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Pharmaceutical and Biotech News

Oncology - ASCO 2010

Summary of Meeting

It is difficult to put a vast meeting such as ASCO in perspective and isolate a small number of specific studies and announcements as being of primary importance.  Therefore, there is always a subjective element in such an exercise.   There were notable highlights: the results with dasatinib in CML,  ipilimumab  in metastatic melanoma and crizotinib in lung cancer.  The announced results were certainly impressive and received substantial coverage.  Certain agents such as crizotinib were directed to a specific, narrow phenotype (in this case ALK+ non-small cell lung carcinoma), but despite the limited numbers of patients that can benefit from such treatments, these agents highlight the promise of targeted therapies.  On the other hand, dasatinib illustrates that the progressive deeper understanding of the chemistry of inhibition can lead to drugs that can be both broader in their effectiveness spectrum and very effective.

Dasatinib is a BMS drug that is being marketed under the SPRYCEL® trade name.  It has been approved for use in patients diagnosed with chronic myeloid leukemia (CML) who have exhibited  resistance to previous treatments (mainly imatinib).  Dasatinib, very much as imatinib (Cleevec®), is an inhibitor of a tyrosine protein kinase, BCR-ABL, certain mutants of which lead to the development of CML.  However, difference in structure between these molecules and the resulting mode of binding to mutant BCR-ABLs is apparently what makes all the difference here.  Dasatinib binding is affected less by conformational changes in mutated BCR-ABLs than imatinib.  Thus, it has activity against BCR-ABL mutants that do not bind to imatinib.[1] This broader spectrum of activity was verified clinically.  The Phase 3 clinical study which was presented at ASCO this year showed superiority of response with dasatinib versus imatinib in newly diagnosed CML.  The results illustrate the degree to which we can improve on existing drugs on well-validated targets, even when the existing drugs have good to excellent efficacy.   

Pfizer’s critozinib is a good example of very narrowing targeting.  This agent is a member of a recent group of compounds that target an oncogenic gene fusion product, the ELM4-ALK.  ALK (anaplastic lymphoma kinase) is an important tyrosine kinase, with very low levels of expression in normal cells.  In mitotic processes, occasional chromosomal translocations in the ALK gene area create oncogenic fusions genes.  These fusion genes express chimeric molecules with highly active elements of ALK.  So far, about seven different such ALK fusion genes have been identified.[2]  They occur mainly in the rare anaplastic large cell lymphoma (ALCL), certain neuroblastomas and a small percentage of non-small cell lung carcinomas (4 -5% of all such tumors). The rather impressive results reported in this year's ASCO with this agent are probably due to the fact that inhibiting the runaway ALK does stop most of the malignant processes in the affected cells.  It should be pointed out that a small number of other ALK inhibitors are entering clinical development. Ariad may soon start development of its ALK inhibitor, AP26113, which the company claims that it possesses superior characteristics to Pfizer’s critozinib.  

There was progress with agents that assist the immune system attack cancerous cells but do not have antitumor activity per se. They were one the prominent stories at this year’s ASCO.   This group of agents includes monoclonal antibodies that bind CTLA-4, such as ipilimumab (BMS) and tremelimumab (Pfizer).  CTLA-4 is a protein that inhibits T-cells action.  Tumors thrive because the progressively “convince” the immune system that they are not intruders.  Blocking CTLA-4 allows the immune cells to “forget” what they know about the tumor and attack it again. Early data with  ipilimumab and tremelimumab show that this approach is working, as there is promise for meaningful extension of survival in advanced melanoma.  

Since much of the exciting data in ASCO have focused on advanced melanoma, it would be important to note other agents that confer substantial treatment benefits such the B-RAF inhibitors by Roche (PLX4032) and GSK (GSK2118436) for which early data were presented in this meeting.  I would expect that we would hear much more on these agents in next year’s ASCO.  B-RAF is a serine/threonine kinase involved in the kinase pathway that affects cell division and differentiation.  Oncogenic mutants of these kinases have been found in a variety of solid and hematology tumors. 

