SBRT Plus Pembrolizumab and Trametinib for Pancreatic Cancer

• ClinicalTrials.gov Identifier: NCT02704156
• Recruitment Status: Completed
• First Posted: March 9, 2016
• Results First Posted: February 16, 2021
• Last Update Posted: May 13, 2022
• Sponsor: Changhai Hospital
• Information provided by (Responsible Party): Zhang Huo Jun, Changhai Hospital

Tracking Information

• First Submitted Date: March 1, 2016
• First Posted Date: March 9, 2016
• Results First Submitted Date: January 6, 2021
• Results First Posted Date: February 16, 2021
• Last Update Posted Date: May 13, 2022
• Actual Study Start Date: October 2016
• Actual Primary Completion Date: December 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 29, 2021)

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

The time from the start of treatment to death

• Original Primary Outcome Measures (submitted: March 8, 2016): The median survival time will be determined. [ Time Frame: 3 years ]

Current Secondary Outcome Measures (submitted: January 29, 2021)

• One- and Two-year Overall Survival Rate Will be Determined. [ Time Frame: 2 year ]
  The number of patients alive at 1 year and 2 years.
• Treatment-related Adverse Effects Will be Determined. [ Time Frame: 3 years ]
  Treatment-related adverse effects are determined by National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0.
• The Median Progression Free Survival Time Will be Determined. [ Time Frame: 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.
• One- and Two-year Progression Survival Rate Will be Determined. Will be Determined. [ Time Frame: 2 years ]
  The proportion of patients without disease progressions at 1 year and 2 years.
• The Quality of Life Will be Analyzed. [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: March 8, 2016)

• One-, two- and three-year overall survival rates will be determined. [ Time Frame: 1year, 2 years and 3 years ]
• The acute toxicities following SBRT will be determined. [ Time Frame: 3 years ]
  The acute toxicities are determined by RTOG Acute Radiation Morbidity Scoring Criteria.
• The late toxicities following SBRT will be determined. [ Time Frame: 3 years ]
  The late toxicities are determined by RTOG/EORTC Late Radiation Morbidity Scoring Criteria.
• The median progression free survival time will be determined. [ Time Frame: 3 years ]
• The time to progression will be determined. [ Time Frame: 3 years ]
• The clinical benefit rates will be determined. [ Time Frame: 3 years ]
• The objective response rates will be determined. [ Time Frame: 3 years ]
• The quality of life will be analyzed. [ Time Frame: 3 years ]
  The analysis of quality of life is based on QLQ-C30 and QLQ-PAN26.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: SBRT Plus Pembrolizumab and Trametinib for Pancreatic Cancer
• 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
• Brief Summary: Hypothesis: Survival benefits could be found in SBRT Plus Pembrolizumab and Trametinib compared with SBRT plus gemcitabine.

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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Pancreatic Cancer

Intervention

• Device: Cyberknife plus Pembrolizumab and Trametinib
  Radiation therapy plus drug
• Device: Cyberknife plus Gemcitabine
  Radiation therapy plus drug

Study Arms

• 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.
  Intervention: Device: Cyberknife plus Pembrolizumab and Trametinib
• Active Comparator: SBRT plus Gemcitabine
  Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine.
  Intervention: Device: Cyberknife plus Gemcitabine

Publications *

• 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.
• Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zulke 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.
• 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.
• 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.
• 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.
• 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.
• 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. doi: 10.1158/0008-5472.CAN-04-0073.
• 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, Grutzmann 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.
• 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.
• 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.
• 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.
• 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;:
• 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.
• Zhu X, Cao Y, Liu W, Ju X, Zhao X, Jiang L, Ye Y, Jin G, Zhang H. Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2022 Mar;23(3):e105-e115. doi: 10.1016/S1470-2045(22)00066-3. Erratum In: Lancet Oncol. 2022 Mar;23(3):330.
• Zhu X, Cao Y, Liu W, Ju X, Zhao X, Jiang L, Ye Y, Jin G, Zhang H. Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2021 Aug;22(8):1093-1102. doi: 10.1016/S1470-2045(21)00286-2. Epub 2021 Jul 5.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 29, 2021): 170
• Original Estimated Enrollment (submitted: March 8, 2016): 140
• Actual Study Completion Date: December 2020
• Actual Primary Completion Date: December 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT02704156
• Other Study ID Numbers: ChanghaiHosp
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Zhang Huo Jun, Changhai Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Changhai Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Changhai Hospital
• Verification Date: February 2022