Abstract "Rituximab-Pecc Induction Followed By y-Ibritumomab Tiuxetan Consolidation in Relapsed or Refractory DLBCL Patients Who Are Not Eligible for or Have Failed ASCT: Results from a Phase II HOVON Study"
Background: Patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for
autologous stem cell transplantation (ASCT) have a poor prognosis. Treatment with salvage chemotherapy has generally been disappointing. In many centers in the Netherlands the oral PECC regimen is used for such patients. Y-ibritumomab tiuxetan (Zevalin , Spectrum Pharmaceuticals) radioimmunotherapy (RIT) is clinically active as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating salvage therapy with Rituximab (R)-PECC, in responsive patients followed by Y-ibritumomab tiuxetan consolidation.
1. The ORR after the end of the entire treatment was 29% (23% CR, 6% PR), RIT consolidation improved the overall best response (from PR to CR) in 5 of the 17 PR pts after the R-PECC only regimen.
2. The median response duration in the patients that received R-PECC only was 9 months (range 3-63 months). The median response duration in the patients that received RIT consolidation was 20
months (range 0-59 months).
Seems like there is more and more evidence that Zevalin is effective as consolidation therapy even after Rituximab treatment.
ASH abstract "Plasma Vincristine Levels Are 100-Fold Higher with Marqibo®(Vincristine Sulfate
LIPOSOME Injection) in Place of Standard Vincristine in Combination Chemotherapy of
Patients ≥ 60 Years Old with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)"
Results: 26 patients were enrolled from May 2012 to June 2014 (13 randomized to each group). 8 patients died during induction therapy, 5 in the VSLI Treatment Group and 3 in the VCR Treatment Group. Treatment-related deaths was 3 (12%): 2 (15%) in the VSLI Treatment Group and 1 (8%) in the VCR Treatment Group. 7 (54%) patients experienced treatment related serious adverse events in the VSLI Treatment Group compared to 5 (38%) patients in the VCR Treatment Group. No patients in the VCR Treatment Group had higher than
grade 3 neuropathy, whereas 4 (31%) patients in the VSLI Treatment Group did. ORR was the same in both
treatment groups with 8 (62%) patients in both treatment groups achieving CR/CRi. PK analysis demonstrated a median plasma vincristine level within 4 hours of infusion of 866 ng/mL for VSLI-treated patients, 100-fold
higher than the 6 ng/mL for VCR-treated patients.
Conclusion: The study was terminated prematurely due to poor enrollment, limiting conclusions that can be made regarding the safety or efficacy of VSLI versus VCR in combination with chemotherapy for older ALL patients.
Abstract for ASH presentation: "Phase II Study of Propylene Glycol-Free Melphalan (Evomela) Combined with
Carmustine, Etoposide, and Cytarabine (BEAM) for Myeloablative Conditioning in Lymphoma Patients Undergoing Autologous Stem Cell Transplantation"
Conclusions: PG-free melphalan can be used in place of the standard, lyophilized formulation of melphalan in
the BEAM regimen for lymphoma patients undergoing ASCT. It was shown to have a safety profile that compares favorably with Alkeran, and it avoids potential PG-associated toxicities. Of note, Grade 3-4 mucositis, diarrhea, and nausea/vomiting each occurred in fewer than 15% of patients, the engraftment rate was high (98%), and response rates were consistent with expectations.
"If you have any info that you can provide that this was a well known fact at time I would appreciate it."
The Journal of Urology Volume 183, Issue 5, May 2010, Pages 1678–1685
You can find "its activity is potentiated by acidic pH (6) and decreased in basic pH (7.35 to 7.45)". As you know, pH of the blood is exactly in 7.35 – 7.45 range.
"Both statements are correct in this context"
Removing negatives is more important to keep p value low than just adding equal number of variables.
"Regarding his quote my notes indicate he said ”had we 20 more patients we would have reached significance, we were underpowered by 20 patients”
Than Raj does not know what he is talking about, since his another quote was "If we exclude those patients, then the data becomes significant even at 2 years."
Therefore, you expect less adverse events associated with mitomycin action in normal tissues and therefore a major advantage of Apaziquone is safety. Safety is going to be a major selling point, not efficacy. That was my point when a started to argue with you.
One more thing. I am skeptical about 30-90-min data for several reasons. First, it points on a much smaller study but Spectrum is going to run a bigger one. If bleeding patients are excluded from the analysis and 30-90-min waiting guarantees no bleeding, why do you want to run a larger trial and even to include a two time-instillation arm? Second, 30-90-min was only one subgroup out of four. A larger subgroup was 120 min and longer. If bleeding stops in 30 min, we should expect at least as good results in 120-min subgroup also. Where are the data? Is bleeding a real problem here? Third, more than three years passed since failure of phase 3 studies. Why not to publish all data with detailed subgroup analysis in per-reviewed journal? I would like to be sure that specialists in urologic oncology looked at all data and data interpretation and accepted them for publication. Fourth, why Allergan walked away? Why weren’t they impressed by subgroup analysis?
