Melanoma

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Carboplatin & Paclitaxel (CP)

CP: Carboplatin, Paclitaxel

Regimen #1, Rao, et al. 2006

• Carboplatin (Paraplatin) AUC 2 IV on days 1, 8, 15
• Paclitaxel (Taxol) 100 mg/m2 IV on days 1, 8, 15

28-day cycles

Regimen #2, Rao, et al. 2006

• Carboplatin (Paraplatin) AUC 5 IV on day 1
• Paclitaxel (Taxol) 175-200 mg/m2 IV on day 1

21-day cycles

Regimen #3, Hauschild, et al. 2009 & Flaherty, et al. 2013 (E2603)

• Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 225 mg/m2 IV over 3 hours once on day 1, given first

21-day cycles x 4 cycles, then

• Carboplatin (Paraplatin) AUC 5 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1, given first

21-day cycles x 6 cycles, until progression of disease, or unacceptable toxicity

References

1. Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer. 2006 Jan 15;106(2):375-82. link to original article contains verified protocol PubMed
2. Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. Epub 2009 Apr 6. link to original article contains verified protocol PubMed
3. Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013 Jan 20;31(3):373-9. doi: 10.1200/JCO.2012.42.1529. Epub 2012 Dec 17. link to original article contains verified protocol PubMed

Carboplatin, Paclitaxel, Sorafenib

Regimen, Hauschild, et al. 2009 & Flaherty, et al. 2013 (E2603)

Hauschild, et al. 2009 and Flaherty, et al. 2013 (E2603) were negative studies. They did not show improved outcomes for Carboplatin, Paclitaxel, Sorafenib as compared to Carboplatin and Paclitaxel.

• Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 225 mg/m2 IV over 3 hours once on day 1, given first
• Sorafenib (Nexavar) 400 mg PO BID on days 2 to 19

21-day cycles x 4 cycles, then

• Carboplatin (Paraplatin) AUC 5 IV over 30 minutes once on day 1, given second
• Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1, given first
• Sorafenib (Nexavar) 400 mg PO BID on days 2 to 19

21-day cycles x 6 cycles, until progression of disease, or unacceptable toxicity; then proceed to sorafenib monotherapy

Sorafenib monotherapy

• Sorafenib (Nexavar) 400 mg PO BID on days 1 to 21

21-day cycles, given until progression of disease or unacceptable toxicity

References

1. Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. 2009 Jun 10;27(17):2823-30. Epub 2009 Apr 6. link to original article contains verified protocol PubMed
2. Flaherty KT, Lee SJ, Zhao F, Schuchter LM, Flaherty L, Kefford R, Atkins MB, Leming P, Kirkwood JM. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol. 2013 Jan 20;31(3):373-9. doi: 10.1200/JCO.2012.42.1529. Epub 2012 Dec 17. link to original article contains verified protocol PubMed

Cisplatin (Platinol), Dacarbazine (DTIC) +/- Carmustine (BiCNU)

Regimen

• Cisplatin (Platinol) 75 mg/m2 IV on day 1
• Dacarbazine (DTIC) 800 mg/m2 IV on day 1
• Optional: Carmustine (BiCNU) 100 mg/m2 (note: in Ridolfi, et al. 2002, in contrast to the treatment text, figure 1 lists a dosage of 150 mg/m2) IV on day 1

21-day cycles x 6 cycles

References

1. Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. link to original article contains verified protocol PubMed

Cisplatin (Platinol), Dacarbazine (DTIC), IL-2, IFN alfa-2b +/- Carmustine (BiCNU)

Regimen

• Cisplatin (Platinol) 75 mg/m2 IV on day 1
• Dacarbazine (DTIC) 800 mg/m2 IV on day 1
• Optional: Carmustine (BiCNU) 100 mg/m2 (note: in Ridolfi, et al. 2002, in contrast to the treatment text, figure 1 lists a dosage of 150 mg/m2) IV on day 1
• IL-2 - Aldesleukin (Proleukin) 4,500,000 units/m2 SC on days 3-5, 8-12
• Interferon alfa-2b (Intron-A) 3,000,000 units/m2 IM on days 3-5 of week 1, then 3 times per week on all later weeks

