7. Secondary Outcome

Title	Rate of Downstaging
Description	To determine the rate of downstaging to surgical resection of FOLFIRINOX-Losartan followed by proton radiation in patients with locally advanced pancreatic cancer
Time Frame	2 years

Outcome Measure Data Not Reported

8. Secondary Outcome

Title	Determine Correlation of Somatic Gene Mutations and Outcome
Description	To determine the correlation between a panel of somatic genetic mutations (SNaPSHOT) and outcome in locally advanced pancreatic cancer treated with FOLFIRINOX-Losartan +/- proton beam radiation/capecitabine
Time Frame	2 years

Outcome Measure Data Not Reported

9. Secondary Outcome

Title	Determine Correlation Between Circulating Biomarkers and Outcome
Description	To determine the correlation between circulating biomarkers of TGF-B1 downregulation, including circulating Collagen I levels, and outcome in locally advanced pancreatic cancer treated with FOLFIRINOX-Losartan +/- proton beam radiation/capecitabine.
Time Frame	2 years

Outcome Measure Data Not Reported

10. Secondary Outcome

Title	Describe Quality of Life, Symptom Burden and Mood
Description	Describe quality of life, symptom burden and mood in the study population
Time Frame	2 years

Outcome Measure Data Not Reported

11. Secondary Outcome

Title	To Measure Utilization of Health Services
Description	To measure utilization of health services (ER, hospital and ICU visits) in the study population
Time Frame	2 years

