High Dose Interluekin-2 followed by low-dose metronomic temozolomide (TMZ) to induce a complete immune Response.Melanoma ..Jim Breitfeller

High Dose Interluekin-2 followed by low-dose metronomic temozolomide (TMZ) to induce a complete immune Response

Background
CD4+CD25+ regulatory T cells (Treg), which constitute about 2–3% of CD4+ human T cells, are the main contributors to the maintenance of immune tolerance. Cancer patients, including Melanoma patients bear increased number of circulating and tumor infiltrating Treg that exert functional inhibition on tumor-specific T cells.

Temozolomide (sometimes referred to as TMZ) is an imidazotetrazine derivative of the alkylating agent dacarbazine.

Immunological factors relating to the antitumor effect of temozolomide ... appeared to suppress the frequency of CD4(+) CD25(+) regulatory T cells (Treg).
So base on the research, if activation occurs (mmune activation induced by the HD IL-2) IL-2 being a growth factor for the T-cells, will help fuel their expansion. Since the Tregs are a subset of the CD4+ T-cells, they too will proliferate.

By adding TMZ to the protocol, it suppresses the Treg function and shifts the balance tolerance toward activation of an immune response.

See the abstract at the ASCO Symposium 2010 "Ability of unsuccessful high-dose IL-2 therapy followed immediately by low-dose metronomic temozolomide to induce complete and near-complete remissions in metastatic melanoma."


Source:http://www.abstract.asco.org/AbstView_74_41534.html







“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”

~Charles Darwin~

Take Care,
Jimmy B

The Top 5 Most Promising Upcoming Drugs for Melanoma..Jim Breitfeller

New Phase III Clinical Trials for the Treatment of Melanoma
From Timothy DiChiara, Ph.D., for About.com
Created: May 21, 2009

About.com Health's Disease and Condition content is reviewed by the Medical Review Board


Treatment of advanced (stage III and IV) melanoma is in desperate need of some good news. Although the incidence of melanoma is increasing by a whopping 3 to 5% per year in the United States, current therapies don't significantly increase survival in most patients and no new first-line medicines have been approved in over 10 years.
Clinical trials are the best hope for a long-lasting reduction or elimination of metastatic melanoma (called a "durable response" or "complete response" by doctors). The US National Institutes of Health lists 27 late-stage (phase III) clinical trials currently recruiting patients with melanoma. Many of the trials are testing new combinations of existing drugs, new ways to administer them, or new surgical procedures, but some are investigating brand new drugs. The most promising are the following:

Allovectin-7 - This novel gene therapy is injected directly into the tumors of patients with stage III or IV disease, which then alerts the body's own immune system to attack the tumor. Earlier trials of Allovectin alone showed that tumors in 4% to 9% of patients responded to the therapy. The new trial is comparing Allovectin-7 to the standard chemotherapy treatment, either dacarbazine or temzolomide. Made by Vical. Find out if you may qualify for the AIMM trial of Allovectin-7.

oblimersen (Genasense) - Genasense is a unique inhibitor of Bcl-2, a protein made by cancer cells that is thought to block chemotherapy-induced cell death (called "apoptosis"). So by reducing the amount of Bcl-2 in cancer cells, Genasense may enhance the effectiveness of current anticancer treatment. Previous studies demonstrated that Genasense combined with the chemotherapy drug dacarbazine tripled response rate and significantly increased overall survival compared to dacarbazine alone. Made by Genta. Find out more about the AGENDA trial of oblimersen.

