Esophageal squamous cell carcinoma
Section editor transclusions Note: these are regimens tested in histology-specific populations, please see the main esophageal cancer page for other regimens.
46 regimens on this page
64 variants on this page
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Neoadjuvant induction therapy
Cisplatin & Etoposide (EP)
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Boonstra et al. 2011 | 1989-1996 | Phase 3 (E-esc) | Surgery alone | Seems to have superior OS |
Patients: 100% squamous cell histology
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV over 4 hours once on day 1
- Etoposide (Vepesid) 100 mg/m2 IV over 2 hours once per day on days 1 & 2, then 200 mg/m2 PO once per day on days 3 & 5
21-day cycle for 2 to 4 cycles
Subsequent treatment
References
- Boonstra JJ, Kok TC, Wijnhoven BP, van Heijl M, van Berge Henegouwen MI, Ten Kate FJ, Siersema PD, Dinjens WN, van Lanschot JJ, Tilanus HW, van der Gaast A. Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer. 2011 May 19;11:181. link to original article contains dosing details in manuscript link to PMC article PubMed
Cisplatin & Paclitaxel
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Awaiting publication (HCHTOG1909) | 2020-ongoing | Phase 3 (C) | Cisplatin, Paclitaxel, Toripalimab | TBD |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 3 cycles
Subsequent treatment
References
- HCHTOG1909: Contains dosing details on CT.gov NCT04280822
Neoadjuvant chemoradiotherapy
Note: while these regimens are listed as neoadjuvant (pre-operative), in some cases they are also used as definitive therapy in patients that are not surgical candidates.
Fluorouracil, Oxaliplatin, RT
Fluorouracil, Oxaliplatin, RT: Fluorouracil, Oxaliplatin, Radiation Therapy
Regimen variant #1, 45 Gy
Study | Evidence |
---|---|
Lorenzen et al. 2008 | Phase 1/2 |
Patients: 100% squamous cell etiology, 65% poor differentiated or undifferentiated
Chemotherapy
- Fluorouracil (5-FU) 225 mg/m2/day IV continuous infusion over 33 days, started on day 1 (total dose: 7425 mg/m2)
- Oxaliplatin (Eloxatin) 45 mg/m2 IV over 2 hours once per day on days 1, 8, 15, 22, 29
Radiotherapy
- Concurrent radiation therapy, 1.8 Gy fractions x 25 fractions, for a total dose of 45 Gy
35-day course
Subsequent treatment
- Surgery, 4 to 6 weeks after finishing chemoradiation
References
- Lorenzen S, Brücher B, Zimmermann F, Geinitz H, Riera J, Schuster T, Roethling N, Höfler H, Ott K, Peschel C, Siewert JR, Molls M, Lordick F. Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial. Br J Cancer. 2008 Oct 7;99(7):1020-6. Epub 2008 Sep 16. link to original article contains dosing details in manuscript link to PMC article PubMed
Definitive therapy
Capecitabine & Cisplatin (CX) & RT
CX & RT: Cisplatin, Xeloda (Capecitabine), Radiation Therapy
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ongoing (KUNLUN) | 2020-ongoing | Phase 3 (C) | 1. CX, Durvalumab, RT 2. CF, Durvalumab, RT |
To be determined |
Chemotherapy
Radiotherapy
- Concurrent radiation therapy
References
- KUNLUN: NCT04550260
Cisplatin, Docetaxel, RT
DC & RT: Docetaxel, Cisplatin, Radiation Therapy
Regimen variant #1, 80/60 x 2
Study | Evidence |
---|---|
Li et al. 2009 | Phase 2 |
Patients: 100% squamous cell histology, 5% gastroesophageal junction. 44% of patients had stage IV disease
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
Supportive medications
- Dexamethasone (Decadron) 10 mg IV or PO once on day -1, then once on day 1; 30 minutes prior to Docetaxel (Taxotere), then once on day 2
- Diphenhydramine (Benadryl) 40 mg IV once on day 1, prior to chemotherapy
