Clinical Trials Resource Center

Metastatic Melanoma

December 7, 2015

Exelixis has issued results of a phase III trial of Cotellic (cobimetinib) in patients with previously untreated resectable, locally advanced or metastatic melanoma carrying a BRAF V600E or V600K mutation, in combination with vemurafenib. In October, Exelixis announced the coBRIM trial met its OS secondary endpoint, demonstrating a statistically significant increase in OS for the combination of Cotellic and vemurafenib compared to vemurafenib monotherapy. The median OS was 22.3 months for the combination of Cotellic and vemurafenib v. 17.4 months for vemurafenib alone, corresponding to a 30% reduction in the rate of death for the combination as compared to vemurafenib alone (hazard ratio [HR]=0.70, 95% confidence interval [CI] 0.55-0.90, p=0.005). Ongoing study monitoring did not identify any new safety signals. On Nov. 10, the FDA approved Cotellic as a treatment for patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, in combination with vemurafenib. Cotellic was first approved in Switzerland in late August. The Cotellic approvals are based on data from coBRIM, the phase III pivotal trial conducted by Genentech in 495 patients with previously untreated unresectable, locally advanced or metastatic melanoma carrying a BRAF V600 mutation. Genentech sponsored the U.S. NDA and Roche sponsored the Swiss regulatory application. Roche also filed a Marketing Authorization Application (MAA) with the EMA in late 2014, and the Committee for Medicinal Products for Human Use issued a positive recommendation on the MAA in September of this year. Roche anticipates a decision from the European Commission by year-end.

July 13, 2015

Novartis issued results of a phase III study of with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) compared to Tafinlar monotherapy alone for BRAF V600E/K mutation-positive metastatic melanoma. COMBI-d is a pivotal, phase III, randomized, double-blinded study in patients with unresectable (stage IIIC) or metastatic (stage IV) BRAF V600E/K mutation-positive cutaneous melanoma. The study randomized 423 patients. The final OS analysis showed that the combination of Tafinlar and Mekinist achieved a statistically significant OS benefit compared to Tafinlar monotherapy (median of 25.1 months v. 18.7 months; Hazard Ratio [HR] 0.71 [95% Confidence Interval (CI), 0.55-0.92], p=0.011). A 33% reduction in the risk of progression or death was demonstrated with the combination therapy compared to monotherapy (median PFS of 11 months in the 211 patients receiving combination therapy v. 8.8 months in the 212 patients receiving monotherapy; HR 0.67 [95% CI, 0.53-0.84], p<0.001). The combination achieved ORR of 69% compared to 53% for monotherapy [difference=15% (95% CI, 6.0%-24.5%), p=0.001]. The median DoR for the 144 responders receiving combination therapy was 12.9 months [95% CI, 9.4-19.5] compared to 10.6 months in the 113 responders receiving monotherapy [95% CI, 9.1-13.8]. The safety results were consistent with the profile observed to date for the combination and consistent with the profile observed for Tafinlar monotherapy; no new safety concerns were observed. Completion of COMBI-d is a post-marketing requirement for the FDA’s accelerated approval for the combination in the U.S.

December 1, 2014

GlaxoSmithKline reported results of a phase III study of trametinib (Mekinist) and dabrafenib (Tafinlar) compared to vemurafenib monotherapy in previously untreated patients with BRAF V600E/K mutation- positive metastatic melanoma. This phase III, randomized (1:1), open-label study enrolled 704 patients globally. The study demonstrated a 31% decrease in the risk of death for patients treated with the trametinib and dabrafenib combination compared to vemurafenib (Hazard Ratio [HR] 0.69; 95% Confidence Interval [CI] 0.53, 0.89; two-sided P=0.005). Median OS for the vemurafenib arm was 17.2 months; median OS for the combination arm had not been reached. At 12 months, the rate of OS was 72% for the combination arm and 65% for the vemurafenib arm. Treatment with the combination increased median progressionfree survival to 11.4 months compared to 7.3 months for the vemurafenib arm. Overall, treatment with the combination resulted in a 44% reduction in risk of disease progression or death (HR, 0.56; 95% CI 0.46, 0.69; two-sided P-value <0.001) compared to vemurafenib. The objective response rate was 64% (95% CI 59.1%, 69.4%) for the combination and 51% (95% CI 46.1%, 56.8%) for vemurafenib (P<0.001); the median duration of response was 13.8 months (95% CI 11.0, not reached) v. 7.5 months (95% CI 7.3, 9.3), respectively. Additionally, 13% of patients treated with the combination achieved a complete response, compared to 8% of patients in the vemurafenib arm.

