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Bristol-Myers Squibb released results of
a phase III trial of Opdivo (nivolumab) v.
investigator’s choice chemotherapy (ICC) in
patients with advanced melanoma who were
previously treated with Yervoy (ipilimumab).
In the randomized, controlled, open-label
study (n=370), patients were randomized
2:1 to receive Opdivo 3mg/kg by intravenous
infusion every two weeks (n=268) or ICC (dacarbazine
1000mg/m2 every three weeks or
carboplatin [AUC] 6 plus paclitaxel 175mg/
m2 every three weeks; n=102) until progression
or unacceptable toxicity. The objective
response rate (ORR) was 32% (95% CI = 24,
41) in the Opdivo arm and 11% (95% CI = 4,
23) in the ICC reference arm in patients with
at least six months of follow up. The majority
of Opdivo treatment-related adverse events
(AEs) were grade 1/2 and managed using
recommended treatment algorithms. Grade
3/4 drug-related AEs were less frequent for
the Opdivo arm (9% versus 31% of patients
treated chemotherapy). Serious Grade 3/4
drug-related AEs were reported in 5% and
9% of patients treated with Opdivo and ICC,
respectively. Discontinuations due to drug-related
AEs, of any grade, occurred in 2% of
Opdivo-treated patients and 8% of patients
Genentech reported results of a phase
III trial of cobimetinib in combination with
vemurafenib in previously untreated patients
with unresectable locally advanced or metastatic
melanoma harboring a BRAF V600 mutation.
The trial was an international, randomized,
double-blind, placebo-controlled study
evaluating 60mg once daily of cobimetinib
in combination with 960mg twice daily of
vemurafenib, compared to 960mg twice
daily of vemurafenib alone. In the study, 495
patients with BRAF V600 mutation-positive
unresectable locally advanced or metastatic
melanoma, and previously untreated for
advanced disease, were randomized to
receive vemurafenib every day on a 28-day
cycle plus either cobimetinib or placebo for
days 1-21. Median follow up was 7.4 months
for the combination arm and 7.2 months
for the control arm. The median PFS was 9.9
months for the combination of cobimetinib
and vemurafenib v. 6.2 months for vemurafenib
alone (hazard ratio [HR]=0.51, 95%
CI 0.39-0.68; p<0.0001), demonstrating the
combination reduced the risk of the disease
worsening by half (49%). The median PFS
by independent review committee (IRC), a
secondary endpoint, was 11.3 months for the
combination arm compared to six months for
the control arm (HR=0.60, 95% CI 0.45-0.79;
p=0.0003). Objective response rate (ORR) was
68% for the combination v. 45% for vemurafenib
alone (p<0.0001). Overall survival
data are not yet mature (HR=0.65, 95% CI
0.42-1.00; p=0.046). Roche has submitted
an MAA to the EMA, and Genentech plans to
submit an NDA to the FDA later this year.
Amgen issued results of a phase III study of
talimogene laherparepvec in patients with
injectable unresected stage IIIB, IIIC or IV melanoma
compared to granulocyte-macrophage
colony-stimulating factor (GM-CSF). Of the
295 patients treated with talimogene laherparepvec,
almost 4,000 tumor lesions were
tracked. Half of these lesions were injected
with talimogene laherparepvec at least once,
while the rest were not injected, including
visceral tumor lesions. The results showed
a 50% or greater reduction in tumor size in
64% of injected tumors. In addition, one-third
of uninjected non-visceral tumors, and 15%
of visceral tumors, also were reduced by at
least 50%. There were 35 melanoma-related
surgeries performed during this trial, of which
30% successfully removed all residual disease.
The most frequently observed adverse events
in the phase III study were fatigue, chills and
pyrexia. The most common serious adverse
events include disease progression in both
groups, and cellulitis and pyrexia in the talimogene
Merck issued results for a phase Ib trial of
MK-3475 for the treatment of advanced
melanoma. The trial is an ongoing, multi-center,
single-arm, open-label study evaluating
MK-3475 monotherapy in more than 1,000
patients with diverse late-stage cancers
lung and melanoma. Three dosing regimens
of MK-3475 were evaluated: 10mg/kg every
two weeks, 10mg/kg every three weeks or
2mg/kg every three weeks. The overall
response rate at five months was 41%
(CI 95%: 32 to 51%); 88% (43/49) of patients
with a partial or complete response showed
no evidence of disease progression. The
maximum ongoing duration of response
recorded was 65 weeks (range 8+ to 65+).
