SBRT Plus Pembrolizumab and Trametinib for Pancreatic Cancer

• Sponsor: Changhai Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT02704156
• Collaborator: (none)
• Enrollment: 170
• Location: 1
• Arms: 2
• Actual Duration (Months): 50
• Patients Per Site Per Month: 3.4

Study Details

Study Description

Brief Summary

Hypothesis: Survival benefits could be found in SBRT Plus Pembrolizumab and Trametinib compared with SBRT plus gemcitabine.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer	Device: Cyberknife plus Pembrolizumab and Trametinib; Device: Cyberknife plus Gemcitabine	Phase 2

Detailed Description

Background and aim:

Pancreatic cancer is one of the most lethal malignancies and fourth leading cause of cancer death in both genders in US, where the mortality and incidence increase over the past decade with a lowest 5-year survival rate of 9% among all cancers. Although surgical resection is deemed to provide long-term disease control, only 20% patients were candidates for upfront surgery and unfortunately, even when adjuvant chemotherapy is prescribed, about 50% of patients will suffer local recurrence. Despite of emergence of immunotherapy as a new treatment paradigm, little improvement of outcomes has been found in pancreatic cancer. This may be ascribed to its inherent genetic mutations and immunosuppressive microenvironment. It has been demonstrated that radiotherapy could enhance the release and uptake of tumor-associated antigens, thus promoting antitumor T cell priming, and enhancing access to tumors due to effects both on the tumor vasculature and the chemokine milieu.

Despite of emergence of immune checkpoint inhibitors as a novel treatment paradigm for cancers, the results of investigations about the efficacy of immunotherapy alone for pancreatic cancer was disappointing. Due to enhanced immunogenicity of tumor irradiation, the underlying rationale of combination of radiotherapy and immunotherapy is that radiation can noninvasively prime the immune system against tumor cells, where antigen presentation and co-stimulation are facilitated, thus creating immune responses against previously hidden epitopes that are shared among distant metastases, while immune checkpoint inhibitors can reverse the immunosuppressive effects of the tumor microenvironment, thus facilitating antitumor immunity.

Although oncogenic mutations in KRAS are frequent in pancreatic cancer, KRAS proteins are difficult to be targeted due to high affinity for GTP and/or GDP. Therefore, efforts have been made to develop therapies targeting the major downstream effector pathways, which include the RAS-RAF-MEK-ERK and PI3K-PDPK1-AKT signaling pathways. MEK inhibitor trametinib alone or in combinations with chemotherapy or autophagy inhibitor hydroxychloroquine may probably have positive effects on tumor regression.

Regarding local recurrence after surgery, it was recommended that chemotherapy with optional radiotherapy may be the first-line treatment without addition of targeted therapy or immunotherapy owing to that no studies have investigated the efficacy of this regimen. Therefore, the aim of our study was to compare the outcomes between stereotactic body radiation therapy (SBRT) with pembrolizumab and trametinib and SBRT with gemcitabine for locally recurrent pancreatic cancer after surgical resection.

Study procedure:

1. All surgical specimens underwent immunohistochemical staining of PD-L1, classified as TC3 ≥ 50% or TC2 ≥ 5% but < 50% or TC1 ≥ 1% but <5% and IC3 ≥ 10% or IC2 ≥ 5% but < 10% or IC1 ≥ 1% but <5%.

2. KRAS mutations were analyzed by PCR amplification and direct sequencing of exon 2. Restriction Length Fragment Polymorphism method was used for further confirmation.

3. In the SBRT plus pembrolizumab and trametinib group, 200mg pembrolizumab was administered intravenously every 3 weeks and 2mg trametinib was given orally once daily.

4. In the SBRT plus gemcitabine group, patients received intravenous gemcitabine (1000mg/m2) on day 1 and 8 of each 21-day cycle for eight cycles in the absence of disease progression.