MVax - MVax is a melanoma vaccine prepared from the patient's own cancer cells. Several studies have shown that MVax followed by interleukin-2 can lead to a complete response in up to 13% of patients, double that of interleukin-2 alone. MVax is also effective in patients with stage III melanoma when given post-surgery: it doubled the 5-year survival rate compared to surgery alone. Made by AVAX Technologies. Find out more about the MVALDI trial for MVax.

ipilimumab (MDX-010, MDX-101, or BMS-734016) - Ipilimumab is an antibody that activates the body's immune system to fight melanoma by inhibiting the CTLA-4 molecule. Three previous phase II clinical trials have shown that treatment with ipilimumab results in a one-year survival rate of 47% to 51% for people with stage III or IV melanoma, which is almost double the average. The current trial is comparing ipilimumab to a dummy treatment (placebo) in patients with stage III melanoma who have already undergone surgery. Made by Medarex and Bristol-Myers Squibb. Find out more about the EORTC 18071 trial for ipilimumab.

OncoVEXGM-CSF - OncoVEXGM-CSF is a vaccine that works by spreading within tumors and causing the death of cancer cells while stimulating the immune system to destroy metastatic tumors. Previous results from 50 patients with inoperable stage IIIc/IV melanoma demonstrated that 28% of patients responded, including 12% with a complete response. The new trial is enrolling patients with previously treated but inoperable stage IIIb, IIIc or IV melanoma and is designed to compare OncoVEXGM-CSF to a naturally-occurring substance in the body called a "granulocyte monocyte colony stimulating factor" (GM-CSF), which increases white blood cells. Made by BioVex. Find out more about the trial for OncoVEXGM-CSF.

Why Participate in Clinical Trials

Those who take part in clinical trials get access to the latest treatments that are often not available anywhere else. These treatments may be better than the standard of care and may offer the only hope for those with advanced disease. Simply put, participation in clinical trials by patients like you is the only way research will advance toward an eventual cure for melanoma.

Talk about the possibilities with your doctor!

Source:

ClinicalTrials.gov. US National Institutes of Health. 10 February 2009.

Take Care,

Jimmy B

You have questions for Me? Why DTIC & PaTrin-2?..Melanoma..Jim Breitfeller

Remember I went to United Kingdom virtually to scour the research papers Last year?

Introduction:

"Temozolomide is an alkylating agent that mediates its cytotoxic effect by forming O6-methylguanine (O6-meG) DNA adducts, which during DNA replication pair preferentially with thymidine. These O6-meG:T mispairs
can result in a G-to-A point mutation during a subsequent round of DNA replication but are also substrates for the postreplication mismatch repair pathway, which after a further round of DNA replication leads to apoptosis (1). O6-meG DNA adducts can be repaired by the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT), which removes adducts from the O6 position of guanine by accepting them onto a cysteine residue within its active site. Furthermore, fibroblasts and
bone marrow cells of MGMT knockout mice are significantly more sensitive to the toxic effects of temozolomide than those from MGMT wild-type mice (2).

The protective role of MGMT against the cytotoxic effect of temozolomide has been shown in human cell lines (3) and human xenograft models (4).

MGMT can be inactivated by free guanine base derivatives that have alkyl groups at the O6 position, which act as ‘‘pseudosubstrates.’’ O6-benzylguanine (5) and O6-(4-bromothenyl) guanine (PaTrin-2, Patrin, Lomeguatrib, KuDOS, Cambridge, United Kingdom; ref. 6) have been identified as the most promising MGMT inactivators. Compared with temozolomide used as a single agent, the combination PaTrin-2-temozolomide has been shown to significantly increase tumor growth inhibition in human melanoma
xenografts (7)."


Source:http://mct.aacrjournals.org/content/3/10/1215.full.pdf

Sensitization of a human ovarian cancer cell line totemozolomide by simultaneous attenuation of the Bcl-2 antiapoptotic protein and DNA repair by O6-alkylguanine-DNA alkyltransferase


That is why, and I forgot to tell you that I did a trial with Patrin and DTIC Prior to CTLA-4 Blockage Therapy.

Take Care

Have a Great Weekend!!!!!