To complete the advanced melanoma story, I also want to draw attention to Genta’s Genasense® (oblimersen sodium) presentation because it sheds a negative light on antisense technology.  Oblimersen sodium is an 18-base pair nucleotide that blocks the mRNA that coding the expression of Bcl-2, an anti-apoptotic regulator protein.  The results with oblimersen in this second pivotal study foray into advanced melanoma are ambivalent (the first attempt earlier in this decade resulted in failure).  In 2009, the FDA dismissed an appeal for use oblimersen in chronic lymphocytic leukemia (CLL); in May of this year, an advisory committee indicated that the current study in advanced melanoma cannot form the basis of successful NDA because the primary endpoint was not met.  The EMEA took similar action just a few days ago, and rejected a marketing authorization application in advanced melanoma.  The company is stating that full results for the studies in advanced melanoma would be available in early 2011.  I assume that if the data show promise, Genta may resubmit the NDA, but this is a continuing story with few bright points.   The disappointment with Genasense® comes at the heels of the failure of Isis’ Affinitak (LY900003) in two Phase III studies.  However, this may not be the end of the road for antisense agents.  ISIS is proceeding with its partners with OGX-011 (a clusterin inhibitor) and LY2181398 (a survivin inhibitor) as well as others in earlier stages of development.  Idera Pharmaceuticals has also outsourced some of the antisense oncology compounds it obtained after its merger with Hybridon such as GEM 231 and GEM 640 (AEG-35156). 

There were certain “conflicts” that I want to highlight concerning the use of certain anti-angiogenic compounds in advanced and pretreated malignancies.  Just a caution: these are most likely "apparent" conflicts, the datasets are not equivalent.  Bevacizumab (Avastin®) apparently had no effect when administered along with cytotoxic compounds in advanced, pretreated ovarian cancer.  In a large, well-controlled Phase 3 study, its only benefit –and somewhat modest at that- was associated with maintenance therapy after the conclusion of chemotherapy.  On the other hand, in a Phase 2 study, Amgen's anti-angiogenesis agent, AMG 386 (which targets angiopoietin-1 and -2),  did appear to have a synergistic effect when given with cytotoxic treatment. One should be careful, however, in interpreting these results.  The Amgen study was relatively small (160 patients) albeit controlled, and the significance level was likely too high to conclude at this stage that this specific anti-angiogenesis agent is effective when given alongside cytotoxic compounds in pretreated patients.  The data on the lack of a bevacizumab synergistic effect with cytotoxic treatment in advanced ovarian cancer are in line with the results obtained in advanced breast cancer.  This highlights the complex set of considerations of using anti-angiogenesis agents repeatedly in previously treated patients with advanced disease.[3] 

Since patients pretreated with anti-angiogenesis agents seem to profit little upon re-treatment, their response to newer members of this class is now an important consideration in clinical development. The relatively small groups in the AMG-386 study in advanced ovarian cancer were stratified on both (a) prior anti-VEGF treatment and (b) time to progression from last treatment, an approach that enhances the validity of the early data.  Stratification of groups for important factors that may affect outcome is very important in studies with small groups, as we have indicated in a prior article.  A different approach appears to have been taken in the Exelixis' uncontrolled Phase 2 study in advanced, pretreated glioblastoma with XL-184 (a VEGFR2-directed anti-angiogenesis agent).  In that study, patients were apparently allocated to different groups based on the previous exposure to anti-angiogenesis compounds (predominantly bevacizumad).    There was some evidence of activity in patients with anti-angiogenesis pretreatment but substantially less than in naïve patients, re-enforcing the overall trend of evidence for this group of agents.

In the area of advanced, platinum-resistant ovarian cancer, one should also not overlook the data presented by Sunesis on voreloxin.  Three different regimens of this intercalating agent (a topoisomerase II inhibitor) were evaluated.  The results showed an 11% objective response rate and a median PFS of 2.8 – 3.5 months.  Although no control group was included in the study, efficacy appears roughly in line with existing 2nd line treatments of platinum-resistant ovarian cancer.  While the results of voreloxin in advanced, recurrent ovarian cancer were not spectacular, this agent appeared to be doing a better job in acute myeloid leukemia (AML).  Again, the absence of control groups in these Phase 2 studies forces comparisons with historical controls, an exercise always fraught with ambiguities.  A thorough examination of the Sunesis development of voreloxin in a variety of solid and hematological tumors would be presented in an upcoming article in this site.