5. The prescribed dose of SBRT varies from 35-40Gy/5f with a single dose of 7-8Gy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 170 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Stereotactic Body Radiation Therapy Plus Pembrolizumab and Trametinib vs. Stereotactic Body Radiation Therapy Plus Gemcitabine for Locally Recurrent Pancreatic Cancer After Surgical Resection: an Open-label, Randomized, Controlled, Phase 2 Trial
• Actual Study Start Date: Oct 1, 2016
• Actual Primary Completion Date: Dec 1, 2020
• Actual Study Completion Date: Dec 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SBRT plus Pembrolizumab and Trametinib Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine.	Device: Cyberknife plus Pembrolizumab and Trametinib; Radiation therapy plus drug
Active Comparator: SBRT plus Gemcitabine Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine.	Device: Cyberknife plus Gemcitabine; Radiation therapy plus drug

Outcome Measures

Primary Outcome Measures

1. The Median Survival Time Will be Determined. [3 years]

   The time from the start of treatment to death

Secondary Outcome Measures

1. One- and Two-year Overall Survival Rate Will be Determined. [2 year]

   The number of patients alive at 1 year and 2 years.

2. Treatment-related Adverse Effects Will be Determined. [3 years]

   Treatment-related adverse effects are determined by National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0.

3. The Median Progression Free Survival Time Will be Determined. [3 years]

   The time from the start of treatment until documentation of any clinical or radiological disease progression or death, whichever occurred first. Progression is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

4. One- and Two-year Progression Survival Rate Will be Determined. Will be Determined. [2 years]

   The proportion of patients without disease progressions at 1 year and 2 years.

5. The Quality of Life Will be Analyzed. [3 years]

   The analysis of quality of life is based on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). All scales and subscales range from 0 to 100. Regarding physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning and global health, higher scores may indicate better outcomes. In the case of fatigue, nausea and vomitting, pain, dyspnea, insomina, appetite loss, constipation, diarrhea and financial difficulties, lower scores may indicate better outcomes. Scales of all items are independent and not combined to compute a total score.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Histologically confirmed pancreatic ductal adenocarcinoma with unequivocal first progression after surgery followed by chemotherapy

2. Without any immunotherapy or targeted therapy

3. A life expectancy of >3months

4. ECOG of 0 to1

5. Age of 18 years or older

6. Analysis of surgical specimens showed KRAS mutations and positive immunohistochemical staining of PD-L1

7. Blood routine examination: Absolute neutrophil count (ANC) ≥ 1.5 ×109 cells/L, leukocyte count≥ 3.5 ×109 cells/L, platelets ≥ 70×109 cells/L, hemoglobin ≥ 8.0 g/dl

8. Liver and kidney function tests: Albumin > 2.5 g/dL, total bilirubin < 3 mg/dL, creatinine < 2.0 mg/dL, AST<2.5 × ULN(Upper Limit of Normal)(0-64U/L), ALT<2.5 × ULN(0-64U/L)

9. INR < 2 (0.9-1.1)

10. Ability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Prior immunotherapy or targeted therapy

2. Evidences of metastatic disease confirmed by chest CT or FDG PET-CT

3. Contraindication to receiving immunotherapy, targeted therapy or SBRT

4. ECOG ≥2

5. Age <18 years

6. Analysis of surgical specimens showed KRAS wild type or negative immunohistochemical staining of PD-L1

7. Secondary malignancy

8. Abnormal results of blood routine examinations and liver and kidney and coagulation tests

9. Patients with active inflammatory bowel diseases or peptic ulcer

10. Gastrointestinal bleeding or perforation within 6 months

11. Heart failure: NYHA III-IV

12. Respiratory insufficiency

13. Women who are pregnant

14. Participation in another clinical treatment trial while on study

15. Patients in whom fiducial implantation was not possible

16. Inability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Changhai hospital	Shanghai	Shanghai	China	200433

Sponsors and Collaborators

• Changhai Hospital

Investigators

• Principal Investigator: Huo Jun Zhang, MD., PH.D, Changhai Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 5, 2021