- Cimetidine (Tagamet) 40 mg IV once on day 1, prior to chemotherapy
- Granisetron 2 mg IV once on day 1, prior to chemotherapy
- 1.5 to 2 liters fluids before Cisplatin (Platinol)
21-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy, 1.8 to 2 Gy fractions, to start within 24 hours of the start of chemotherapy
- Patients with stage I to III disease received a total dose of 60 to 64 Gy over 4 to 6 weeks
- Patients with stage IV disease (lymph node only) received a total dose of 50 to 56 Gy
Note, dose reductions were permitted, see article for specifications
One course
References
- Li QQ, Liu MZ, Hu YH, Liu H, He ZY, Lin HX. Definitive concomitant chemoradiotherapy with docetaxel and cisplatin in squamous esophageal carcinoma. Dis Esophagus. 2010 Apr;23(3):253-9. Epub 2009 Aug 28. link to original article contains dosing details in manuscript PubMed
Cisplatin & Fluorouracil (CF) & RT
CF & RT: Cisplatin, Fluorouracil, Radiation Therapy
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ongoing (KUNLUN) | 2020-ongoing | Phase 3 (C) | 1. CX, Durvalumab, RT 2. CF, Durvalumab, RT |
To be determined |
Chemotherapy
Radiotherapy
- Concurrent radiation therapy
References
- KUNLUN: NCT04550260
Cisplatin, Paclitaxel, RT
TP & RT: Taxol (Paclitaxel), Platinol (Cisplatin), Radiation Therapy
Regimen variant #1
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wu et al. 2018 (Shixiu - 1) | 2007-2015 | Phase 3 (C) | Cisplatin, Paclitaxel, Erlotinib, ENI | Seems to have inferior OS |
Chemotherapy
- Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 3
- Paclitaxel (Taxol) 135 mg/m2 IV once on day 1
28-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy
Regimen variant #2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Awaiting publication (RATIONALE 311) | 2019-ongoing | Phase 3 (C) | Cisplatin, Paclitaxel, Tislelizumab, RT | To be determined |
Chemotherapy
- Cisplatin (Platinol) 25 mg/m2 IV once per day on days 1 to 3
- Paclitaxel (Taxol) 135 mg/m2 IV once on day 1
21-day cycle for 2 cycles
Radiotherapy
- Concurrent radiation therapy 50.4 Gy in 28 fractions
References
- Shixiu - 1: Wu SX, Wang LH, Luo HL, Xie CY, Zhang XB, Hu W, Zheng AP, Li DJ, Zhang HY, Xie CH, Lian XL, Du DX, Chen M, Bian XH, Tan BX, Jiang H, Zhang HB, Wang JH, Jing Z, Xia B, Zhang N, Zhang P, Li WF, Zhao FJ, Tian ZF, Liu H, Huang KW, Hu J, Xie RF, Du L, Li G. Randomised phase III trial of concurrent chemoradiotherapy with extended nodal irradiation and erlotinib in patients with inoperable oesophageal squamous cell cancer. Eur J Cancer. 2018 Apr;93:99-107. Epub 2018 Mar 20. link to original article contains dosing details in abstract PubMed NCT00686114
- Update: Xie C, Jing Z, Luo H, Jiang W, Ma L, Hu W, Zheng A, Li D, Ding L, Zhang H, Xie C, Lian X, Du D, Chen M, Bian X, Tan B, Xia B, Xie R, Liu Q, Wang L, Wu S. Chemoradiotherapy with extended nodal irradiation and/or erlotinib in locally advanced oesophageal squamous cell cancer: long-term update of a randomised phase 3 trial. Br J Cancer. 2020 Nov;123(11):1616-1624. Epub 2020 Sep 22. link to original article link to PMC article PubMed
- KEYSTONE-002: NCT04807673
- RATIONALE 311: contains dosing details on CT.gov NCT03957590
- SHR-1210-III-323: NCT04426955
Fluorouracil, Paclitaxel, RT
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Chen et al. 2019 (ESO-Shanghai1) | 2012-2015 | Phase 3 (E-switch-ic) | Cisplatin, Flourouracil, RT | Did not meet primary endpoint of OS36 |
Inclusion criteria: Esophageal SCC, stage IIA-IVA (AJCC 6th edition), ECOG 0-2, previously untreated. The total dose of 5-FU for this portion of the protocol is unclear in the manuscript; dosing here is as clarified by the authors.