There was also a variety of presentations of interim results of early studies with a number of mTOR, PI 3K, MEK and Akt kinase inhibitors by a variety of companies.  I would expect that updates on these studies and these agents will feature prominently in next year’s ASCO.

References

[1]               Shah NP, Tran C, Lee FY, et al.: Overriding imatinib resistance with a novel ABL kinase inhibitor.  Science 305: 399-401, 2004

[2]               Amin HM, Lai R: Pathobiology of ALK+ anaplastic cell lymphoma,  Blood 110: 2259-2267, 2007

[3]               Rakesh K Jain RK*, Duda DG, Clark JW et al.: Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nature Clinical Practice Oncology  3: 24-40, 2006

 

Selected Announcements

Ipilimumab Demonstrates Improved Overall Survival in Phase 3 Trial of Previously-Treated Patients with Metastatic Melanoma: Ipilimumab is a humanized monoclonal antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a molecule on T-cells involved in the regulation of natural immune responses. Suppression of CTLA-4 may allow an amplified and continuing response by the immune system’s T-cells in fighting malignant cells.  Bristol Myers Squibb and Medarex announced positive results from a Phase 3 randomized, double blind study which demonstrated that overall survival (OS) was significantly extended in patients with previously-treated metastatic melanoma who received ipilimumab.

The Phase 3 study enrolled patients diagnosed with unresectable Stage III or IV metastatic melanoma who have received prior treatment and were positive for the antigen HLA-A2. HLA-A2 antigen is important for the recognition of malignant cells by by autologous T-lymphocytes.  In this study, an experimental anti-melanoma peptide vaccine, the gp100, was utilized as an active control. This is a synthetic peptide vaccine consisting of amino acid residues 209 through 217 of the glycoprotein 100 (gp100) melanoma antigen, with a methionine substitution at position 210 designed to improve immunogenicity. Vaccination with gp100 peptide may stimulate the host immune system to mount a cytotoxic T lymphocyte (CTL) response against tumor cells expressing gp100.

In the study, patients were randomized to receive ipilimumab + gp100 (3 mg/kg and 1mg/kg every three weeks for four doses; n=403), ipilimumab (3 mg/kg every three weeks for four doses) + placebo (n=137), or gp100 + placebo (n=136). The primary endpoint was overall survival (OS) between patients who received ipilimumab + gp100 vs. gp100 alone. The secondary endpoints were comparison of OS of ipilimumab alone vs. gp100, progression free survival (PFS), objective response rate (ORR) and disease control rate (DCR).

The results were statistically significant for OS prolongation for patients receiving ipilimumab alone (hazard ratio 0.66, p=0.0026) or ipilimumab in combination with a gp100 peptide vaccine (hazard ratio 0.68, p=0.0004) when compared to those patients who received gp100 + placebo.  Median OS was 10, 10.1 and 6.4 months for the ipilimumab + gp100, ipilimumab alone and gp100 alone groups, respectively.  At one year, 44-46% of patients treated with ipilimumab were alive compared to 25% of patients treated with gp100 alone. At two years, 22-24% of patients treated with ipilimumab were alive compared to 14% of patients treated with gp100 alone. 

Grade 3/4 drug-related adverse events (AEs) were observed in 17%, 23% and 11% of the ipilimumab + gp100, ipilimumab and gp100 arms, respectively. Grade 3/4 immune-related AEs (irAEs) were seen in 10-15% of the ipilimumab treatment arms and 3% in the gp100 alone arm. Fourteen drug-related deaths (2.1%, 3.1% and 1.5% of the ipilimumab + gp100, ipilimumab and gp100 arms, respectively) occurred in the study, with seven (1.3%, 1.5% and 0%, of the ipilimumab + gp100, ipilimumab and gp100 arms, respectively) attributed to immune-related AEs, but no specific information about these AEs was released.