More Information

Publications

• Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grützmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM; Australian Pancreatic Cancer Genome Initiative, Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24.
• Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. Epub 2012 Jun 2.
• Bryant KL, Stalnecker CA, Zeitouni D, Klomp JE, Peng S, Tikunov AP, Gunda V, Pierobon M, Waters AM, George SD, Tomar G, Papke B, Hobbs GA, Yan L, Hayes TK, Diehl JN, Goode GD, Chaika NV, Wang Y, Zhang GF, Witkiewicz AK, Knudsen ES, Petricoin EF 3rd, Singh PK, Macdonald JM, Tran NL, Lyssiotis CA, Ying H, Kimmelman AC, Cox AD, Der CJ. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med. 2019 Apr;25(4):628-640. doi: 10.1038/s41591-019-0368-8. Epub 2019 Mar 4. Erratum in: Nat Med. 2020 Jun;26(6):982.
• Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res. 2004 Jun 15;64(12):4328-37.
• Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009 Sep 1;15(17):5379-88. doi: 10.1158/1078-0432.CCR-09-0265. Epub 2009 Aug 25.
• Eser S, Schnieke A, Schneider G, Saur D. Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer. 2014 Aug 26;111(5):817-22. doi: 10.1038/bjc.2014.215. Epub 2014 Apr 22. Review.
• Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, Schuman SS, Shea JE, Seipp MT, Yap JT, Burrell LD, Lum DH, Whisenant JR, Gilcrease GW 3rd, Cavalieri CC, Rehbein KM, Cutler SL, Affolter KE, Welm AL, Welm BE, Scaife CL, Snyder EL, McMahon M. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019 Apr;25(4):620-627. doi: 10.1038/s41591-019-0367-9. Epub 2019 Mar 4. Erratum in: Nat Med. 2019 Mar 27;:.
• McCormick F. KRAS as a Therapeutic Target. Clin Cancer Res. 2015 Apr 15;21(8):1797-801. doi: 10.1158/1078-0432.CCR-14-2662. Review.
• Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. doi: 10.1001/jama.2013.279201.
• Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, Sherry RM, Topalian SL, Yang JC, Lowy I, Rosenberg SA. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010 Oct;33(8):828-33. doi: 10.1097/CJI.0b013e3181eec14c.
• Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020 May;70(3):145-164. doi: 10.3322/caac.21601. Epub 2020 Mar 5.
• Vena F, Li Causi E, Rodriguez-Justo M, Goodstal S, Hagemann T, Hartley JA, Hochhauser D. The MEK1/2 Inhibitor Pimasertib Enhances Gemcitabine Efficacy in Pancreatic Cancer Models by Altering Ribonucleotide Reductase Subunit-1 (RRM1). Clin Cancer Res. 2015 Dec 15;21(24):5563-77. doi: 10.1158/1078-0432.CCR-15-0485. Epub 2015 Jul 30.
• Verbrugge I, Hagekyriakou J, Sharp LL, Galli M, West A, McLaughlin NM, Duret H, Yagita H, Johnstone RW, Smyth MJ, Haynes NM. Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res. 2012 Jul 1;72(13):3163-74. doi: 10.1158/0008-5472.CAN-12-0210. Epub 2012 May 8.

• Responsible Party: Zhang Huo Jun, Director of Radiation Oncology Department, Changhai Hospital
• ClinicalTrials.gov Identifier: NCT02704156
• Other Study ID Numbers: ChanghaiHosp
• First Posted: Mar 9, 2016
• Last Update Posted: May 13, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Zhang Huo Jun, Director of Radiation Oncology Department, Changhai Hospital: Stereotactic body radiation therapy; CyberKnife; Initial treatment
• Additional relevant MeSH terms: Pancreatic Neoplasms; Gemcitabine; Pembrolizumab; Trametinib

Study Results

Participant Flow

Recruitment Details	Recruitment date was from October 2016 to October 2017. Patients were enrolled in our center.