August 5, 2013

OncoSec Medical released results of a phase II study of DNA IL-12 and electroporation for the treatment of advanced melanoma. The 24-week, single-arm, open-label, multi-center study enrolled 25 patients with stage III or IV cutaneous and in-transit metastatic melanoma. One treatment cycle consisted of three treatments applied to up to four lesions on days one, five and eight with a maximum dose of 1.5mg DNA IL-12 per treatment cycle. At day 90 following treatment, it was demonstrated that there was a significant decrease in circulating “exhausted” CD8/PD-1+ (p=0.0017) and CD8/CD69+ (p=0.008) T-cells. PD-1 is expressed in activated exhausted T cells, and blocking PD-1 is an emerging treatment modality for multiple cancers including melanoma. In addition, an increase in NK cell frequency and activation was also observed from baseline. It was also demonstrated that antigen-specific T-cell responses to melanoma were increased while other antibody responses were modulated and appeared to narrow over time. These data confirm the systemic effects of DNA IL-12 administered locally with electroporation. At 12 months, patients are moved to the follow-up phase of the study and will be followed for up to five years for safety.

November 28, 2012

OncoSec Medical issued preliminary results from a phase II trial of ImmunoPulse for the treatment of metastatic melanoma. This single-arm, open-label and multi-center study has enrolled 13 patients with stage III or IV cutaneous and in-transit metastatic melanoma, of 25 patients expected. Subjects received a maximum dose of 1.5mg of DNA IL-12 via ImmunoPulse on days one, five and eight, applied to up to four lesions. Subjects also received electroporation treatment. Results suggested that ImmunoPulse is able to induce regression or stabilization of distant untreated metastases following a single cycle of treatment. Ninety-five percent of treated lesions demonstrated response at day 39 (5% progressive disease, 14% stable disease (SD), 42% partial response (PR), 39% complete response (CR)). All treated lesions at day 90 (5% SD, 50% PR, 45% CR), and at day 180 (33% PR, 67% CR) demonstrated a response. At day 180, two subjects were evaluable for the primary endpoint of objective overall response (ORR). One patient has a confirmed stable disease, and the second patient has a confirmed complete response of all treated and untreated lesions. ImmunoPulse and DNA IL-12 were well tolerated. The most frequent adverse events were generally limited to transient pain related to electroporation treatment. OncoSec Medical will continue the phase II study, which it expects to be completed by the end of 2012.

November 5, 2012

Specialised Therapeutics Australia issued results from a phase III comparative trial of Abraxane versus standard chemotherapy for the treatment of metastatic melanoma. This randomized, open-label, international study enrolled 529 chemotherapy-naïve patients. Subjects received either Abraxane 150mg/m2 weekly for three out of four weeks, or dacarbazine 1000mg/m2 every three weeks. The Abraxane arm showed statistically significant improvement in progression-free survival (PFS) (4.8 months) compared to patients receiving dacarbazine chemotherapy (2.5 months) (HR:0.792; 95.1% CI: 0.631, 0.992; P=0.044). Data shows overall survival trends in favor of the Abraxane arm (12.8 months) compared to dacarbazine (10.7 months) (HR:0.831; 99.9% CI: 0.578, 1.196; P=0.094). The drug was well tolerated. The most frequent adverse events were neuropathy and neutropenia. Specialised Therapeutics Australia hopes to have Abraxane approved by the Therapeutic Goods Administration in Australia by 2014.

July 18, 2011

Cytavis reported results from a phase II trial of Aviscumine (CY503) for the treatment of melanoma. This open label trial enrolled 31 subjects with Stage IV unresectable metastatic melanoma after antineoplastic treatment failure. The subjects received subcutaneous injections of Aviscumine 350 ng twice weekly. The progression-free survival rate after three months was 32%, the one year-survival rate was 45% and median overall survival time (mOS) was 11 months. This compares favorably to standard therapy, Dacarbazine, which has a usual one-year-survival rate of 30% and mOS between six and eight months.

January 24, 2011

Plexxikon reported positive interim results from a phase III trial of PLX4032 for melanoma. This global, randomized, open-label, controlled trial, BRIM3, enrolled 675 subjects with previously untreated mutation-positive metastatic melanoma. The subjects were randomized to receive either: PLX4032 960 mg orally twice daily, or dacarbazine 1000 mg/m2 intravenously every three week until disease progression. Interim data showed that the co-primary endpoints, overall survival and progression free survival, were improved with the PLX4032 treatment arm when compared with the dacarbazine treatment arm. The safety profile was consistent with the previous PLX4032 studies.