Chemotherapy
- Fluorouracil (5-FU) 75 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 300 mg/m2)
- Paclitaxel (Taxol) 50 mg/m2 IV once on day 1
7-day cycle for 5 cycles
Radiotherapy
- Concurrent radiation therapy, 1.8 Gy fractions x 34 fractions, for a total dose of 61.2 Gy
7-week course
Subsequent treatment
References
- ESO-Shanghai1: Chen Y, Ye J, Zhu Z, Zhao W, Zhou J, Wu C, Tang H, Fan M, Li L, Lin Q, Xia Y, Li Y, Li J, Jia H, Lu S, Zhang Z, Zhao K. Comparing Paclitaxel Plus Fluorouracil Versus Cisplatin Plus Fluorouracil in Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Cancer: A Randomized, Multicenter, Phase III Clinical Trial. J Clin Oncol. 2019 Jul 10;37(20):1695-1703. Epub 2019 Mar 28. link to original article PubMed NCT01591135
Consolidation after definitive therapy
Fluorouracil & Paclitaxel
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Chen et al. 2019 (ESO-Shanghai1) | 2012-2015 | Phase 3 (E-switch-ic) | Cisplatin & Flourouracil | Did not meet primary endpoint of OS36 |
Inclusion criteria: Esophageal SCC, stage IIA-IVA (AJCC 6th edition), ECOG 0-2, previously untreated
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m2)
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
28-day cycle for 2 cycles
References
- ESO-Shanghai1: Chen Y, Ye J, Zhu Z, Zhao W, Zhou J, Wu C, Tang H, Fan M, Li L, Lin Q, Xia Y, Li Y, Li J, Jia H, Lu S, Zhang Z, Zhao K. Comparing Paclitaxel Plus Fluorouracil Versus Cisplatin Plus Fluorouracil in Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Cancer: A Randomized, Multicenter, Phase III Clinical Trial. J Clin Oncol. 2019 Jul 10;37(20):1695-1703. Epub 2019 Mar 28. link to original article contains dosing details in manuscript PubMed NCT01591135
Metastatic or locally advanced disease, first-line
Cisplatin & Docetaxel (DC)
DC: Docetaxel, Cisplatin
TC: Taxotere (Docetaxel), Cisplatin
Regimen
Study | Evidence |
---|---|
Kim et al. 2009 | Phase 2 |
Patients: 100% squamous cell histology. 5% with ECOG PS of 2.
Chemotherapy
- Cisplatin (Platinol) 70 mg/m2 IV over 60 minutes once on day 1
- Docetaxel (Taxotere) 70 mg/m2 IV over 60 minutes once on day 1, given 3 hours before cisplatin
Supportive medications
- Dexamethasone (Decadron) 8 mg PO twice per day x 1 day, starting 1 day before Docetaxel (Taxotere) administration
- At least 3 liters hydration (with mannitol, magnesium, and potassium chloride)
- "Antiemetic treatment"
21-day cycle for up to 6 cycles
References
- Kim JY, Do YR, Park KU, Kim MK, Lee KH, Bae SH, Ryoo HM, Baek JH, Song HS. A multi-center phase II study of docetaxel plus cisplatin as first-line therapy in patients with metastatic squamous cell esophageal cancer. Cancer Chemother Pharmacol. 2010 May;66(1):31-6. Epub 2009 Sep 18. link to original article contains dosing details in manuscript PubMed
Cisplatin & Fluorouracil (CF)
CF: Cisplatin, Fluorouracil
FP: Fluorouracil, Platinol
Regimen variant #1, 80/4000, 4-day infusion, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Moehler et al. 2019 (POWER) | 2012-2015 | Phase 3 (C) | CFP | Did not meet primary endpoint of OS |
Note: this was the dosing after a mid-protocol amendment.
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
28-day cycles
Regimen variant #2, 80/4000, 5-day infusion, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Doki et al. 2022 (CheckMate 648) | 2017-2019 | Phase 3 (C) | 1. CF & Nivolumab 2. Ipilimumab & Nivolumab |
Inferior OS1 |
1Reported efficacy is for the overall randomized population.
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
28-day cycles
Regimen variant #3, 100/5000 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lorenzen et al. 2009 | 2004-2006 | Randomized Phase 2 (C) | CF & Cetuximab | Did not meet primary endpoint of ORR |
Patients: 100% squamous cell histology. 87% with metastatic disease. No patients with ECOG PS greater than 1.