21-day cycles x 6 cycles

References

1. Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. link to original article contains verified protocol PubMed

Cisplatin (Platinol), Paclitaxel (Taxol), Dacarbazine (DTIC)

Regimen

• Cisplatin (Platinol) 20 mg/m2 IV on days 1-4
• Paclitaxel (Taxol) 100-120 mg/m2 IV on days 1 & 8
• Dacarbazine (DTIC) 800 mg/m2 IV on day 1

References

1. Papadopoulos NE, Bedikian A, Ring S, Kim KB, Hwu WJ, Gerber DL, Homsi J, Hwu P. Phase I/II Study of a Cisplatin-Taxol-Dacarbazine Regimen in Metastatic Melanoma. Am J Clin Oncol. 2009 Oct;32(5):509-14. link to original article contains protocol PubMed

CVD

CVD: Cisplatin, Vinblastine, Dacarbazine

Regimen #1, McDermott, et al. 2000 & Atkins, et al. 2008

• Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes on days 1-4, given first
• Vinblastine (Velban) 1.2 mg/m2 IV push on days 1-4, given second
• Dacarbazine (DTIC) 800 mg/m2 IV over 1 hour on day 1, given third

21-day cycles x up to 4 cycles

Supportive medications:

• Antiemetics and Dexamethasone (Decadron) premedication for chemotherapy

Regimen #2, Eton, et al. 2002

• Cisplatin (Platinol) 20 mg/m2 IV on days 1-4, 22-25
• Vinblastine (Velban) 2 mg/m2 IV on days 1-4, 22-25
• Dacarbazine (DTIC) 800 mg/m2 IV on days 1 & 22

6-week cycles x up to 5 cycles

References

1. McDermott DF, Mier JW, Lawrence DP, van den Brink MR, Clancy MA, Rubin KM, Atkins MB. A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin 2, and interferon alpha-2B in patients with metastatic melanoma. Clin Cancer Res. 2000 Jun;6(6):2201-8. link to original article contains verified protocol PubMed
2. Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002 Apr 15;20(8):2045-52. link to original article contains verified protocol PubMed content property of HemOnc.org
3. Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; Eastern Cooperative Oncology Group. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008 Dec 10;26(35):5748-54. Epub 2008 Nov 10. link to original article contains verified protocol PubMed

CVD, IL-2, IFN alfa-2b - sequential biochemotherapy

CVD: Cisplatin, Vinblastine, Dacarbazine

Example orders

• Example orders for CVD, IL-2, IFN alfa-2b - sequential biochemotherapy in melanoma

Regimen #1, McDermott, et al. 2000 & Atkins, et al. 2008

• Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes on days 1-4, given first
• Vinblastine (Velban) 1.2 mg/m2 IV push on days 1-4, given second
• Dacarbazine (DTIC) 800 mg/m2 IV over 1 hour on day 1, given third
• IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m2/day IV continuous infusion over 96 hours on days 1-4
• Interferon alfa-2b (Intron-A) 5,000,000 units/m2 SC on days 1-5, 8, 10, 12; days 8, 10, 12 given as outpatient doses

21-day cycles x up to 4 cycles

Supportive medications:

• All antihypertensive therapy discontinued at least 24 hours before each cycle
• Cephalexin (Keflex) or Ciprofloxacin (Cipro) 250 mg PO BID on days 1-14
• Filgrastim (Neupogen) 5 mcg/kg SC on days 7-16, or until ANC >10,000
• Ondansetron (Zofran) 32 mg IV daily
• Lorazepam (Ativan) 1 mg PO/IV every 6 hours
• Acetaminophen (Tylenol) 650 mg PO every 6 hours
• Ranitidine (Zantac) 150 mg PO every 12 hours
• Hydroxyzine (Atarax) 25-50 mg PO or Diphenhydramine (Benadryl) 25 mg PO every 6 hours for pruritis
• Meperidine (Demerol) 25-50 mg IV every 3 hours for chills and rigors
• Antidiarrheals & anxiolytics as needed