Arm/Group Title	SBRT Plus Gemcitabine	SBRT Plus Pembrolizumab and Trametinib
Arm/Group Description	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Gemcitabine: Radiation therapy plus drug	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Pembrolizumab and Trametinib: Radiation therapy plus drug
Period Title: Overall Study
STARTED	85	85
COMPLETED	85	85
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	SBRT Plus Gemcitabine	SBRT Plus Pembrolizumab and Trametinib	Total
Arm/Group Description	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Gemcitabine: Radiation therapy plus drug	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Pembrolizumab and Trametinib: Radiation therapy plus drug	Total of all reporting groups
Overall Participants	85	85	170
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	66	65	65
Sex: Female, Male (Count of Participants)
Female	33 38.8%	32 37.6%	65 38.2%
Male	52 61.2%	53 62.4%	105 61.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	85 100%	85 100%	170 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
China	85 100%	85 100%	170 100%
PD-L1 intensity (participants) [Number]
IC1 or TC1	56 65.9%	60 70.6%	116 68.2%
IC2 or TC2	23 27.1%	20 23.5%	43 25.3%
IC3 or TC3	6 7.1%	5 5.9%	11 6.5%

Outcome Measures

1. Primary Outcome

Title	The Median Survival Time Will be Determined.
Description	The time from the start of treatment to death
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SBRT Plus Gemcitabine	SBRT Plus Pembrolizumab and Trametinib
Arm/Group Description	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Gemcitabine: Radiation therapy plus drug	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Pembrolizumab and Trametinib: Radiation therapy plus drug
Measure Participants	85	85
Median (95% Confidence Interval) [months]	12.8	14.9

2. Secondary Outcome

Title	One- and Two-year Overall Survival Rate Will be Determined.
Description	The number of patients alive at 1 year and 2 years.
Time Frame	2 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SBRT Plus Gemcitabine	SBRT Plus Pembrolizumab and Trametinib
Arm/Group Description	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Gemcitabine: Radiation therapy plus drug	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Pembrolizumab and Trametinib: Radiation therapy plus drug
Measure Participants	85	85
1-year OS rate	48 56.5%	53 62.4%
2-year OS rate	0 0%	2 2.4%

3. Secondary Outcome

Title	Treatment-related Adverse Effects Will be Determined.
Description	Treatment-related adverse effects are determined by National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SBRT Plus Gemcitabine	SBRT Plus Pembrolizumab and Trametinib
Arm/Group Description	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Gemcitabine: Radiation therapy plus drug	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Pembrolizumab and Trametinib: Radiation therapy plus drug
Measure Participants	85	85
Grade 3 pyrexia	0 0%	2 2.4%
Grade 3 vomitting	2 2.4%	1 1.2%
Grade 3 and 4 increased ALT or AST	6 7.1%	10 11.8%
Grade 3 stomatitis	0 0%	1 1.2%
Grade 3 rash	0 0%	2 2.4%
Grade 3 and 4 neutropenia	9 10.6%	1 1.2%
Grade 3 thrombocytopenia	4 4.7%	1 1.2%
Grade 3 increased blood bilirubin	0 0%	4 4.7%
Grade 3 hypokalemia	0 0%	1 1.2%
Grade 3 hyponatremia	0 0%	3 3.5%
Grade 3 pneumonia	0 0%	1 1.2%
Grade 3 hypertension	0 0%	2 2.4%

4. Secondary Outcome

Title	The Median Progression Free Survival Time Will be Determined.
Description	The time from the start of treatment until documentation of any clinical or radiological disease progression or death, whichever occurred first. Progression is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SBRT Plus Gemcitabine	SBRT Plus Pembrolizumab and Trametinib
Arm/Group Description	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Gemcitabine: Radiation therapy plus drug	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Pembrolizumab and Trametinib: Radiation therapy plus drug
Measure Participants	85	85
Median (95% Confidence Interval) [months]	5.4	8.2

5. Secondary Outcome

Title	One- and Two-year Progression Survival Rate Will be Determined. Will be Determined.
Description	The proportion of patients without disease progressions at 1 year and 2 years.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SBRT Plus Gemcitabine	SBRT Plus Pembrolizumab and Trametinib
Arm/Group Description	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Gemcitabine: Radiation therapy plus drug	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Pembrolizumab and Trametinib: Radiation therapy plus drug
Measure Participants	85	85
1-year PFS rate	7 8.2%	18 21.2%
2-year PFS rate	0 0%	0 0%