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on day 1, given first
- Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1, given second (total dose per cycle: 5000 mg/m2)
Supportive medications
- "Standard antiemetic prophylaxis and pre- and post- Cisplatin (Platinol) hydration"
29-day cycle for up to 6 cycles
References
- Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. link to original article contains dosing details in manuscript PubMed
- POWER: Moehler M, Maderer A, Thuss-Patience PC, Brenner B, Meiler J, Ettrich TJ, Hofheinz RD, Al-Batran SE, Vogel A, Mueller L, Lutz MP, Lordick F, Alsina M, Borchert K, Greil R, Eisterer W, Schad A, Slotta-Huspenina J, Van Cutsem E, Lorenzen S. Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER). Ann Oncol. 2020 Feb;31(2):228-235. Epub 2019 Dec 16. link to original article contains dosing details in manuscript PubMed NCT01627379
- CheckMate 648: Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. link to original article contains dosing details in manuscript PubMed NCT03143153
Cisplatin & Fluorouracil (CF) & Cetuximab
CF-C: Cisplatin, Fluorouracil, Cetuximab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lorenzen et al. 2009 | 2004-2006 | Randomized Phase 2 (E-esc) | CF | Did not meet primary endpoint of ORR |
Patients: 100% squamous cell histology. 87% with metastatic disease. No patients with ECOG PS greater than 1.
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on day 1, given first
- Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m2)
Targeted therapy
- Cetuximab (Erbitux) as follows:
- Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8, 15, 22
- Cycles 2 to 6: 250 mg/m2 IV once per day on days 1, 8, 15, 22
Supportive medications
- "Standard antiemetic prophylaxis and pre- and post- Cisplatin (Platinol) hydration"
29-day cycle for up to 6 cycles
References
- Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, Moehler M, Grabowski P, Arnold D, Greten T, Müller L, Röthling N, Peschel C, Langer R, Lordick F. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23. link to original article contains dosing details in manuscript PubMed
Cisplatin & Fluorouracil (CF) & Nivolumab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Doki et al. 2022 (CheckMate 648) | 2017-2019 | Phase 3 (E-RT-esc) | 1. CF | Superior OS1 Median OS: 13.2 vs 10.7 mo (HR 0.74, 99.1% CI 0.58-0.96) |
2. Ipilimumab & Nivolumab | Not reported |
1Reported efficacy is for the overall randomized population.
Chemotherapy
- Cisplatin (Platinol) 80 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
Immunotherapy
- Nivolumab (Opdivo) as follows:
- Cycle 1 up to 26: 240 mg IV once per day on days 1 & 15
28-day cycles
References
- CheckMate 648: Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. link to original article contains dosing details in manuscript PubMed NCT03143153
Cisplatin & Fluorouracil (CF) & Pembrolizumab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Awaiting publication (LEAP-014) | 2021-ongoing | Phase 3 (C) | 1. FP, Lenvatinib, Pembrolizumab 2. TP, Lenvatinib, Pembrolizumab 3. mFOLFOX6, Lenvatinib, Pembrolizumab |
TBD |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm. There is no doubt that the 5-FU is given as a continuous infusion, but these details are not provided on CT.gov.
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 up to 3: 80 mg/m2 IV once per day on days 1 & 22
- Fluorouracil (5-FU) 4000 mg/m2 IV once per day on days 1 & 22
Immunotherapy
- Pembrolizumab (Keytruda) 400 mg IV once on day 1
42-day cycle for up to 18 cycles (2 years)
References
- LEAP-014: contains dosing details on CT.gov NCT04949256
Cisplatin & Fluorouracil (CF) & Sintilimab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lu et al. 2022 (ORIENT-15) | 2018-2021 | Phase 3 (E-esc) | 1. CF 2. Cisplatin & Paclitaxel |
Superior OS1 Median OS: 17.2 vs 13.6 mo (HR 0.64, 95% CI 0.48-0.85) |
1Reported efficacy is for the primary efficacy population (CPS of 10 or more).