Regimen #2, Eton, et al. 2002

• Cisplatin (Platinol) 20 mg/m2 IV on days 1-4, 22-25
• Vinblastine (Velban) 1.5 mg/m2 IV on days 1-4, 22-25
• Dacarbazine (DTIC) 800 mg/m2 IV on days 1 & 22
• IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m2/day IV continuous infusion over 96 hours on days 5-8, 17-20, 26-29
• Interferon alfa-2b (Intron-A) 5,000,000 units/m2 SC on days 5-9, 17-21, 26-30

6-week cycles x up to 5 cycles

References

1. McDermott DF, Mier JW, Lawrence DP, van den Brink MR, Clancy MA, Rubin KM, Atkins MB. A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin 2, and interferon alpha-2B in patients with metastatic melanoma. Clin Cancer Res. 2000 Jun;6(6):2201-8. link to original article contains verified protocol PubMed
2. Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002 Apr 15;20(8):2045-52. link to original article contains verified protocol PubMed
3. Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; Eastern Cooperative Oncology Group. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008 Dec 10;26(35):5748-54. Epub 2008 Nov 10. link to original article contains verified protocol PubMed

Dabrafenib (Tafinlar)

Regimen, Long, et al. 2012 (BREAK-MB); Flaherty, et al. 2012; Hauschild, et al. 2012

• Dabrafenib (Tafinlar) 150 mg PO BID

given until progression of disease

References

1. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25. link to original article contains verified protocol PubMed
2. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Nov;13(11):1087-95. doi: 10.1016/S1470-2045(12)70431-X. Epub 2012 Oct 8. link to original article contains verified protocol PubMed
3. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov;367(18):1694-703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29. link to original article contains verified protocol PubMed

Dabrafenib & Trametinib

Regimen, Flaherty, et al. 2012

• Dabrafenib (Tafinlar) 150 mg PO BID
• Trametinib (Mekinist) 2 mg PO once per day

References

1. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov;367(18):1694-703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29. link to original article contains verified protocol PubMed

Dacarbazine (DTIC)

Regimen #1, Robert, et al. 2011

• Dacarbazine (DTIC) 850 mg/m2 IV on day 1

21-day cycles x 8 cycles

Regimen #2, Chapman, et al. 2011; Hauschild, et al. 2012; Flaherty, et al. 2012

• Dacarbazine (DTIC) 1000 mg/m2 IV on day 1

21-day cycles, given until progression of disease or unacceptable toxicity

Regimen #3, Middleton, et al. 2000

• Dacarbazine (DTIC) 250 mg/m2 IV over 30 minutes on days 1-5

21-day cycles, given until progression of disease or unacceptable toxicity

References

1. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. link to original article contains verified protocol PubMed
2. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. Epub 2011 Jun 5. link to original article contains verified protocol PubMed
3. Robert C, Thomas L, Bondarenko I, O'Day S, M D JW, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains verified protocol PubMed
4. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25. link to original article contains verified protocol PubMed
5. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. doi: 10.1056/NEJMoa1203421. Epub 2012 Jun 4. link to original article contains verified protocol PubMed

Docetaxel (Taxotere)

Regimen, Aamdal, et al. 1994

• Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1

21-day cycles

Supportive medications:

• "No prophylactic treatment with steroids or antihistamines was given."