Jimmy B

Genomic and Molecular Profiling Predicts Response toTemozolomide in Melanoma Jim Breitfeller

Temozolomide (brand names Temodar and Temodal Schering-Plough Corporation) is an oral alkylating agent which can be used for the treatment of Grade IV astrocytoma -- an aggressive brain tumor, also known as glioblastoma multiforme. The agent was developed by Malcolm Stevens and his team at Aston University in Birmingham, UK.[1] A derivative of imidazotetrazine, temozolomide is the prodrug of MTIC (3-methyl-(triazen-1-yl)imidazole-4-carboxamide). It has been available in the US since August 1999, and in other countries since the early 2000s.

A 2005 study has showed that its benefits depend on the epigenetic silencing of the MGMT gene; MGMT encodes a protein that removes alkyl groups from the O-6 position of guanine

Source: Wikipedia

When I came across this Research paper "Genomic and Molecular Profiling Predicts Response to Temozolomide in Melanoma", I contacted Dr. Christina Augustine.

Christina Augustine, PhD
Assistant Professor
Department of Surgery
Duke University Medical Center
Box 3118 Med Ctr
Durham NC 27710
(919) 286.0411 x 5191
christi.augustine@duke.edu


Temozolomide is the only chemo drug of it's kind to cross over the Brain/blood barrier. If you could predict which patients will
respond to Temozolomide, then you could help those with the right genotype.

"With the increasing incidence of melanoma and the historicallypoor
response rates to traditional chemotherapy, it is important
to develop tools that can be used prospectively to
characterize apatient’s tumor with regard to chemoresistance
pathways.The findings in this study show striking differences
in terms of DNA repair pathway efficiency and temozolomide
response across a broad sampling of melanoma cell lines and
that, in melanoma, resistance to temozolomide is conferred
largely by the activity of the DNA repair enzyme O6-methylguanine-
DNA methyltransferase (MGMT). Our results suggest that MGMT expression could potentially be a useful tool for personalizing treatment strategies in melanoma patients by identifying those patients most likely to respond to temozolomide and those patients for whom combination therapy
or alternative chemotherapeutic reagentsmight be desirable."

I will post the paper on Melanoma Missionary

Jimmy B

Tremelimumab dose selected for further testing due to favorable Safety, Tumor Response in Melanoma ..JimBreitfeller

Posted February 25, 2009
Tremelimumab given at two dosing regimens afforded durable tumor responses in patients with metastatic melanoma, according to data from a phase-1/2 trial.

Researchers conducted a phase-1/2 trial to assess the safety of tremelimumab in multiple doses and to examine the efficacy of the agent and the appropriate dosing regimen.

To determine the recommended phase-2 dose, phase-1 IV infusions of tremelimumab at 3 mg/kg, 6 mg/kg or 10 mg/kg were given to 28 patients with metastatic melanoma for up to one year. During phase 2, 89 patients received tremelimumab 10 mg/kg once each month or 15 mg/kg every three months.

The researchers reported no dose-limiting toxicity during phase 1. Eighty-four patients were assessable for response during phase 2 at which time 10% reached objective antitumor responses; one complete response and three partial responses in each dosing regimen comprised the best overall objective response.

Most responses ranged from three to 30 or more months and the most common adverse events were diarrhea, rash and pruritus. Grade-3/4 adverse events had a frequency of 13% in the 15 mg/kg arm and 27% in the 10 mg/kg arm. Frequency of serious adverse events was 9% in the 15 mg/kg arm vs. 23% in the 10 mg/kg arm.