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 to 6: 75 mg/m2 IV once on day 1
- Fluorouracil (5-FU) as follows:
- Cycles 1 to 6: 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
Immunotherapy
- Sintilimab (Tyvyt) by the following weight-based criteria:
- Weight less than 60 kg: 3 mg/kg IV once on day 1
- Weight 60 kg or more: 200 mg IV once on day 1
28-day cycle for up to 26 cycles (2 years)
References
- ORIENT-15: Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, Wang B, Sun G, Ji Y, Cao G, Liu H, Cui T, Li N, Qiu W, Li G, Hou X, Luo H, Xue L, Zhang Y, Yue W, Liu Z, Wang X, Gao S, Pan Y, Galais MP, Zaanan A, Ma Z, Li H, Wang Y, Shen L; ORIENT-15 study group. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ. 2022 Apr 19;377:e068714. link to original article contains dosing details in manuscript PubMed NCT03748134
Cisplatin & Paclitaxel
Regimen variant #1, 6 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Luo et al. 2021 (ESCORT-1st) | 2018-2020 | Phase 3 (C) | Cisplatin, Paclitaxel, Camrelizumab | Inferior OS |
Wang et al. 2022 (JUPITER-06) | 2019-2020 | Phase 3 (C) | Cisplatin, Paclitaxel, Toripalimab | Inferior OS |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
Regimen variant #2, indefinite
Study | Evidence |
---|---|
Zhang et al. 2008 | Phase 2 |
Patients: 100% squamous cell carcinoma with advanced or metastatic disease. 18% ECOG PS of 2.
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV over 2 hours once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycles
References
- Zhang X, Shen L, Li J, Li Y, Li J, Jin M. A phase II trial of paclitaxel and cisplatin in patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol. 2008 Feb;31(1):29 to 33. link to original article contains dosing details in abstract PubMed
- ESCORT-1st: Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, Li J, Fu Z, Gu K, Liu Z, Wu L, Zhang X, Feng J, Niu Z, Ba Y, Zhang H, Liu Y, Zhang L, Min X, Huang J, Cheng Y, Wang D, Shen Y, Yang Q, Zou J, Xu RH; ESCORT-1st Investigators. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA. 2021 Sep 14;326(10):916-925. link to original article contains dosing details in abstract link to PMC article PubMed NCT03691090
- JUPITER-06: Wang ZX, Cui C, Yao J, Zhang Y, Li M, Feng J, Yang S, Fan Y, Shi J, Zhang X, Shen L, Shu Y, Wang C, Dai T, Mao T, Chen L, Guo Z, Liu B, Pan H, Cang S, Jiang Y, Wang J, Ye M, Chen Z, Jiang D, Lin Q, Ren W, Wang J, Wu L, Xu Y, Miao Z, Sun M, Xie C, Liu Y, Wang Q, Zhao L, Li Q, Huang C, Jiang K, Yang K, Li D, Liu Y, Zhu Z, Chen R, Jia L, Li W, Liao W, Liu HX, Ma D, Ma J, Qin Y, Shi Z, Wei Q, Xiao K, Zhang Y, Zhang Y, Chen X, Dai G, He J, Li J, Li G, Liu Y, Liu Z, Yuan X, Zhang J, Fu Z, He Y, Ju F, Liu Z, Tang P, Wang T, Wang W, Zhang J, Luo X, Tang X, May R, Feng H, Yao S, Keegan P, Xu RH, Wang F. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell. 2022 Mar 14;40(3):277-288.e3. Epub 2022 Mar 3. link to original article contains dosing details in manuscript PubMed NCT03829969
Cisplatin, Paclitaxel, Camrelizumab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Luo et al. 2021 (ESCORT-1st) | 2018-2020 | Phase 3 (E-esc) | Cisplatin & Paclitaxel | Superior OS Median OS: 15.3 vs 12 mo (HR 0.70, 95% CI 0.56-0.88) |
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 up to 6: 75 mg/m2 IV once on day 1
- Paclitaxel (Taxol) as follows:
- Cycles 1 up to 6: 175 mg/m2 IV once on day 1
Immunotherapy
- Camrelizumab (AiRuiKa) 200 mg IV once on day 1
21-day cycles
References
- ESCORT-1st: Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, Li J, Fu Z, Gu K, Liu Z, Wu L, Zhang X, Feng J, Niu Z, Ba Y, Zhang H, Liu Y, Zhang L, Min X, Huang J, Cheng Y, Wang D, Shen Y, Yang Q, Zou J, Xu RH; ESCORT-1st Investigators. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA. 2021 Sep 14;326(10):916-925. link to original article contains dosing details in abstract link to PMC article PubMed NCT03691090
Cisplatin, Paclitaxel, Sintilimab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lu et al. 2022 (ORIENT-15) | 2018-2021 | Phase 3 (E-esc) | 1. CF 2. Cisplatin & Paclitaxel |
Superior OS1 Median OS: 17.2 vs 13.6 mo (HR 0.64, 95% CI 0.48-0.85) |
1Reported efficacy is for the primary efficacy population (CPS of 10 or more).
