Ipilimumab (ipi, yervoy) is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that down regulates the immune system in melanoma patients. Alone, it has a response rate of 10-15%. But, has 4 year survival rates of 37-49%, and 3-10 year survival rates in 17-25% in melanoma patients. Given its potential, investigators have been examining drugs that can be safely combined with ipi, in ways that will improve response rate.
A phase IB study of ipilimumab with peginterferon alfa-2b for patients with unresectable stages IIIB/C/IV melanoma
Abstract 9098, Kudchadkar, Gibney, Corman, Merek, Weber, et al.
Ipi, at 3mg/kg every 3 weeks for 4 doses was given with concurrent peginterferon at 3mcg/kg weekly for up to 156 weeks. 31 patients. 2 complete responses, 9 partial responses, 3 with stable disease, and 12 with progressive disease in 26 patients evaluable for response so far. 5 patients have not yet completed the first cycle. Toxicities for peginterferon were dose-limiting with 7 patients requiring dose reduction (nausea, vomiting, leukopenia, dehydration, and hyponatremia). Conclusion: The combo had a 42.3% response rate.
Outcome with stereotactic radiosurgery and ipilimumab for malignant melanoma brain metastases.
Abstract 9076, Shoukat, Marcus, Rizzo, et al.
Patients with melanoma brain mets who underwent SRS between 1998-2012 (n=176) were compared to those who additionally received ipi (n-38). Median overall survival for the cohort was 9 vs 7 months in the non-ipi group. Patients in the ipi group had a median survival of 28 vs 7 months in the non-ipi group. No increased toxicity or need for repeated SRS in the ipi group. Conclusion: SRS with ipi appears safe and associated with an increase in overall survival in patients in melanoma brain mets.
Preliminary results from a phase 1/2 study of INCB024360 combined with ipi in patients with melanoma
Abstract 3010, Gibney, Hamid, Gangadhar, et al
Indoleamine2,3-dioxygenase 1 is a tryptophan-catabolizing enzyme that is over expressed in cancers and induces immune tolerance by suppressing T-cell responses. It has been well tolerated as monotherapy. This was an ongoing dose-escalation study of INCB024360 with ipi. 7 patients were enrolled at 300mg twice daily. 5 patients developed ALT elevations after 30-76 days on treatments and enrollment was stopped. ALT increases reversed with steroids and discontinuation of the drug. 6 of 7 patients had scans before discontinuation and all showed immune response stable disease. Enrollment was restarted at 25mg twice daily with 8 patients. 1 patient progressed with extensive liver mets. 6 of the 8 patients had tumor reduction by the first evaluation. Confirmed disease control rate was 75%. 3 patients had confirmed immune response partial response. A 50mg twice daily cohort is enrolling. Clinical trial info = NCT01604889. This study started enrolling in 2012, but as of postings in Feb and March 2014, it seems recruiting is ongoing. Locations appear to be available in CA, FL, PA, NC, and IL. It is ipi and drug vs ipi with placebo. Hopefully the lower doses of INCB024360 will not cause problems with elevated liver enzymes.
Phase 1 study of the BRAF inhibitor dabrafenib with or without the MEK inhibitor trametinib in combination with ipi for V600E/K mutation-positive unresectable or metastatic melanoma
Abstract 2511, Puzanov, Callahan, Linette, et al
Patients with Stage IIIC/IV BRAF V600E/K, melanoma with one prior treatment or less are eligible. 10 patients enrolled thus far. 4 had ipi and dabrafenib. 2 had dabrafenib only [thus far]. 4 had ipi/dabrafenib/trametinib. In the ipi + D group - no dose limiting toxicities were observed. Most common adverse events = chills, fatigue, hand-foot syndrome, fever, and rash. Of the 4 patients - 2 are ongoing and 2 had disease progression. Patients are currently being enrolled at this level. At the ipi/D/T level - 1 dose limiting toxicity (colitis associated with ipi occurred), most frequent adverse effect = fever, chills, arthralgia, insomnia, and rash. One patient had renal insufficiency that reversed rapidly. Of these 4 patients, 1 stopped due to the dose limiting colitis and 3 are ongoing. Clinical trial info - NCT01767454. Recruitment began in 2012, but was verified to be continuing as of April 2014. Participants must have the V600 mutation, measurable tumor, treated/stable brain mets, and NO prior ipi, anti-PD1, Brafi, or MEK. Patients will be given dabrafenib and ipi or dabrafenib + trametinib and ipi. Locations: San Fran, LA, Boston, St Louis, NY, Nashville, Houston.
Sending my love to the ratties - c
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