“Both phase-2 regimens generated durable tumor responses,” the researchers wrote. “Based on its more favorable safety profile, 15 mg/kg every three months was selected for further clinical testing.” – by Stacey L. Adams

J Clin Oncol. 2009;doi:10.1200/JCO.2008.19.2435

The phase-3 data from ASCO, in terms of survival, show that tremelimumab given at 15 mg/kg every three months is a bit better than for the control arm of dacarbazine (DTIC-Dome, Bayer Healthcare) or temozolomide (Temodar, Schering). But, the difference was not statistically significant; median survival was a month better, but this is less than we were looking for. So we must ask: What is the real difference between clinical responses to tremelimumab and dacarbazine? In the recently published study of Camacho et al reporting the phase-1/2 experience and the larger phase-2 multicenter study I presented to ESMO and ASCO in 2008, as well as in the phase-3 experience that Toni Ribas presented to ASCO, there are very profound differences between the type of responses seen with anti-CTLA4-blocking antibodies and with conventional chemotherapy. About 8% to 10% of patients with melanoma have objective response to this modality and the majority of these have a very durable response. For example, in the phase-2 trial results I reported to ASCO and ESMO, 15 of 16 patients who had objective response with tremelimumab response was durable past six months -a very different pattern than we see for dacarbazine and temozolomide. Tremelimumab and ipilimumab are active agents in a fraction that is roughly the same as interleukin-2, interferon-alfa, and dacarbazine or temozolomide. In the largest trial of temozolomide ever conducted - results recently presented at ESMO by Patel et al.- response rates were 10% for dacarbazine vs. 14.8% for temozolomide, but there was no difference in the overall survival or the progression-free interval between these regimens. Dacarbazine and temozolomide responses do not seem to confer survival benefit in part because these responses are rarely durable. The 10% of patients who responded to the anti-CTLA4-blocking antibodies exhibit characteristically and qualitatively different kinds of responses in metastatic stage-4 disease.

When looking at the difference between the phase-3 and phase-1/2 trials, the phase-1/2 results clearly show that for tremelimumab there are very durable, high-quality responses--and the same can be said for ipilimumab. But the problem is, when you conduct a conventional trial in advanced metastatic melanoma to look at median survival, the survival median provides a different readout than the readout of durable responses. The quality of responses to tremelimumab and ipilimumab are still worthy of pursuit. The fact that the phase-3 trial of tremelimumab shows a little better outcome than dacarbazine in terms of median survival does not reflect these high-quality responses that go out well past six months, and will take different follow-up to document. So that is what is going on now: the long-term follow-up of those patients to make a qualitative assessment of the kind of response that they exhibited is really what we need.

Looking at the data from the phase-3 presentation by Ribas, the one thing that may have weighed differentially in favor of tremelimumab in the forest plot of the data was higher lactate dehydrogenase (LDH). This is curious when you think about it. It may or may not be real, but if patients who have higher LDH (perhaps worse disease) benefit more from tremelimumab than from dacarbazine or temozolomide, the study was designed in a way that may have disfavored the anti-CTLA4-blocking antibody. The protocol excluded those people who had higher than twofold elevated LDH – so, by the design of the trial, curiously the outcome may have been slanted in favor of temozolomide or dacarbazine.

Finally, it remains to test the role of anti-CTLA4 blocking antibodies in the disease setting where we have found the greatest relative benefit for other immunotherapy, such as IFN alpha. The adjuvant exploration of anti-CTLA4 blocking antibodies may show even greater relative benefit and warrants phase-3 study in relationto IFN alpha.

– John Kirkwood, MD

Source:http://www.hemonctoday.com/article.aspx?rid=36459

Tremelimumab dose selected for further testing due to favorable safety, tumor response in melanoma


Jimmy B

Genomic and Molecular Profiling Predicts Response to Temozolomide in Melanoma!! Jim Breitfeller

Christina K. Augustine1,5, Jin Soo Yoo1, Anil Potti2,4, Yasunori Yoshimoto1,5, Patricia A. Zipfel1,5, Henry S. Friedman1, Joseph R. Nevins3,4, Francis Ali-Osman1 and Douglas S. Tyler1,5

Authors' Affiliations: Departments of 1 Surgery, 2 Medicine, and 3 Molecular Genetics and Microbiology, and 4 Duke Institute for Genome Sciences and Policy, Duke University Medical Center and 5 Durham VA Medical Center, Durham, North Carolina

Requests for reprints: Christina K. Augustine, Box 3118, Medical Center, Duke University Medical Center, Durham, NC 27710. Phone: 919-286-0411, ext. 5191; Fax: 919-684-6044; E-mail: Christi.augustine@duke.edu.