Outcome Measure Data Not Reported

Adverse Events

Time Frame	From the start of treatment until 30 days after the end of treatment, up to approximately 2 years
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Experimental Arm
Arm/Group Description	FOLFIRINOX, Losartan, Proton Beam Radiation Therapy FOLFIRINOX: Oxaliplatin via IV on Day 1 over 2 hours; Irinotecan via IV on Day 1 over 90 minutes, 5FU via IV on Day 1 over 2-4 minutes Losartan: Taken orally every day during Phase I for all 8 cycles Proton Beam Radiation: 30-45 minutes per day, daily Monday-Friday
All-Cause Mortality
	Experimental Arm
	Affected / at Risk (%)
Total	0/49 (0.00%)
Serious Adverse Events
	Experimental Arm
	Affected / at Risk (%)	# Events
Total	15/49 (30.61%)
Blood and lymphatic system disorders
Anemia † 1	2/49 (4.08%)	4
Febrile neutropenia † 1	1/49 (2.04%)	1
Gastrointestinal disorders
Abdominal pain † 1	2/49 (4.08%)	2
Colitis † 1	1/49 (2.04%)	1
Diarrhea † 1	5/49 (10.20%)	6
Mucositis oral † 1	1/49 (2.04%)	1
Nausea † 1	3/49 (6.12%)	4
Vomiting † 1	2/49 (4.08%)	3
General disorders
Fatigue † 1	2/49 (4.08%)	2
General disorders and administration site conditions - Other, specify † 1	1/49 (2.04%)	1
Investigations
Alanine aminotransferase increased † 1	2/49 (4.08%)	3
Aspartate aminotransferase increased † 1	1/49 (2.04%)	2
Neutrophil count decreased † 1	5/49 (10.20%)	7
Platelet count decreased † 1	3/49 (6.12%)	3
Weight loss † 1	1/49 (2.04%)	1
White blood cell decreased † 1	1/49 (2.04%)	1
Metabolism and nutrition disorders
Dehydration † 1	2/49 (4.08%)	2
Nervous system disorders
Ataxia † 1	1/49 (2.04%)	1
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Experimental Arm
	Affected / at Risk (%)	# Events
Total	40/49 (81.63%)
Blood and lymphatic system disorders
Anemia † 1	5/49 (10.20%)	11
Cardiac disorders
Cardiac disorders - Other, specify † 1	6/49 (12.24%)	8
Gastrointestinal disorders
Abdominal distension † 1	9/49 (18.37%)	13
Abdominal pain † 1	37/49 (75.51%)	105
Bloating † 1	13/49 (26.53%)	16
Colitis † 1	3/49 (6.12%)	3
Constipation † 1	32/49 (65.31%)	72
Diarrhea † 1	29/49 (59.18%)	101
Dry mouth † 1	5/49 (10.20%)	7
Dyspepsia † 1	9/49 (18.37%)	13
Dysphagia † 1	7/49 (14.29%)	9
Flatulence † 1	13/49 (26.53%)	20
Gastritis † 1	3/49 (6.12%)	3
Gastroesophageal reflux disease † 1	3/49 (6.12%)	3
Hemorrhoidal hemorrhage † 1	3/49 (6.12%)	4
Malabsorption † 1	11/49 (22.45%)	11
Mucositis oral † 1	12/49 (24.49%)	15
Nausea † 1	33/49 (67.35%)	123
Oral pain † 1	4/49 (8.16%)	4
Vomiting † 1	22/49 (44.90%)	53
Gastrointestinal disorders - Other, specify † 1	13/49 (26.53%)	23
General disorders
Chills † 1	6/49 (12.24%)	7
Edema limbs † 1	10/49 (20.41%)	13
Fatigue † 1	40/49 (81.63%)	124
Fever † 1	10/49 (20.41%)	13
Localized edema † 1	6/49 (12.24%)	7
Malaise † 1	3/49 (6.12%)	3
Non-cardiac chest pain † 1	3/49 (6.12%)	3
Immune system disorders
Allergic reaction † 1	5/49 (10.20%)	10
Infections and infestations
Upper respiratory infection † 1	3/49 (6.12%)	4
Urinary tract infection † 1	4/49 (8.16%)	4
Infections and infestations - Other, specify † 1	4/49 (8.16%)	6
Injury, poisoning and procedural complications
Bruising † 1	3/49 (6.12%)	3
Investigations
Alanine aminotransferase increased † 1	10/49 (20.41%)	14
Aspartate aminotransferase increased † 1	5/49 (10.20%)	6
Blood bilirubin increased † 1	9/49 (18.37%)	14
Neutrophil count decreased † 1	6/49 (12.24%)	7
Platelet count decreased † 1	13/49 (26.53%)	16
Weight loss † 1	33/49 (67.35%)	91
Metabolism and nutrition disorders
Anorexia † 1	36/49 (73.47%)	80
Dehydration † 1	22/49 (44.90%)	59
Hypokalemia † 1	11/49 (22.45%)	21
Hyponatremia † 1	4/49 (8.16%)	5
Musculoskeletal and connective tissue disorders
Arthralgia † 1	3/49 (6.12%)	6
Back pain † 1	19/49 (38.78%)	33
Generalized muscle weakness † 1	6/49 (12.24%)	8
Myalgia † 1	5/49 (10.20%)	5
Pain in extremity † 1	4/49 (8.16%)	8
Musculoskeletal and connective tissue disorder - † 1	9/49 (18.37%)	20
Nervous system disorders
Concentration impairment † 1	4/49 (8.16%)	4
Dizziness † 1	22/49 (44.90%)	37
Dysarthria † 1	3/49 (6.12%)	3
Dysgeusia † 1	18/49 (36.73%)	24
Paresthesia † 1	4/49 (8.16%)	5
Peripheral sensory neuropathy † 1	35/49 (71.43%)	131
Spasticity † 1	3/49 (6.12%)	3
Tremor † 1	3/49 (6.12%)	3
Nervous system disorders - Other, specify † 1	9/49 (18.37%)	14
Psychiatric disorders
Anxiety † 1	22/49 (44.90%)	31
Depression † 1	7/49 (14.29%)	8
Insomnia † 1	20/49 (40.82%)	36
Renal and urinary disorders
Hematuria † 1	3/49 (6.12%)	3
Urinary frequency † 1	6/49 (12.24%)	8
Urine discoloration † 1	3/49 (6.12%)	3
Renal and urinary disorders - Other, specify † 1	3/49 (6.12%)	3
Respiratory, thoracic and mediastinal disorders
Cough † 1	6/49 (12.24%)	7
Dyspnea † 1	12/49 (24.49%)	15
Epistaxis † 1	8/49 (16.33%)	11
Hiccups † 1	7/49 (14.29%)	7
Hoarseness † 1	4/49 (8.16%)	6
Sore throat † 1	6/49 (12.24%)	8
Respiratory, thoracic and mediastinal disorders - Other, specify † 1	12/49 (24.49%)	24
Skin and subcutaneous tissue disorders
Alopecia † 1	10/49 (20.41%)	14
Hyperhidrosis † 1	3/49 (6.12%)	7
Pruritus † 1	7/49 (14.29%)	11
Skin and subcutaneous tissue disorders - Other, specify † 1	13/49 (26.53%)	27
Vascular disorders
Hypertension † 1	3/49 (6.12%)	3
Hypotension † 1	16/49 (32.65%)	28
Thromboembolic event † 1	5/49 (10.20%)	5
Vascular disorders - Other, specify † 1	6/49 (12.24%)	7
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. Theodore Hong
• Organization: Massachusetts General Hospital
• Phone: 617-726-6050
• EMail: TSHONG1@mgh.harvard.edu

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

Murphy JE, Wo JY, Ryan DP, Clark JW, Jiang W, Yeap BY, Drapek LC, Ly L, Baglini CV, Blaszkowsky LS, Ferrone CR, Parikh AR, Weekes CD, Nipp RD, Kwak EL, Allen JN, Corcoran RB, Ting DT, Faris JE, Zhu AX, Goyal L, Berger DL, Qadan M, Lillemoe KD, Talele N, Jain RK, DeLaney TF, Duda DG, Boucher Y, Fernandez-Del Castillo C, Hong TS. Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial. JAMA Oncol. 2019 Jul 1;5(7):1020-1027. doi: 10.1001/jamaoncol.2019.0892.

• Responsible Party: Theodore Sunki Hong, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01821729
• Other Study ID Numbers: 13-051
• First Submitted: March 27, 2013
• First Posted: April 1, 2013
• Results First Submitted: August 27, 2019
• Results First Posted: September 17, 2019
• Last Update Posted: September 25, 2020