“If you can’t see that apaziquone will be efficacious than I think that we still have to disagree.”
I already said that I think Apaziquone will be an effective drug. I think that reduction of recurrent rate from 45.5% to 38.8% with p=0.022 in pooled patient population is OK but not great. What else? Remember, Raj said that 20 bleeding patients screwed up entire 1600-patient trial. He wanted to emphasize the importance of his “discovery”. However, it also tells us that anti-tumor activity of apaziquone is not outstanding. Think about it. 20 patients made a difference in winning or losing game against PLACEBO in 1600-patient trial. Never mind, even 6.7% reduction in recurrence rate which translates in 15% benefit is quite respectable. Without bleeders, the benefit should be even stronger. With Apaziqoune, patients will need less TUR procedures in their lives. Remember, “TUR is butchery, not a surgery” as Raj said. Seriously, some studies demonstrate that each TUR treatment leads to significant decrements in the quality of life.
What to expect from the current trial? Since Apaziquone is an improved version of mitomycin C we should look at the results of mitomycin trial(s). In one 502-patient study, a single instillation of mitomycin C decreased tumor recurrence by 50% compared with those patients who did not receive any intravesical therapy. Another study of patients with low-risk NMIBC found that single-dose mitomycin C resulted in a significantly lower early recurrence rate (11% versus 21% for placebo) within the first 24 months following initial TURBT. I hope, Apaziquone will demonstrate similar efficacy in a new trial and I think, nobody is expecting that Apaziquone effect will be stronger. It is why all trials with Apaziquone include placebo arm, not mitomycin arm. However, stronger efficacy is not what Apaziquone was designed for. It is a pro-drug which is not active under normal conditions and become activated only in hypoxic environment within the tumor.
Previous phase 3 trials were designed to demonstrate efficacy in EACH trial, not combined. In each trial they had 400 patients per arm. Now, they learned a lot from both studies, as they think, made all changes in their favor and proposed a new trial with 623 patients instead of 400 patients per arm. It shows that they think that drug works not as good as they expected in earlier days. All post hoc analysis presentations are good to impress investors but not statisticians, especially statisticians from FDA.
"So there is no question that they know they have an effective drug"
Agree. Drug is effective but not very potent. Therefore, a large trial is needed. I don't buy 30-90-min interval data analysis. Based on this analysis, you need only 150 patients per arm and only two arms to demonstrate stat significance. If Spectrum and FDA were so sure about 30-90-min data, they would agree on a much smaller phase 3 study. It is a nice working hypothesis which needs to be proved.
"the more efficacious it is the better the pricing dynamics"
Spectrum does not think that Apaziquone is a very effective drug. Therefore, you need 1869 patients in a new trial to prove efficacy. Most important advantage of Apaziquone is safety.
I am sure, Raj will be asked about it more than one time during 3dQ earning call. Key question is how many patients FDA wants to see in the study before the approval.
The outcomes of clinical trials do not depend on who is a CEO. Especially, when studies are conducted by different companies. In the near future, watch the results of NEMO trial (Ron cannot guarantee positive data) and partnership in Europe (will depend on NEMO results and Ron's negotiation skills). These two events will affect stock price much stronger than NASDAQ performance. IMHO, so far, Ron is OK as CEO.
A year ago, Lundbeck LLC received CRL for Captisol-Carbamazepine IV.
"The Complete Response Letter only requested additional Chemistry, Manufacturing and Controls (CMC) data."
Could be the same issue here.
October 23, 2015 11:10 AM EDT
Shares dropped after the company announced receiving a CRL from the FDA for Evomela. Analyst Adnan Butt called the decline an over reaction and he thinks now is a good time to buy.
"While the complete response letter for Evomela is unexpected, the downtick in SPPI seems like an overreaction to us. Our sales forecast 2015-2017 was $2.5M, $5M and $10M previously so this would be a small product from a top-line growth or defrayed expense standpoint. Since we care more on SPI-2012, apaziquone and poziotinib, we think this is a good opportunity to add," said Butt.
The analyst continued, "Though approval would have provided revenues that could defray expenses, our prior projections for Evomela are modest, $2.5M in 2015, $5M in 2016, and $10M in 2017, all of which we move out by 1-year. The stock reaction appears perplexing because these figures are neither significant enough to be key top-line drivers nor to meaningfully offset pipeline development expenses. In fact, Evomela approval could require SPPI to pay Ligand up to $66M in regulatory and commercial milestones and would have paid Ligand $6M upon approval."