November 15, 2010

Plexxikon issued positive preliminary results from a phase II trial of PLX4032 for the treatment of metastatic melanoma. This open label, single-arm trial. BRIM-2, enrolled 132 subjects with previously treated metastatic melanoma and the BRAF V600 mutation. The subjects received PLX4032 orally at a dose of 960 mg twice-daily. Data show a confirmed response rate of 52%, including three confirmed complete responses and 66 confirmed partial responses (tumor shrinkage of at least 30 percent) In addition, 39 subjects had stable disease. The median progression-free survival (PFS) was 6.2 months, compared to historical PFS of less than two months. The median duration of response was 6.8 months. Median overall survival has not yet been reached.

Provectus reported positive preliminary results from a phase II trial of PV-10, an injectable formulation of Rose Bengal for the treatment of metastatic melanoma. This open label trial enrolled 80 subjects with Stage III/IV melanoma in the US and Australia. Provecta was injected in up to 20 tumors and response was to be observed for one year. The primary endpoint was objective response rate (ORR). An ORR was observed in 49% of subjects, and 71% achieved locoregional disease control (stable disease or better) in their injected lesions. A mean Progression Free Survival of 11.7 months was observed among subjects achieving an ORR. A Complete Response of PV-10 injected lesions was achieved in 24% of subjects, Partial Response in 25% and Stable Disease in 18% of subjects, with 23% of subjects experiencing disease progression. The mean Progression Free Survival was 8.2 months for all subjects.

October 4, 2010

Zymogenetics reported results from a phase IIa trial evaluating recombinant Interleukin 21 (IL-21) for metastatic melanoma. This open-label, multi-center study enrolled 40 subjects who were placed in one of three cohorts: Cohort One received 50 mcg/kg/day by outpatient intravenous bolus injection daily for five days in weeks one, three and five of an eight week treatment cycle. Cohort Two received 30 mcg/kg/day in the same schedule, and Cohort Three received 50 mcg/kg/day daily for five days in weeks one and three of a six week treatment cycle. Thirty-nine of the 40 subjects were evaluable for response. The overall response rate was 23% and the median progression-free survival was 4.3 months. The median overall survival was 12.4 months, and 53% of subjects had survived to 12 months.

August 30, 2010

Plexxikon and Roche issued positive results from a phase I extension evaluating PLX4032 (RG7204) for the treatment of BRAF V600E positive metastatic melanoma. A total of 32 subjects received PLX4032 at 960 mg twice daily until disease progression. Data showed an 81% response rate by RECIST criteria, including two complete responses and 24 partial responses (tumor shrinkage of at least 30%). In the entire population, the estimated median progression-free survival extended more than seven months. Sixteen subjects are still on study. Drug-related adverse events were predominantly mild in severity and included rash, joint pain, photosensitivity and fatigue.

June 14, 2010

Bristol-Myers Squibb reported positive results from a phase III trial of ipilimumab for the treatment of metastatic melanoma. This international, randomized, double-blind study (202) enrolled 676 treatment experienced subjects with unresectable Stage III or IV metastatic melanoma who were HLA-A2+. The subjects received ipilimumab plus a gp100 peptide vaccine (3 mg/kg and 1mg/kg every three weeks for four doses), ipilimumab (3 mg/kg every three weeks for four doses) plus placebo or gp100 plus placebo. The primary endpoint was comparison of overall survival (OS) between ipilimumab plus gp100 versus gp100 alone. The median OS was 10, 10.1 and 6.4 months for the ipilimumab plus gp100, ipilimumab alone and gp100 alone groups, respectively (p≡ 0.0004 and 0.0026). At one year, approximately 46% of subjects treated with ipilimumab were alive compared to 25% of subjects treated with gp100 alone. At two years, approximately 24% of the subjects treated with ipilimumab were alive compared to 14% of patients treated with gp100 alone.