References

1. Aamdal S, Wolff I, Kaplan S, Paridaens R, Kerger J, Schachter J, Wanders J, Franklin HR, Verweij J. Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group. Eur J Cancer. 1994;30A(8):1061-4. contains protocol PubMed

High-dose (HD) IL-2

Example orders

• Example orders for High-dose (HD) IL-2 in melanoma

Regimen, Atkins, et al. 1999

• IL-2 - Aldesleukin (Proleukin) 600,000 or 720,000 units/kg IV every 8 hours x up to 14 doses per week, on days 1-5
  • After a 6-9 day rest period, another 14 doses per week given over 5 days is given as described above

6-12 weeks per cycle x up to 5 cycles

Supportive medications:

• Included Acetaminophen (Tylenol), Indomethacin (Indocin), Meperidine (Demerol), Ranitidine (Zantac), Cimetidine (Tagamet), Hydroxyzine (Atarax), Diphenhydramine (Benadryl), dopamine, phenylephrine, antidiarrheals, antiemetics, anxiolytics, diuretics, and, if needed, antibiotics.

References

1. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. link to original article contains verified protocol PubMed
2. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4. PubMed

IL-2 maintenance biotherapy

Regimen

Low-dose cycles 1, 4, 7, 9, 11:

• IL-2 - Aldesleukin (Proleukin) 1,000,000 units/m2 SC every Monday-Friday on days 1-28
• Sargramostim (Leukine) 125 mcg/m2 SC on days 1-14

28-day cycles x a total of 12 cycles after being combined with the pulse cycles below

Pulse cycles 2, 3, 5, 6, 8, 10, 12:

• IL-2 - Aldesleukin (Proleukin) 18,000,000 units/m2 IV continuous infusion over 6 hours, then 18,000,000 units/m2 IV continuous infusion over 12 hours, then 18,000,000 units/m2 IV continuous infusion over 24 hours on days 1-2
  • Then as an outpatient: IL-2 - Aldesleukin (Proleukin) 1,000,000 units/m2 SC every Monday-Friday on days 3-28
• Sargramostim (Leukine) 125 mcg/m2 SC on days 3-17 (note: this was possibly a typo in the regimen since shifting the schedule 2 days forward would be days 3-16)

28-day cycles x a total of 12 cycles after being combined with the low dose cycles above

Supportive medications:

• Ondansetron (Zofran) 32 mg IV or Granisetron (Kytril) 2 mg IV daily
• Omeprazole (Prilosec) 20 mg PO QPM
• Acetaminophen (Tylenol) 650 mg PO every 4 hours, starting prior to IL-2 and continuing on days 1-2
• Meperidine (Demerol) 25 mg IV every 6 hours as needed for chills and rigors

References

1. O'Day SJ, Boasberg PD, Piro L, Kristedja TS, Wang HJ, Martin M, Deck R, Ames P, Shinn K, Kim H, Fournier P, Gammon G. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res. 2002 Sep;8(9):2775-81. link to original article contains verified protocol PubMed

Ipilimumab (Yervoy)

Example orders

• Example orders for Ipilimumab (Yervoy) in melanoma

Regimen #1, Hodi, et al. 2010

• Ipilimumab (Yervoy) 3 mg/kg IV on day 1

21-day cycles x 4 cycles

Regimen #2, Wolchok, et al. 2010

• Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes on day 1
  • Lower doses including 3 mg/kg (the FDA approved dose) were investigated, but the 10 mg/kg dose was recommended in this study

21-day cycles x 4 cycles

Regimen #3, O'Day, et al. 2010

Induction phase:

• Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes on day 1

21-day cycles x 4 cycles

Maintenance phase:

• Ipilimumab (Yervoy) 10 mg/kg IV over 90 minutes on day 1

12-week cycles, given until progression of disease or unacceptable toxicity; starts 12 weeks after completion of induction phase