Purpose: Despite objective response rates of only 13%, temozolomide remains one of the most effective single chemotherapy agents against metastatic melanoma, second only to dacarbazine, the current standard of care for systemic treatment of melanoma. The goal of this study was to identify molecular and/or genetic markers that correlate with, and could be used to predict, response to temozolomide-based treatment regimens and that reflect the intrinsic properties of a patient's tumor.

Experimental Design: Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O6-methylguanine-DNA methyltransferase (MGMT) activity, MGMT protein expression and promoter methylation status, and mismatch repair proficiency, as well as the expression profile of 38,000 genes using an oligonucleotide-based microarray platform.

Results: The results showed a broad spectrum of temozolomide sensitivity across the panel of cell lines, with IC50 values ranging from 100 µmol/L to 1 mmol/L. There was a significant correlation between measured temozolomide sensitivity and a gene expression signature–derived prediction of temozolomide sensitivity (P < 0.005). Notably, MGMT alone showed a significant correlation with temozolomide sensitivity (MGMT activity, P < 0.0001; MGMT expression, P 0.0001). The promoter methylation status of the MGMT gene, however, was not consistent with MGMT gene expression or temozolomide sensitivity. Conclusions: These results show that melanoma resistance to temozolomide is conferred predominantly by MGMT activity and suggest that MGMT expression could potentially be a useful tool for predicting the response of melanoma patients to temozolomide therapy. Source: Clinical Cancer Research 15, 502-510, January 15, 2009. doi: 10.1158/1078-0432.CCR-08-1916 http://clincancerres.aacrjournals.org/cgi/content/short/15/2/502

Trends in Melanoma -----Sanjiv. S. Aqarwala, MD January 29, 2009 Jim Breitfeller

Trends in Melanoma

Sanjiv. S. Aqarwala, MD
January 29, 2009

Sunbelt Melanoma Trial: Final Results
The Sunbelt Melanoma Trial, a multicenter prospective randomized trial, assessed high-dose interferon alfa-2b (IFN) or completion lymph node dissection (CLND) in the treatment of melanoma staged by sentinel lymph node (SLN) biopsy.

Eligible patients 18 to 70 years of age who had primary melanoma with Breslow thickness Ž1.0 mm underwent SLN biopsy and were assigned to one of two protocols. In protocol A, patients with a single positive lymph node after SLN biopsy and CLND were randomized to observation vs high-dose IFN (20 MU/m2/day IV 2 4 weeks followed by 10 MU/m2 /three times per week SC 2 48 weeks). Protocol B included patients with negative SLN determined by standard histopathology and immunohistochemistry. To detect melanoma-specific mRNA, these patients underwent molecular staging of the SLN by RT-PCR. Patients with RT-PCR–positive SLN were randomized to observation vs CLND vs CLND plus IFN (20 MU/m2/day IV 2 4 weeks only).

Randomization was stratified for Breslow thickness and ulceration. The primary end points were disease-free survival (DFS) and overall survival (OS). Intent-to-treat (ITT) and efficacy analyses were performed by Kaplan-Meier and Cox proportional hazards models, and the Data Safety and Monitoring Committee (DSMC) approved the final analysis.

Patients were enrolled between June 24, 1997, and October 31, 2003; median follow-up was 64 months. In the protocol A ITT analysis, there were no significant differences in DFS (HR 0.82; 95% CI, 0.47-1.40; P=0.46) or OS (HR 1.07; CI 0.65-1.78; P=0.79) for patients randomized to IFN (n=112) vs observation (n=106). In protocol B, there were no significant differences in DFS or OS among patients randomized to CLND (n=192; DFS: HR 0.72; CI 0.42-1.23; P=0.23; OS: HR 0.94; CI 0.55-1.59; P=0.81) or CLND plus IFN (n=184; DFS: HR 0.90; CI 0.54-1.50; P=0.69; OS: HR 0.96; CI 0.56-1.63; P=0.88) vs observation (n=180). The efficacy analysis did not demonstrate significant differences in DFS or OS.