Bevacizumab (Avastin®) Prolongs Progression-free Survival for Women with Advanced Ovarian Cancers:   Bevacizumab (Avastin®) an anti-angiongenesis directed agent.  It is a humanized monoclonal antibody that blocks vascular endothelial growth factor A (VEGF-A).[1]  and thus inhibits the growth of new blood vessels (angiogenesis). Avastin® is currently approved in the treatment of metastatic colon, non-small cell lung and breast cancers.  Determination of its efficacy in other metastatic cancers is ongoing.  Its potential role in the treatment of advanced ovarian cancer was investigated in  a double-blind, placebo-controlled, phase III trial (GOG-0218) that enrolled nearly 1,900 patients with chemotherapy-naive stage III or IV epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. All women underwent abdominal surgery for staging and maximal tumor debulking before being randomly assigned to one of three treatment arms: (1) Carboplatin + paclitaxel (CP) plus placebo during the induction phase (cycles 1 to 6), followed by placebo maintenance (cycles 7 to 22); (2) CP plus concurrent bevacizumab during induction, followed by placebo maintenance; and (3) CP plus concurrent bevacizumab during induction, followed by bevacizumab maintenance. Bevacizumab was not administered during the first 21-day induction cycle so as to limit postsurgical bleeding complications. The entire treatment schedule took 15 months to complete. NB: It is interesting that in this study,  Overall Survival (OS) was originally selected as the primary endpoint, but this was later changed to Progression-Free Survival (PFS).  Genentech/Roche explained the change as been “in accord with international consensus as a more appropriate endpoint for frontline phase III trials in this patient population”, as well as “pressure by patients to unblind their treatment assignment in the event of disease progression”. Overall Survival (OS) was converted to a secondary endpoint.  

The investigators monitored disease progression based on radiographic evidence, CA-125 measurements, and global clinical deterioration. At a median follow-up of 17.4 months (range: 0 to 50.7 months), PFS was significantly prolonged by 3.8 months with CP + concomitant and maintenance bevacizumab compared with CP alone (14.1 months compared with 10.3 months, respectively. Moreover, all patient subgroups analyzed exhibited consistent improvements in PFS with the concomitant and maintenance bevacizumab regimen regardless of disease stage, performance status, and patient age. 

No significant difference in PFS was observed between the arm that received CP plus concomitant bevacizumab only and the arm that received CP alone (11.2 months compared with 10.3 months, respectively; HR = 0.908; p = 0.080). NB: this is quite interesting as it shows (as in other studies) that there is little or no synergy between cytotoxic chemotherapy (CP) and cytostatic treatment (bevacizumab).  Most of the benefit seems to accrue from the maintenance treatment with the cytostatic agent.

The investigators have not yet discerned any differences in overall survival across the three arms; however, the survival data are not yet mature. At the time of data analysis, median overall survival ranged from 38.7 to 39.7 months, and 1-year survival ranged from 90.4% to 91.3%.  NB: The improvement so far in PFS has been quite moderate.  No significant differences in OS have been discerned, but the study is still ongoing and it takes a substantial period of time to compile OS data.  

Results of Phase 3 ABRAXANE(R) Combination Trial In First-Line Non-Small Cell Lung Cancer Show 31 Percent Improvement In Response Rate Compared With Taxol Combination:  The positive results of this study were originally announced on March 17, 2010.  Abraxane® is paclitaxel bound to albumin nanoparticles (nab), an Abraxis proprietary technology.  It is already approved for the treatment of metastatic breast cancer.  In the phase 3 study, 1,052 patients with advanced NSCLC (stage IIIB or IV) were treated. Patients had not received prior treatment for metastatic disease. Patients were randomized 1:1 to receive up to six cycles of test or control treatment until disease progression or unacceptable toxicity.  The test and control treatment included carboplatin with a target AUC 6 mg/ml.min on day 1 of a three-week treatment cycle in combination with either nab-paclitaxel (100 mg/m2) weekly – test treatment-  or cremophor-based paclitaxel (200 mg/m2) every three weeks -control treatment-. The primary endpoint for this study was objective response, measured as defined by the RECIST criteria. The secondary endpoint was progression-free survival (PFS).