6. Secondary Outcome

Title	The Quality of Life Will be Analyzed.
Description	The analysis of quality of life is based on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). All scales and subscales range from 0 to 100. Regarding physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning and global health, higher scores may indicate better outcomes. In the case of fatigue, nausea and vomitting, pain, dyspnea, insomina, appetite loss, constipation, diarrhea and financial difficulties, lower scores may indicate better outcomes. Scales of all items are independent and not combined to compute a total score.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SBRT Plus Gemcitabine	SBRT Plus Pembrolizumab and Trametinib
Arm/Group Description	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Gemcitabine: Radiation therapy plus drug	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Pembrolizumab and Trametinib: Radiation therapy plus drug
Measure Participants	85	85
Physical functioning	86.2	83.7
Role functioning	81.8	84.5
Emotional functioning	73.9	72.1
Cognitive functioning	84.7	83.3
Social functioning	85.5	84.1
Global health	83.6	83.2
Fatigue	29.6	26.6
Nausea and vomitting	29.4	28.8
Pain	23.9	26.5
Dyspnea	16.1	13.7
Insomina	14.9	17.6
Appetite loss	31.0	33.3
Constipation	14.5	16.5
Diarrhea	15.7	15.7
Financial difficulties	16.8	17.2

Adverse Events

Time Frame	3 years
Arm/Group Title	SBRT Plus Gemcitabine		SBRT Plus Pembrolizumab and Trametinib
Arm/Group Description	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Gemcitabine: Radiation therapy plus drug		Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. Cyberknife plus Pembrolizumab and Trametinib: Radiation therapy plus drug
All Cause Mortality
	SBRT Plus Gemcitabine		SBRT Plus Pembrolizumab and Trametinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/85 (100%)		83/85 (97.6%)
Serious Adverse Events
	SBRT Plus Gemcitabine		SBRT Plus Pembrolizumab and Trametinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/85 (24.7%)		29/85 (34.1%)
Blood and lymphatic system disorders
Grade 3 and 4 neutropenia	9/85 (10.6%)		1/85 (1.2%)
Grade 3 thrombocytopenia	4/85 (4.7%)		1/85 (1.2%)
Cardiac disorders
Grade 3 hypertension	0/85 (0%)		2/85 (2.4%)
Gastrointestinal disorders
Grade 3 vomitting	2/85 (2.4%)		1/85 (1.2%)
Grade 3 stomatitis	0/85 (0%)		1/85 (1.2%)
General disorders
Grade 3 pyrexia	0/85 (0%)		2/85 (2.4%)
Hepatobiliary disorders
Grade 3 and 4 increased ALT or AST	6/85 (7.1%)		10/85 (11.8%)
Grade 3 increased blood bilirubin	0/85 (0%)		4/85 (4.7%)
Metabolism and nutrition disorders
Grade 3 hypokalemia	0/85 (0%)		1/85 (1.2%)
Grade 3 hyponatremia	0/85 (0%)		3/85 (3.5%)
Respiratory, thoracic and mediastinal disorders
Grade 3 pneumonia	0/85 (0%)		1/85 (1.2%)
Skin and subcutaneous tissue disorders
Grade 3 rash	0/85 (0%)		2/85 (2.4%)
Other (Not Including Serious) Adverse Events
	SBRT Plus Gemcitabine		SBRT Plus Pembrolizumab and Trametinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/85 (100%)		85/85 (100%)
Blood and lymphatic system disorders
Grade 1-2 neutropenia	21/85 (24.7%)		6/85 (7.1%)
Grade 1-2 thrombocytopenia	15/85 (17.6%)		7/85 (8.2%)
Gastrointestinal disorders
Grade 1-2 Nausea and vomitting	17/85 (20%)		11/85 (12.9%)
Grade 1-2 diarrhea	16/85 (18.8%)		18/85 (21.2%)
Grade 1-2 stomatitis	0/85 (0%)		8/85 (9.4%)
Hepatobiliary disorders
Grade 1-2 increased ALT or AST	12/85 (14.1%)		16/85 (18.8%)
Renal and urinary disorders
Grade 1-2 proteinuria	2/85 (2.4%)		5/85 (5.9%)
Skin and subcutaneous tissue disorders
Grade 1-2 rash	2/85 (2.4%)		14/85 (16.5%)

Limitations/Caveats

The major limitation of the study was the small number of the randomized patients.

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.