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 to 6: 75 mg/m2 IV once on day 1
- Paclitaxel (Taxol) as follows:
- Cycle 1: 87.5 mg/m2 IV once per day on days 1 & 8
- Cycles 2 to 6: 175 mg/m2/day IV once on day 1
Immunotherapy
- Sintilimab (Tyvyt) by the following weight-based criteria:
- Weight less than 60 kg: 3 mg/kg IV once on day 1
- Weight 60 kg or more: 200 mg IV once on day 1
28-day cycle for up to 26 cycles (2 years)
References
- ORIENT-15: Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, Wang B, Sun G, Ji Y, Cao G, Liu H, Cui T, Li N, Qiu W, Li G, Hou X, Luo H, Xue L, Zhang Y, Yue W, Liu Z, Wang X, Gao S, Pan Y, Galais MP, Zaanan A, Ma Z, Li H, Wang Y, Shen L; ORIENT-15 study group. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ. 2022 Apr 19;377:e068714. link to original article contains dosing details in manuscript PubMed NCT03748134
Cisplatin, Paclitaxel, Toripalimab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wang et al. 2022 (JUPITER-06) | 2019-2020 | Phase 3 (E-esc) | Cisplatin & Paclitaxel | Superior OS Median OS: 17 vs 11 mo (HR 0.58, 95% CI 0.43-0.78) |
Chemotherapy
- Cisplatin (Platinol) as follows:
- Cycles 1 up to 6: 75 mg/m2 IV once on day 1
- Paclitaxel (Taxol) as follows:
- Cycle 1 up to 6: 175 mg/m2/day IV once on day 1
Immunotherapy
- Toripalimab (Tuoyi) 240 mg IV once on day 1
21-day cycles
References
- JUPITER-06: Wang ZX, Cui C, Yao J, Zhang Y, Li M, Feng J, Yang S, Fan Y, Shi J, Zhang X, Shen L, Shu Y, Wang C, Dai T, Mao T, Chen L, Guo Z, Liu B, Pan H, Cang S, Jiang Y, Wang J, Ye M, Chen Z, Jiang D, Lin Q, Ren W, Wang J, Wu L, Xu Y, Miao Z, Sun M, Xie C, Liu Y, Wang Q, Zhao L, Li Q, Huang C, Jiang K, Yang K, Li D, Liu Y, Zhu Z, Chen R, Jia L, Li W, Liao W, Liu HX, Ma D, Ma J, Qin Y, Shi Z, Wei Q, Xiao K, Zhang Y, Zhang Y, Chen X, Dai G, He J, Li J, Li G, Liu Y, Liu Z, Yuan X, Zhang J, Fu Z, He Y, Ju F, Liu Z, Tang P, Wang T, Wang W, Zhang J, Luo X, Tang X, May R, Feng H, Yao S, Keegan P, Xu RH, Wang F. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell. 2022 Mar 14;40(3):277-288.e3. Epub 2022 Mar 3. link to original article contains dosing details in manuscript PubMed NCT03829969
Etoposide monotherapy
Regimen
Study | Evidence |
---|---|
Harstrick et al. 1992 | Phase 2 |
Note: this is higher than the dose usually employed in modern settings.
Patients: metastatic 100% squamous cell carcinoma of the esophagus, with ECOG PS range 1-2.