The disease control rate across doses for
patients in the melanoma cohort was 61%
(CI 95%: 52 to 70%), and median progressionfree
survival at time of analysis was 36 weeks.
The company plans to initiate combination
trials this year and in early 2014.
Amgen reported results of a phase III trial of talimogene laherparepvec in patients with unresected stage IIIB, IIIC or IV melanoma compared to granulocyte-macrophage colony-stimulating factor (GM-CSF). The trial was a global, randomized, open-label trial enrolling over 400 patients. Patients were randomized 2:1 to receive either talimogene laherparepvec intralesionally every two weeks or GM-CSF subcutaneously for the first 14 days of each 28-day cycle. Treatment could last for up to 18 months. The median time to response was 4.1 months (range 1.2 months to 16.7 months). The duration of response was longer in the talimogene laherparepvec arm, with an estimated 68% of talimogene laherparepvec responders achieving responses lasting at least nine months compared to 47% among the GM-CSF responders. The most frequently observed adverse events were fatigue, chills and pyrexia. The most common serious adverse events include disease progression, cellulitis and pyrexia. Serious adverse events occurred in 26% of talimogene laherparepvec patients and 13% of GM-CSF patients.
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.
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.
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.
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.
Curis and Genentech released interim results from a phase II trial of vismodegib for basal cell carcinoma. This international, single-arm, two-cohort study (ERIVANCE BCC) enrolled 104 subjects with inoperable metastatic or locally advanced basal cell carcinoma. The subjects received 150 mg once daily until disease progression or toxicity. The primary endpoint was overall response rate as assessed by an independent review facility. The overall response rate was 43% in the locally advanced cohort and 30% in the metastatic cohort. The independent review also showed a clinical benefit rate (response as well as prolonged stable disease for more than 24 weeks) in 75% of the locally advanced cohort and 76% of the metastatic cohort. The median duration of progression free survival and response for both cohorts was 9.5 months and 7.6 months, respectively.
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.
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.
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.
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.
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.
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.
Genta issued interim results from an ongoing study evaluating a high dose injection of Genasense for Stage IV melanoma. Genasense (900 mg) was administered as a brief intravenous infusion over one hour twice per week for four consecutive weeks, in addition to Temodar and Abraxane chemotherapy. This schedule compresses approximately 48 hours of standard dosing into a brief one-hour infusion. Of the 10 subjects treated to date, three achieved confirmed partial responses after the first two treatment cycles, with current durations lasting from 24 to 40 weeks. One subject maintained stable disease that lasted for 16 weeks, two subjects had progressed, and four subjects were too early to evaluate, having received only a single cycle. The preliminary disease control rate (complete or partial responses plus stable disease lasting at least three months) was 67%. The treatment was generally well tolerated.
CuraGen issued positive results from a phase II trial of CRO11-vcMMAE for the treatment of melanoma. This open-label, multi-center trial enrolled 36 subjects with Stage III and Stage IV melanoma in the US. The subjects received CR011-vcMMAE 1.88 mg/kg administered intravenously once every three weeks. Endpoints included objective response rate, progression free rate, time to response and duration of response. The study successfully met its primary endpoint, with 5 objective responses (1 unconfirmed) observed in 34 evaluable subjects; the median duration of response was 5.3 months. The median overall progression-free survival was 4.4 months. Tumor shrinkage was observed in 58% of the subjects and 20 had best response of stable disease.