References

1. Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T Jr, Grob JJ, Chesney J, Chin K, Chen K, Hoos A, O'Day SJ, Lebbé C. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010 Feb;11(2):155-64. Epub 2009 Dec 8. link to original article contains verified protocol PubMed
2. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. Epub 2010 Jun 5. link to original article contains verified protocol PubMed
3. O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, Queirolo P, Lundgren L, Mikhailov S, Roman L, Verschraegen C, Humphrey R, Ibrahim R, de Pril V, Hoos A, Wolchok JD. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010 Aug;21(8):1712-7. Epub 2010 Feb 10. link to original article contains verified protocol PubMed

Ipilimumab (Yervoy) & Dacarbazine (DTIC)

Regimen

Induction phase:

• Ipilimumab (Yervoy) 10 mg/kg IV on day 1
• Dacarbazine (DTIC) 850 mg/m2 IV on day 1

21-day cycles x 4 cycles, then

• Dacarbazine (DTIC) 850 mg/m2 IV on day 1

21-day cycles x 4 cycles; if patient has stable disease or objective response, proceed to maintenance phase

Maintenance phase:

• Ipilimumab (Yervoy) 10 mg/kg IV on day 1

12-week cycles, given until progression of disease or unacceptable toxicity

References

1. Robert C, Thomas L, Bondarenko I, O'Day S, M D JW, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. Epub 2011 Jun 5. link to original article contains verified protocol PubMed

Paclitaxel (Taxol)

Regimen #1, Flaherty, et al. 2012

This was a therapy option for patients in the control arm of Flaherty, et al. 2012.

• Paclitaxel (Taxol) 175 mg/m2 IV once on day 1

21-day cycles

Regimen #2, O'Day, et al. 2013 (SYMMETRY)

This was the control arm in O'Day, et al. 2013, which was a negative study.

• Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15

28-day cycles, given until progression of disease or unacceptable toxicity

References

1. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. doi: 10.1056/NEJMoa1203421. Epub 2012 Jun 4. link to original article contains verified protocol PubMed
2. O'Day SJ, Eggermont AM, Chiarion-Sileni V, Kefford R, Grob JJ, Mortier L, Robert C, Schachter J, Testori A, Mackiewicz J, Friedlander P, Garbe C, Ugurel S, Collichio F, Guo W, Lufkin J, Bahcall S, Vukovic V, Hauschild A. Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. J Clin Oncol. 2013 Mar 20;31(9):1211-8. doi: 10.1200/JCO.2012.44.5585. Epub 2013 Feb 11. link to original article contains verified protocol PubMed

Temozolomide (Temodar)

Regimen

• Temozolomide (Temodar) 200 mg/m2 PO on days 1-5, taken while fasting

28-day cycles, given until progression of disease or unacceptable toxicity

References

1. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000 Jan;18(1):158-66. link to original article contains verified protocol PubMed

Trametinib (Mekinist)

Regimen, Flaherty, et al. 2012 (METRIC); Falchook, et al. 2012; Kim, et al. 2013

• Trametinib (Mekinist) 2 mg PO once per day

References

1. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D; METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14. doi: 10.1056/NEJMoa1203421. Epub 2012 Jun 4. link to original article contains verified protocol PubMed
2. Falchook GS, Lewis KD, Infante JR, Gordon MS, Vogelzang NJ, DeMarini DJ, Sun P, Moy C, Szabo SA, Roadcap LT, Peddareddigari VG, Lebowitz PF, Le NT, Burris HA 3rd, Messersmith WA, O'Dwyer PJ, Kim KB, Flaherty K, Bendell JC, Gonzalez R, Kurzrock R, Fecher LA. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012 Aug;13(8):782-9. doi: 10.1016/S1470-2045(12)70269-3. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
3. Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013 Feb 1;31(4):482-9. doi: 10.1200/JCO.2012.43.5966. Epub 2012 Dec 17. link to original article contains verified protocol PubMed

Vemurafenib (Zelboraf)

Regimen

• Vemurafenib (Zelboraf) 960 mg PO BID

given until progression of disease or unacceptable toxicity

References

1. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. Epub 2011 Jun 5. link to original article contains verified protocol PubMed