An independent review showed nab-paclitaxel provided a significant improvement in overall response rate as compared with taxol, both administered in combination with carboplatin. Complete and partial response (CR and PR) was obtained in 170 nab-paclitaxel patients (33%) versus  132 patients (25%) treated with the paclitaxel combination (p=0.005). Histological analysis showed significantly improved objective response rate (ORR)  for nab-paclitaxel versus paclitaxel in squamous cell carcinoma patients (41% versus 24%, p<.001), a 67 percent improvement, and comparative effectiveness in patients with non-squamous histology (26% versus 25%, respectively).

The safety results were in line with the known toxicity profile of Abraxane®. The most common grade 3 and 4 adverse events that occurred were neutropenia (45 percent), anemia (27 percent), leucopenia (22 percent) and thrompocytopenia (17 percent). Of particular note, there was significantly less sensory neuropothy in the nab-paclitaxel versus the paclitaxel (3 percent versus 10 percent, p<.001).

SPRYCEL® (dasatinib) Demonstrates Superior Confirmed Complete Cytogenetic Response Rates Compared to Gleevec®*  in Study of Adult Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase.  SPRYCEL® (dasatinib) is a BCR-ABL inhibitor, a constitutively activated tyrosine kinase  that causes chronic myeloid leukemia.  SPRYCEL® (dasatinib) is currently approved by the U.S. for the treatment of adults for all phases of CML with resistance or intolerance to prior therapy including Gleevec. It is also approved for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy.  The announced results concerned the DASISION study.  This was an open-label, randomized, Phase 3 clinical trial of SPRYCEL 100 mg taken once daily vs. Gleevec 400 mg taken once daily, in the treatment of newly diagnosed chronic-phase CML. The study enrolled 519 patients; 259 patients were randomized to receive SPRYCEL® and 260 patients were randomized to receive Gleevec. The primary study endpoint was confirmed complete cytogenic response (CCyR) by 12 months. In the DASISION study, 77% of SPRYCEL patients vs. 66% of Gleevec patients achieved confirmed CCyR (two consecutive assessments of CCyR) by 12 months (p=0.007). Additionally, 83% of SPRYCEL patients vs. 72% of Gleevec patients achieved CCyR by one year (p=0.001). The time to CCyR was shorter for SPRYCEL patients than Gleevec patients (hazard ratio = 1.5, p<0.0001), with more than half of SPRYCEL® patients (54%) achieving CCyR within three months. SPRYCEL® patients were also twice as likely as Gleevec patients to achieve a major molecular response‡ (MMR) (hazard ratio = 2.0, p<0.0001).  Commonly reported adverse events with SPRYCEL®L and Gleevec included superficial edema (9% and 36%), nausea (8% and 20%), rash (11% and 17%) and muscle inflammation (4% and 17%). Overall rates of fluid retention observed in the study were 19% with SPRYCEL®L and 42% with Gleevec. Pleural effusions were seen only in the SPRYCEL® arm (10%).

Pfizer’s crizotinib shows promise in early data from an open-label Phase 2 study in patients with non-small cell lung cancer (NSCLC) positive for the ALK fusion gene: Crizotinib is an inhibitor of anaplastic lymphoma kinase, a tumor specific protein found in certain  non-small cell lunch cancers, neuroblastomas and rare sarcomas.   The Phase 2 study (PROFILE 105) was a single arm, non-randomized clinical trial investigating objective response (tumor shrinkage) following continuing treatment with oral crizotinib at 250 mg twice daily in patients with advanced or metastatic NSCLC who have failed previous chemotherapy.  Data for this study indicate objective responses in as much as 57% of the treated patients so far (the study is expected to treated 250 patients overall), an impressive result for advanced and metastatic NSCLC, if it is fully realized at the end of the study.  A Phase 3 study (PROFILE 107) is ongoing.  It is an open-label, randomized, two-arm clinical trial of oral crizotinib (250 mg twice daily) versus pemetrexed or docetaxed (both administered by an intravenous infusion on Day 1 of a 21 day cycle).  The treated patients must be diagnosed with locally advanced or metastatic NSCLC and displayed disease progression after platinum treatment.  The study would access overall 318 patients.  It should be noted that only 4 -7% of NSCLC tumors are positive for the ALK gene.