This study failed to demonstrate a benefit for adjuvant high-dose IFN for patients with a single positive SLN. In addition, there was no significant benefit to CLND or CLND plus IFN among patients with melanoma cells detected in the SLN by RT-PCR analysis.

Combination Thalidomide Plus Temozolomide in a Phase II Trial in Metastatic Malignant Melanoma (MMM): SWOG S0508
After response rates up to 32% were achieved in single-institution phase II studies of thalidomide plus temozolomide as combination therapy in MMM, some clinicians have used thalidomide plus temozolomide as a standard therapy. This large multicenter phase II trial evaluated the clinical efficacy of this
therapy and the immune modulatory effects of thalidomide when combined with temozolomide in patients with MMM.

Eligible patients had cutaneous MMM proven by biopsy, no active brain metastases, Zubrod PS 0-1, no more than 1 prior systemic therapy for melanoma (excluding thalidomide, temozolomide, or dacarbazine), and adequate organ function. Six-month progression-free survival (PFS) was the primary end point; per study design, if the 6-month PFS rate was 10%, the regimen would not be of interest; if PFS was Ž25%, further study would be warranted. Response rate, OS, toxicities, and assessment of the relationship between immunologic biomarkers and clinical outcomes were secondary end points.

Patients received thalidomide (200 mg/day escalated to 400 mg/day for patients younger than 70 years, or 100 mg/day escalated to 250 mg/day for patients 70 years of age or older) plus concomitant temozolomide (75 mg/m2/day 2 6 weeks with a 2-week rest between cycles). Anticoagulation agents were not required. Treatment was continued until toxicity became unacceptable or disease progressed.

Of the 64 patients enrolled, 2 were ineligible, and 2 refused treatment. The 6-month PFS was 15% (95% CI, 6%-24%), and 1-year OS was 36% (95% CI, 24%-49%). Fifty-one patients had measurable disease by RECIST and were evaluable for response. All responses were partial, at a rate of 14% (95% CI, 6%-26%). One treatment-related death occurred due to MI. Three grade 4 events occurred: one case each of PE, neutropenia, and CNS ischemia; fatigue was the most common of 21 grade 3 events. Immunologic biomarkers were obtained at baseline and at 5, 9, and 13 weeks, including PBMC as a percentage and as an absolute count of CD4+/CD25+/CD69+ and CD16+/CD56+ cells, and ELISPOT reactivity to a recall pool of antigens.

Thalidomide plus temozolomide has little additional clinically meaningful activity compared with temozolomide alone in MMM. In a meta-analysis of systemic therapy for MMM, thalidomide plus temozolomide compared poorly. This regimen should not be considered a standard treatment for MMM.
Clark J, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 9007

Unresectable Metastatic Melanoma: A Phase II Clinical Trial With a Second-Generation GM-CSF–
Encoding Oncolytic Herpesvirus
OncoVEX (GM-CSF) is a second-generation oncolytic herpes simplex virus that encodes granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase I trial, it was well tolerated in patients with several types of tumors, and antitumor effects were seen in both injected and uninjected tumors.
Patients eligible for this phase II trial had unresectable stage IIIc/IV melanoma with Ž1 injectable tumor (ultrasound allowed) and had failed prior therapy. Patients with clinically active brain, liver, or bone metastases were excluded. Fewer than 10 lesions were to be injected, and more than 1 lesion was to be left uninjected. The dosing schedule consisted of one injection of 4 mL of 106 plaque forming units (pfu)/mL split between target tumors, followed 3 weeks later by 24 injections of 108 pfu/mL every 2 weeks. The study was designed to assess single-arm monotherapy in up to 50 evaluable patients, and more than one RECIST response among the first 24 patients was required to continue the trial. Response rate was the primary end point; safety, response kinetics, and survival were secondary end points.