May 31, 2010

Provecta released positive interim results from a phase II trial of PV-10, an injectable formulation of Rose Bengal, for the treatment of metastatic melanoma. A total of 80 subjects with Stage III/IV melanoma were enrolled across the U.S. and Australia. Following initial treatment of 1-20 cutaneous, subcutaneous or nodal lesions, new or incompletely responsive lesions could be retreated at weeks 8, 12 or 16, with follow-up at 52 weeks. The primary end-point was objective response (OR) of injected lesions. These results are from the first 40 subjects completing treatment. Objective Response of PV-10 injected lesions was achieved in 61% of subjects, with a Complete Response (CR) in 33% of subjects and locoregional disease control (Stable Disease, SD) in 79% of subjects. The mean progression free survival (PFS) was 8.5 months for all subjects, while the OR cohort had a significantly longer PFS, estimated to be at least 11.1 months versus 2.8 months or less for SD or Progressive Disease subjects. Adverse events were mild to moderate.

January 7, 2008

Cephalon reported positive results from a phase III trial of Treanda for the treatment of chronic lymphocytic leukemia (CLL). This randomized, international, multicenter, open-label study enrolled three-hundred and five subjects. It was designed to compare Treanda to chlorambucil. The subjects received Treanda (100 mg /M2 on days one and two) or chlorambucil (0.8 mg/kg on days one and fifteen) for up to six treatment cycles. The co-primary endpoints, overall response rate and progression-free survival, were both achieved. Overall response rate was significantly higher with Treanda than with chlorambucil (68% versus 39%; p<0.0001) with a strong complete response rate of 30% compared to 2%, a nodular partial response of 10% compared to 3%, and a partial response of 28% compared to 34%, respectively. Treanda significantly improved progression-free survival compared to chlorambucil (median 21.7 months versus 9.3 months, respectively; p<.0001). The median duration of response in the Treanda arm was 18.9 months compared to 6.1 months in the chlorambucil arm. An NDA is currently under review by the FDA.

Gloucester reported positive preliminary results from a phase II trial of romidepsin for the treatment of cutaneous t-cell lymphoma (CTCL) at the American Society of Hematology (ASH) Annual Meeting. Subjects enrolled in this non-randomized, open-label, single-arm international study received romidepsin at a dose of 14 mg/m(2), intravenously over four hours, on days one, eight and fifteen of a twenty-eight day cycle. The duration was six cycles, although those subjects who had an objective response or stable disease were eligible to continue therapy until disease progression. Of seventy- three evaluable subjects, an overall response rate of 37% was reported, with four complete responses, twenty-three partial responses and forty reports of stable disease. Six subjects had progressive disease. Of the subjects with severe pruritus at baseline, 37% reported significant relief. In addition, 38% of the subjects who exhibited any pruritus at baseline reported significant relief from symptoms. Treatment was determined to be safe and well tolerated. Based on the results, this phase II trial continues as planned.

Medarex and Bristol-Myers Squibb announced mixed top-line results from three phase III registrational trials (008, 022, 007) evaluating ipilimumab monotherapy for the treatment of metastatic melanoma. These international trials included an open-label, single arm trial (008) evaluating overall response rate in one hundred and fifty-five subjects who progressed on or following standard treatment; a randomized, double-blind trial (022) evaluating the efficacy of three dose levels of ipilimumab in two hundred and sixteen subjects who were previously treated, relapsed or failed to respond to experimental treatment or were unable to tolerate currently approved therapies; and a randomized, double-blind, placebo-controlled trial (007) in one-hundred and sixteen subjects comparing the safety of ipilimumab, with or without prophylactic oral budesonide (primarily evaluating the rate of grade 2+ diarrhea). The results from study 008, conducted under a SPA, did not meet the primary endpoint, which was to rule out a best objective response rate of less than ten percent. However, the totality of data from the trials included a clear dose response effect observed in study 022 and best objective response rates across the three studies ranging from mid-single digits to mid-teens as determined by independent radiology review. The objective responses included complete and partial responses. Medarex and BMS were planning to meet with the regulatory authorities and file for US approval by the first half of 2008.

January 24, 2002

Phase III trial results indicate that a combination therapy consisting of histamine and interleukin-2 (IL-2) is well tolerated and improves the survival of advanced malignant melanoma subjects. In the multicenter trial, 305 subjects with stage IV melanoma were randomly assigned to receive IL-2, or IL-2 plus histamine. The IL-2/histamine combination resulted in a median survival of 283 days in subjects with metastases to their livers, compared to 154 days with IL-2 alone. For all randomized subjects entering the trial, the combination produced a median survival of 272 days, compared to 245 days for the IL-2-treated group. At 24 months follow-up, 25% of subjects receiving the histamine/IL-2 combination were alive, versus 17% of subjects receiving IL-2 alone. The trial was sponsored by Maxim Pharmaceuticals.

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