AMG 386 Data Demonstrate Promising Antitumor Activity in Patients with Recurrent Ovarian Cancer: AMG 386 is a first-in-class investigational peptibody that is designed to block angiogenesis by inhibiting angiopoietin-1 and -2 (Ang1 and Ang2). Peptibodies are antibody-Fc region + peptide fusion proteins that improve the pharmacokinetic properties and antitumor activities of the pharmacologically active peptide.

AMG 386, combined with paclitaxel, demonstrated antitumor activity in a randomized, double blind, Phase 2 trial involving 161 patients with recurrent ovarian cancer. Patients were randomized to receive paclitaxel intravenously weekly, three weeks on and one week off, plus AMG 386 at 10 mg/kg (Group A, n=53), AMG 386 at 3 mg/kg (Group B, n=53), or placebo (Group C, n=55).

Median progression-free survival (PFS), the study's primary endpoint, in the 10 mg/kg arm was 7.2 months versus 5.7 months in the 3 mg/kg arm and 4.6 months in the placebo group (80%, CI, 0.59 - 0.98; p=0.17).     The objective response rate assessed according to the RECIST criteria was 37% in the 10 mg/kg arm versus 19% in the 3 mg/kg arm and 27% in the placebo group.  Response rate measured by serum CA-125 levels was 71% in the 10 mg/kg arm versus 58%  in the 3 mg/kg arm and 28% in the placebo group.   NB: Amgen, in its announcements, made no mention of the level of significance in this study.  If one assumes that Amgen regards this study as positive, the level of significance was likely set higher than what would be typically employed in pivotal studies (a typical approach in Phase 2 studies).  Objective response differences do not appear to be statistically significant.

Grade 3 or higher adverse events (AEs), where the difference in incidence was more than five percent in the AMG 386 arm than the placebo arm, included: hypokalemia (Arm A/B/C percentages 12/11/4), peripheral neuropathy (10/2/4), anorexia (2/6/0), neutropenia (8/9/4), and dyspnea (2/9/4). Other grade 3 or higher AEs of interest included thromboembolic events (arterial 2/2/0; venous 6/6/9). No grade 3 or higher hypertension was observed and there were no bowel perforations in patients treated with AMG 386. No treatment-related deaths occurred in the study.

AMG 386 antitumor activity is investigated in a variety of solid tumors including metastatic breast cancer, colorectal carcinoma as well in a variety of gastric, esophageal liver and kidney malignancies.

Aeterna Zentaris Presents Positive Efficacy and Safety Data for AEZS-108 in Ovarian Cancer at ASCO Meeting:  AEZS-108 is a targeted cytotoxic drug in which doxorubicin is linked to [D-Lys(6)]-luteinizing hormone-releasing hormone (LHRH).  The Phase 2 study enrolled 42 women with histologically confirmed, taxane-pretreated, platinum-resistant, LHRH-R positive, advanced (FIGO III or IV) or recurrent ovarian cancer. Patients received a recommended dose of 267 mg/m2 by intravenous infusion over 2 hours, with retreatment every 3 weeks.  Up to six treatment cycles were allowed. Response rate (RECIST and/or GCIG criteria) was defined as primary endpoint. Secondary endpoints were safety, time-to-progression (TTP) and overall survival (OS).  Efficacy included partial response in 5 patients (11.9%) and stable disease for more than 12 weeks in 11 patients (26.2%). Median time to progression (TTP) and overall survival (OS) were 3.5 months (104 days) and 15.6 months (475 days), respectively. In all, tolerability of AEZS-108 was good and commonly allowed retreatment as scheduled. Only one patient (2.4%) presented with a dose limiting toxicity that necessitated dose reduction.  Severe (Grade 3 or 4) toxicity was mainly restricted to rapidly reversible hematologic toxicity (leukopenia / neutropenia) associated with fever in 3 cases. Good tolerability of AEZS-108 was also reflected with only a few patients with non-hematological toxicities of grade 3 (none with grade 4), including single cases (2.4%) each of nausea, constipation, poor general condition, and an enzyme elevation. No cardiac toxicity was reported.