Chemotherapy
- Etoposide (Vepesid) 200 mg/m2 (route not specified) once per day on days 1 to 3
21-day cycles
References
- Harstrick A, Bokemeyer C, Preusser P, Köhne-Wömpner CH, Meyer HJ, Stahl M, Knipp H, Schmoll HJ, Wilke H. Phase II study of single-agent etoposide in patients with metastatic squamous-cell carcinoma of the esophagus. Cancer Chemother Pharmacol. 1992;29(4):321-2. link to original article contains dosing details in abstract PubMed
Ipilimumab & Nivolumab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Doki et al. 2022 (CheckMate 648) | 2017-2019 | Phase 3 (E-RT-switch-ooc) | 1. CF | Superior OS Median OS: 12.7 vs 10.7 mo (HR 0.78, 98.2% CI 0.62-0.98) |
2. CF & Nivolumab | Not compared |
Immunotherapy
- Ipilimumab (Yervoy) 1 mg/kg IV once on day 1
- Nivolumab (Opdivo) 3 mg/kg IV once per day on days 1, 15, 29
42-day cycle for up to 17 cycles (2 years)
References
- CheckMate 648: Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, Ogata T, Kawakami H, Hsu CH, Adenis A, El Hajbi F, Di Bartolomeo M, Braghiroli MI, Holtved E, Ostoich SA, Kim HR, Ueno M, Mansoor W, Yang WC, Liu T, Bridgewater J, Makino T, Xynos I, Liu X, Lei M, Kondo K, Patel A, Gricar J, Chau I, Kitagawa Y; CheckMate 648 Trial Investigators. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022 Feb 3;386(5):449-462. link to original article contains dosing details in manuscript PubMed NCT03143153
Metastatic or locally advanced disease, subsequent lines of therapy
Camrelizumab monotherapy
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Huang et al. 2020 (ESCORT) | 2017-2018 | Phase 3 (E-switch-ooc) | 1. Docetaxel 2. Irinotecan |
Superior OS Median OS: 8 mo vs 6 mo (HR 0.71, 95% CI 0.57-0.87) |
Immunotherapy
- Camrelizumab (AiRuiKa) 200 mg IV once on day 1
14-day cycles
References
- ESCORT: Huang J, Xu J, Chen Y, Zhuang W, Zhang Y, Chen Z, Chen J, Zhang H, Niu Z, Fan Q, Lin L, Gu K, Liu Y, Ba Y, Miao Z, Jiang X, Zeng M, Chen J, Fu Z, Gan L, Wang J, Zhan X, Liu T, Li Z, Shen L, Shu Y, Zhang T, Yang Q, Zou J; ESCORT Study Group. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study. Lancet Oncol. 2020;21(6):832-842. link to original article contains dosing details in abstract PubMed NCT03099382
Docetaxel monotherapy
Regimen variant #1, 75 mg/m2, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kojima et al. 2020 (KEYNOTE-181) | 2015-2017 | Phase 3 (C) | Pembrolizumab | Inferior OS1 |
1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.
Prior treatment criteria
- One prior line of standard therapy
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycles
Regimen variant #2, 100 mg/m2
Study | Evidence |
---|---|
Albertsson et al. 2007 | Phase 2 |
Patients: squamous cell or adenocarcinoma histology of the esophagus or gastric cardia.
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycles
References
- Albertsson M, Johansson B, Friesland S, Kadar L, Letocha H, Frykholm G, Wagenius G. Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer. Med Oncol. 2007;24(4):407-12. link to original article contains dosing details in abstract PubMed
- KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains dosing details in manuscript PubMed NCT02564263
- RATIONALE 302: NCT03430843
Irinotecan monotherapy
Regimen variant #1, 14-day cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kojima et al. 2020 (KEYNOTE-181) | 2015-2017 | Phase 3 (C) | Pembrolizumab | Inferior OS1 |
1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.
Prior treatment criteria
- One prior line of standard therapy
Chemotherapy
- Irinotecan (Camptosar) 180 mg/m2 IV once on day 1
14-day cycles
Regimen variant #2, 4 out of 6 weeks
Study | Evidence |
---|---|
Mühr-Wilkenshoff et al. 2003 | Phase 2, <20 patients |
Note: In contrast to the primary reference, some guidelines list a dosing schedule of 125 mg/m2 IV once per day on days 1 & 8, with 21-day cycles.