CuraGen issued positive preliminary results from a phase II trial of CR011-vcMMAE for the treatment of melanoma. This open label, multi-center study enrolled 36 subjects with Stage III or Stage IV melanoma. The subjects received CR011-vcMMAE 1.88 mg/kg administered intravenously once every three weeks. At this time, 31 subjects were evaluable for efficacy and 18 subjects were continuing to receive ongoing treatment in the study. The median overall progression-free survival (PFS) to date was 4.5 months. RECIST-defined partial responses were reported in three subjects, two ongoing, and an unconfirmed partial response in one subject. Stable disease was observed in 19 subjects 14 ongoing, with tumor shrinkage observed in 12 of these subjects. Treatment was well tolerated. Additional phase I and II trials of CRO11-vcMMAE are currently underway
CuraGen issued positive preliminary results from a phase II trial of CR011-vcMMAE for the treatment of melanoma. This open label, multi-center study enrolled 36 subjects with Stage III or Stage IV melanoma. The subjects received CR011-vcMMAE 1.88 mg/kg administered intravenously once every three weeks. At this time, 31 subjects were evaluable for efficacy and 18 subjects were continuing to receive ongoing treatment in the study. The median overall progression-free survival (PFS) to date was 4.5 months. RECIST-defined partial responses were reported in three subjects, two ongoing, and an unconfirmed partial response in one subject. Stable disease was observed in 19 subjects 14 ongoing, with tumor shrinkage observed in 12 of these subjects. Treatment was well tolerated. Additional phase I and II trials of CRO11-vcMMAE are currently underway.
Bayer Schering reported positive results from a phase II trial of Leukine for the treatment of melanoma. This 24-month, single-arm, open-label study enrolled 45 subjects who had undergone potentially curative surgery. In the first year of treatment, Leukine was administered subcutaneously at 125mcg/m2/day for 14 consecutive days, followed by Interleukin-2 (IL-2) subcutaneously at nine million IU/m2/day for four days. The subjects then received no treatment for ten days. In the second year of treatment, Leukine was administered alone two times per week. In the subjects who experienced resected recurrence, the same adjuvant therapy was re-administered. At the end of the study, 32 of the original 45 subjects were alive. The survival data, expressed by Kaplan- Meier, showed disease-free survival of 60% and overall survival of 64% at 21 months. There was no statistical difference in survival by Log Rank between those who received only Leukine versus those treated by Leukine and IL-2 (p=.8). In addition, there was no increase in the number of dendritic cells during or after Leukine administration in 11 subjects who donated blood for dendritic cell counts. Leukine was generally well-tolerated, with toxicities mild to moderate in nature. Based on the results Bayer plans to move forward with the development of Leukine for this indication.
Epeius reported positive results from an ongoing phase I/II trial of Rexin-G for the treatment of breast cancer. This US, open-label, dose-comparison enrolled 24 subjects with rapidly progressive chemotherapy resistant breast cancer. The subjects received dose-escalations of Rexin-G given intravenously two to three times a week for four weeks, with doses ranging from 2 x 10e11 cfu to 6 x 10e11 cfu per week. The goal of the adaptive trial design was to confirm the over-all safety of Rexin-G and to determine the optimal dosing regimen. Rexin-G demonstrated significant biological activity without toxicity. Escalating doses of Rexin-G were associated with stabilization of disease, significant reductions in CA 15.3 levels, a median progression-free survival of six months and a median over-all survival of greater than seven months, with all subjects surviving at the 8-month follow-up period. Rexin-G was safe and well-tolerated up to the highest tested dose. Based on the results Epeius plans to continue with the trial as planned.
Gloucester released positive results from a phase IIb trial of romidepsin for the treatment of cutaneous T-cell lymphoma (CTCL). This non-randomized, open-label, single-arm international study, dubbed GPI-04-0001, enrolled 96 subjects. The subjects received romidepsin at a dose of 14 mg/m(2) intravenously on days 1, 8 and 15 of each 28-day cycle, for 6 cycles. Data is from 72 evaluable subjects. The primary endpoint, overall response rate, was achieved. In subjects who had failed previous therapy, 40.3% reached this goal. Partial response was observed in 33.3% and 6.9% of subjects achieved a complete response. The overall response rate in subjects with advanced stage disease was 47.9%, with 37.5% experiencing a partial response and 10.4% experiencing a complete response. Additionally, 92.3% of subjects with pruritus at the outset of the trial had some relief. Gloucester plans to file an NDA with the FDA later in 2008.