At the time of this report, the study had enrolled 40 patients, 31 of whom were evaluable. Patients had up to 18 injection cycles. By 2 months on therapy, injected tumors routinely responded, often with local complete response (CR); often, palliative benefit was also achieved. Systemic responses included: 3 patients with CR, 3 with partial response (PR), 4 with durable stable disease (SD), and 2 with mixed response (ŽPR of existing disease and ŽPR of lesions, which later became measurable); 2 patients had posttreatment objective responses. Patients with both stage IIIc and IV disease achieved systemic responses, including resolution of visceral disease. Systemic responses are delayed since injected tumor responses take up to 10 months to fully develop. All objective responses have been maintained to date at 4 to 23 months after the first dose, with those patients not achieving CR still on therapy. Side effects have been grade 1 flu-like symptoms.

Data show that 32% of patients achieved CR, PR, or durable SD. Other patients also experienced clinical benefit: 2 patients had response in tumors that were first noted during therapy; 2 patients responded after leaving the study due to progressive disease; additional patients experienced local palliative benefit in otherwise difficult-to-treat tumors. The rate and durability of response is considered impressive compared with other treatments for advanced melanoma, particularly in the second-line/salvage therapy setting, and further evaluation is therefore warranted.

Tremelimumab and Temozolomide or Dacarbazine: A Phase III, Open-Label, Randomized, Comparative Study in Patients With Advanced Melanoma
This phase III study compared OS achieved with tremelimumab, a fully human anticytotoxic T lymphocyte–associated antigen 4 monoclonal antibody, with OS achieved with standard, single-agent chemotherapy.
Eligible patients had unresectable stage IIIc/IV melanoma without brain metastasis, LDH below 2 2 ULN, and no prior systemic treatment for advanced melanoma. Patients were randomized 1:1 to either tremelimumab 15 mg/kg IV every 90 days, or physician's choice of temozolomide 200 mg/m2 po on days 1-5 every 28 days or dacarbazine 1000 mg/m2 IV every 21 days (chemotherapy arm). Primary end point was OS, and secondary end points included response, durable tumor response, 6-month PFS, and safety. Two equally spaced interim analyses were planned based on the group sequential design using the Lan-DeMets alpha and beta spending approach to an O'Brien-Fleming boundary.

Between March 2006 and July 2007, 655 patients enrolled, with 328 patients randomized to tremelimumab (324 treated) and 327 to chemotherapy (319 treated). Significant imbalances were not noted in age, sex, LDH, or disease stage (5% stage IIIc, 15% M1a, 22% M1b, 58% M1c). The most common treatment-related adverse events in the tremelimumab arm were diarrhea (43% overall, 14% grade 3/4), pruritus (25%), and rash (23%). Pituitary or adrenal gland toxicities occurred in 3% of patients, and thyroid toxicities in 4%. There were three treatment-related deaths in the tremelimumab arm but none in the chemotherapy arm.

The independent DSMC advised researchers to end the study on March 28, 2008, because the log-rank test-statistic (P=0.729) had crossed the O'Brien-Fleming futility boundary based on a protocol-specified second interim analysis that reported 340 deaths. The ITT median OS was 11.8 months (95% CI, 10.4-13.9) in the tremelimumab arm and 10.7 months (95% CI, 9.3-12.0) in the chemotherapy arm, with a HR (chemotherapy over tremelimumab) of 1.04 (95% CI, 0.84-1.28).

Tremelimumab as a single agent failed to demonstrate an improvement in OS as a first-line treatment in patients with metastatic melanoma when compared with standard chemotherapy. Analysis of the secondary end points may yield additional information.

Ribas A, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract LBA9011.