Patients: Ten with esophageal squamous cell carcinoma, three with esophageal adenocarcinoma
Chemotherapy
- Irinotecan (Camptosar) 125 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22
42-day cycles
References
- Mühr-Wilkenshoff F, Hinkelbein W, Ohnesorge I, Wolf KJ, Riecken EO, Zeitz M, Scherübl H. A pilot study of irinotecan (CPT-11) as single-agent therapy in patients with locally advanced or metastatic esophageal carcinoma. Int J Colorectal Dis. 2003 Jul;18(4):330-4. Epub 2003 Feb 1. link to original article PubMed
- KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains dosing details in manuscript PubMed NCT02564263
- RATIONALE 302: NCT03430843
Nivolumab monotherapy
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kato et al. 2019 (ATTRACTION-3) | 2016-2017 | Phase 3 (E-RT-switch-ooc) | 1. Docetaxel 2. Paclitaxel |
Seems to have superior OS Median OS: 11 mo vs 8 mo (HR 0.77, 95% CI 0.62-0.96) |
Inclusion Criteria: Unresectable advanced or recurrent esophageal SCC regardless of PDL1 expression, ECOG 0-1, refractory or intolerance to one prior 5-FU or platinum-based chemotherapy
Immunotherapy
- Nivolumab (Opdivo) 240 mg IV once on day 1
14-day cycles
References
- ATTRACTION-3: Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, Kadowaki S, Ahn MJ, Hamamoto Y, Doki Y, Yen CC, Kubota Y, Kim SB, Hsu CH, Holtved E, Xynos I, Kodani M, Kitagawa Y. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Nov;20(11):1506-1517. Epub 2019 Sep 30. link to original article PubMed NCT02569242
Paclitaxel monotherapy
Regimen variant #1, weekly
Study | Evidence |
---|---|
Ilson et al. 2007 | Phase 2 |
Patients: 100% esophageal cancers. 66% adenocarcinoma, 34% squamous cell. Median ECOG PS 1, ranging 0-2.
Chemotherapy
- Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22
Supportive medications
- Dexamethasone (Decadron) 20 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to Paclitaxel (Taxol)
- Cimetidine (Tagamet) 300 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to Paclitaxel (Taxol)
- Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22; 30 to 60 minutes prior to Paclitaxel (Taxol)
28-day cycles
Regimen variant #2, 80 mg/m2, 3 out of 4 weeks
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kojima et al. 2020 (KEYNOTE-181) | 2015-2017 | Phase 3 (C) | Pembrolizumab | Inferior OS1 |
1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.
This is the lower bound of dosing specified in KEYNOTE-181.
Prior treatment criteria
- One prior line of standard therapy
Chemotherapy
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #3, 100 mg/m2, 3 out of 4 weeks
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kojima et al. 2020 (KEYNOTE-181) | 2015-2017 | Phase 3 (C) | Pembrolizumab | Inferior OS1 |
1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the control arm might have inferior OS.
This is the upper bound of dosing specified in the protocol.
Prior treatment criteria
- One prior line of standard therapy
Chemotherapy
- Paclitaxel (Taxol) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
References
- Ilson DH, Wadleigh RG, Leichman LP, Kelsen DP. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007 May;18(5):898-902. Epub 2007 Mar 9. link to original article contains dosing details in manuscript PubMed
- KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains dosing details in manuscript PubMed NCT02564263
- RATIONALE 302: NCT03430843
Pembrolizumab monotherapy
Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kojima et al. 2020 (KEYNOTE-181) | 2015-2017 | Phase 3 (E-RT-switch-ooc) | Investigator's choice of: 1. Docetaxel 2. Irinotecan 3. Paclitaxel |
Superior OS1 |
Shah et al. 2019 (KEYNOTE-180) | 2016-2017 | Phase 2 (RT) |
1Reported efficacy in KEYNOTE-181 is for patients with squamous cell carcinoma or with PD-L1 combined positive score of at least 10; in all patients the experimental arm might have superior OS.
Patients in KEYNOTE-180 had 100% squamous histology.
Prior treatment criteria
- KEYNOTE-181: One prior line of standard therapy
- KEYNOTE-180: 2 or more lines of therapy
Biomarker eligibility criteria
- PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test
Immunotherapy
- Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
References
- KEYNOTE-180: Shah MA, Kojima T, Hochhauser D, Enzinger P, Raimbourg J, Hollebecque A, Lordick F, Kim SB, Tajika M, Kim HT, Lockhart AC, Arkenau HT, El-Hajbi F, Gupta M, Pfeiffer P, Liu Q, Lunceford J, Kang SP, Bhagia P, Kato K. Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus: The Phase 2 KEYNOTE-180 Study. JAMA Oncol. 2019 Apr 1;5(4):546-550. link to original article link to PMC article PubMed
- KEYNOTE-181: Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, Doi T, Moriwaki T, Kim SB, Lee SH, Bennouna J, Kato K, Shen L, Enzinger P, Qin SK, Ferreira P, Chen J, Girotto G, de la Fouchardiere C, Senellart H, Al-Rajabi R, Lordick F, Wang R, Suryawanshi S, Bhagia P, Kang SP, Metges JP; KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020 Dec 10;38(35):4138-4148. Epub 2020 Oct 7. link to original article contains dosing details in manuscript PubMed NCT02564263