Genta reported positive preliminary results from a phase III trial of Genasense for the treatment of melanoma. This international, randomized, double-blind, placebo-controlled study, dubbed AGENDA, enrolled 300 chemotherapy nave subjects that had shown maximal benefit in a previous trial. The subjects received Genasense plus dacarbazine (DTIC) or placebo plus DTIC in 21-day cycles for up to 8 cycles. They were subsequently followed every 2 months for 24 months and evaluated for the primary endpoints of progression free survival (PFS) and overall survival (OS) and the secondary endpoint of response rate (RR). Reported data is from 14 subjects enrolled in the first cohort. Of these 14 subjects, 6 (43%) have achieved major objective responses: one with complete response after 6 cycles of treatment, and 5 subjects with at least a partial response after only one treatment cycle. Three additional subjects have maintained stable disease after at least three treatment cycles, for an overall clinical benefit response of 64%. Treatment was well tolerated and no dose-limiting toxicities were observed. Based on the results Genta plans to continue with the study.
Cytos issued positive preliminary results from three phase IIa trials of CYT004 -MelQbG10, a vaccine for the treatment of melanoma. These parallel open-label studies enrolled twenty-two subjects with various stages of malignant melanoma. The trial was designed to assess safety, tolerability and T cell immunogenicity of three different dose regimens of CYT004-MelQbG10 as well as to compare two different routes of administration. All doses of the vaccine were safe and well tolerated, with no reported serious adverse events. Upon vaccination, Melan-A (MART-1)-specific CD8+ T cell responses could be detected directly ex vivo in fourteen of twenty-two subjects, indicating a good T cell immunogenicity. In the subjects who responded to the vaccine, the melanoma-specific CD8+ T cells increased by a median factor of three (individual increases were two to eight fold). Seven of the twenty-two subjects entered the study without detectable tumor after surgical intervention. Of these seven, six subjects remained tumor free throughout the treatment period. Fifteen subjects entered the study with detectable metastases. Of these fifteen, eleven subjects had progressive disease leading to death of two; one subject had stable disease, one subject showed partial response, one subject was not assessable because the tumor lesion was removed during the trial, and one subject died before the final assessment. Based on the results Cytos plans to move forward with the development of CYT004-MelQbG10, with additional trials planned for 2008.
Immutep reported positive interim results from a phase I/II trial of ImmuFact IMP321 for the treatment of metastatic breast cancer. This open-label, fixed dose-escalation study was designed to evaluate standard doses of weekly paclitaxel in combination with two IMP321 doses, 0.25 and 1.25 mg given subcutaneously at day two and day sixteen of a four-week cycle, for six courses. Data are from the first cohort of eight subjects who received the 0.25 mg dose of IMP321. Treatment was well tolerated. Out of the eight subjects, there were six tumor regressions and one disease stabilization. A three-fold increase in activated MHC class II+ monocyte blood counts and a two-fold increase in activated CD8+ circulating T cells were observed two weeks after the last injection. This trial is ongoing at the Ren Huguenin Cancer Centre, Saint Cloud in France.
Antigenics reported positive results from a phase II study of their cancer vaccine, Oncophage. The treatment uses surgically removed tumor cells to develop a personalized vaccine in order to reprogram the body's immune system to target and destroy only cancer cells. The phase II study, involving 39 subjects with stage IV melanoma, suggested a correlation between Oncophage-induced immunological activity and a measurable clinical response. Of the 28 subjects who had residual disease after surgery, two experienced complete disappearance of disease after treatment with Oncophage. Of the 23 subjects tested for immunological response, significant increases in melanoma-specific T-cell activity were observed in 11 subjects, five of whom also experienced complete response or long-term disease stabilization.
Preliminary phase I/IIa trial results indicate that three dosage levels of a therapeutic vaccine utilizing Mojave Therapeutics' Javelin antigen delivery system are safe and well tolerated. The trial included 27 subjects with stage III or stage IV melanoma. Subjects each received five subcutaneous injections comprised of a recombinant human heat shock protein (HSP-70) complexed with one, 10 or 100 micrograms each of tyrosinase and gp100 peptides modified with the Javelin sequence. Of 15 subjects evaluated for immune responses, nine exhibited a positive immune response. At this time, none of the nine responders have shown evidence of disease progression.