ZymoGenetics Reports Positive IL-21 Phase 2 Results in Metastatic Melanoma: Interleukin 21 (IL-21) is a cytokine that enhances the activity of natural killer (NK) and cytotoxic T cells.  These cells attack and eliminate infected and cancerous cells.  The open-label, non-randomized Phase 2 study was conducted in various sites in Canada. A total of 40 patients were enrolled and treated with IL-21 using 3 dosing regimens. The initial cohort received 50 μg/kg/day by intravenous bolus injection daily for 5 days in weeks 1, 3 and 5 of an 8-week treatment cycle. Cohort 2 received 30 μg/kg/day with the same schedule, and Cohort 3 received 50 μg/kg/day daily for 5 days in weeks 1 and 3 of a 6-week treatment cycle. Of the 40 patients treated, 10 patients received 50 μg/kg/day, and 30 patients received 30 μg/kg/day. The most common adverse events were fatigue, rash, fever, myalgia, anorexia, chills and nausea.

Thirty-nine of the 40 patients were evaluable for response, and 9 of the 39 (23.1%) had a confirmed partial response as  assessed by utilizing the RECIST criteria. In addition, 16/39 patients (41%) had stable disease, and 14/39 (36%) progressed. Two patients had 100% shrinkage of tumor target lesions, and responses were seen in patients with visceral disease, including liver metastases. Of the 30 patients treated with 30 mcg/kg/day (the dose selected for further study), 29 were evaluable for response: of those 6/29 (21%) had a partial response, and 11/29 (38%) had stable disease.

The NCIC Clinical Trials Group in Canada evaluated their historical Phase 2 melanoma trial results with patients matching the IL-21 clinical trial entry criteria; the progression-free survival in the historical group was 1.58 months.  The most commonly used treatment for patients with melanoma, dacarbazine, has shown median progression-free survival of 1.5 months and an overall response rate of less than 15%. NB: non-randomized, uncontrolled studies provide acceptable information for a “go, no-go” decision only if the characteristics of the treated patients match well those of the historical control and have been structured to provide “optimal results”.  The deficiencies of these studies are discussed extensively in “Why do so many Phase 3 clinical trials fail”.

Genta announces Pooled Results of Early Endpoints from Phase 3 Trials of Genasense® in Advanced Melanoma:  Genasense is a 18-base pair DNA construct that binds to the mRNA that encodes the Bcl-2 protein.  Bcl-2 blocks apoptosis of damaged malignant cells.  By reducing its concentration in cancerous cells, their rate of apoptosis following cytotoxic chemotherapy is increased.  Genta has conducted two Phase 3 randomized controlled trials of chemotherapy with dacarbazine (DTIC) with or without Genasense, known as GM301 and AGENDA, which comprised a total of 1,085 patients.  AGENDA was designed to confirm results from GM301 that showed increased survival in patients with low to normal baseline levels of a biomarker (lactate dehydrogenase [LDH].  Initial results did not show a statistically significant difference in early endpoints (overall response and progression-free survival).  AGENDA was powered to detect differences in overall survival, and the late endpoints of overall survival and durable response are currently being collected in blinded follow up.   The ASCO 2010 presentation included data from a “pooled analysis” that assessed combined efficacy results for the secondary endpoints of overall response and progression-free survival from both studies.

 Results for overall objective response are shown below.

Pooled Analysis

 Intent-to-Treat

Low-Normal LDH

Genasense/DTIC

 DTIC

 

14.5% 

8.9% 

0.004

19.0%

9.9%

0.002

NB: It should be pointed out that enhanced objective response may not necessarily correspond to increased overall survival.  Final results for this study are expected in the first quarter of 2011.