Yesterday was quite day, with one thing and another. For starters, the FDA ODAC committee finally held a session for Cell Therapeutics pixantrone in 3rd line NHL and ChemGenenex's omacetaxine, for people with the T315i mutation in CML. The previously scheduled meeting was cancelled due to the Snowpocalyse that hit DC last month.
I had to dash off to a doctor's appointment myself so missed most of the action on Twitter and rushed back to catch up at lunchtime by checking Twitter buddies such as Kerri Wachter who was live tweeting from the meeting and Adam Feuerstein of The Street's excellent live blog.
You can see my original review of the February FDA documents here. Sadly, the analysis turned out to be accurate and Adam had noted:
"That was brutal."
Approximately 20 minutes into Richard Pazdur's opening introduction.
In particular, the FDA felt that:
"Pixantrone has demonstrated evidence of biologic activity, but the mere demonstration of biologic activity is not sufficient for approval."
Ouch! At that point it becomes incumbent upon the company presenters to argue persuasively to the nine panel members to convince them otherwise. However, that was going to be a tall order given the FDA concerns regarding:
Neutropenia and infections were higher in pixantrone than the control
Cardiac toxicity was higher in pixantrone than control, including heart failure and ejection fraction
As highlighted in the original analysis of the pixantrone filing, the FDA were also unhappy about the shortened study given only 140 people were enrolled out of the planned 320, leading them to conclude:
Study was not well executed or complete.
Study was inconsistent (only 8 people enrolled in the US and none had a complete response).
Trial did not demonstrate statistical significance or robust findings.
What was weird about the proceedings though, was a clear disconnect between the two parties, as Adam Feuerstein reported live via the webcast:
"Pazdur: FDA not consulted about halting enrollment in trial, not pre-specified in study's statistical plan."
"Bianco: In March 2008 after 140th patient was enrolled, study was closed to enrollment. We consulted with FDA about this."
Checking my Twitter stream, Kerri reported:
Personally, I was surprised that CTI thought that the statistical parameters would not change if they only recruited 140 of the 320 people expected and could proceed on that basis. This is basic college level statistics – if you majorly change one input, the outliers must also be adjusted. For this reason, the FDA's decision to treat the data as if an interim analysis had been done is fair and reasonable.
Going forward, it is likely that either all 320 patients would need to be enrolled in a study to meet the minimum FDA requirements or new studies in combination with other agents would be needed. This latter approach is probably more likely, because the US sites (28 of them) only enrolled 8 people because the preferred treatment in the 3rd line refractory setting is combination chemotherapy, not single agent therapy.
Perhaps the snowpocalypse last month was a portend of what was to happen. Either way, yesterday was a bad day in DC for CTIC.
While reading my pile of mail on Friday, I realised that an interesting paper on Hodgkins Lymphoma (HL) appeared in the current edition of the New England Journal of Medicine (full reference below).
The basics of the paper are that despite advances in HL, including curative radiation in the early stages if the disease, one third of patients with advanced disease and about 15% of those with early disease have a relapse after treatment. 20% of people still die from the disease.
The question is why?
Well, unfortunately, current prognostic models have not been shown to be very accurate and so far, no biomarker has been found to be particularly useful.
The authors set out to use gene-expression profiling obtained from people with HL during diagnostic lymph node biopsy to determine which signatures were correlated with treatment. They confirmed their findings with an independent cohort of 166 patients using standard immunohistochemical analysis.
What they found was fascinating:
A gene signature of of tumour associated macrophages was associated with primary treatment failure.
An increased number of CD68 macrophages correlated with likelihood of relapse after autologous stem cell transplantation.
The adverse prognostic factor (macrophages) outperformed the current International Prognostic Score for disease-specific survival.
The absence of an elevated number of CD68+ cells in patients with limited stage disease defined a sub-group of patients with long-term disease specific survival of 100% with the current therapies.
When I was at school, we learned that macrophages were associated with an immune response to invasion. According to the NEJM Editorial, by DeVita and Costa, this may not be the case:
"Most of the evidence, however, now links the presence of tumor-associated macrophages with a poor prognosis."
In short, the data shows that increased number of tumour associated macrophages was strongly associated with shortened survival in HL and provides a biomarker for prognosis and risk stratification. What does this all mean though, for clinical practice?
DeVita and Costa noted that:
"If at the time of diagnosis we could identify patients who are destined to have a poor response to treatment, most patients could be spared a combination of therapies or radiotherapy with its attendant long-term toxic effects."
This is an important observation alone.
For the future, though, the data suggests some new directions that clinical research could go in, such as an anti-CD68 monoclonal antibody perhaps. There are some that have been identified for rheumatoid arthritis (RA) as the Kunisch paper shows below, but I don't think any are currently in commercial development at the moment.
For the moment, though, I'm left wondering more than there are answers.
Why do people with macrophages do worse, what is the mechanism for this? How can we best target the macrophages or the CD68 cells? If people are screened and are found to have a poorer prognosis and are spared the exposure to chemotherapy or radiation as DeVita and Costa suggest, how should they be treated instead?
Perhaps more research will be galvanised by Steidl et al's findings. Time will tell.
Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, Bast MA, Rosenwald A, Muller-Hermelink HK, Rimsza LM, Campo E, Delabie J, Braziel RM, Cook JR, Tubbs RR, Jaffe ES, Lenz G, Connors JM, Staudt LM, Chan WC, & Gascoyne RD (2010). Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. The New England journal of medicine, 362 (10), 875-85 PMID: 20220182
DeVita, V., & Costa, J. (2010). Toward a Personalized Treatment of Hodgkin's Disease New England Journal of Medicine, 362 (10), 942-943 DOI: 10.1056/NEJMe0912481
Kunisch, E. (2004). Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM11, and PGM1) widely used for immunohistochemistry and flow cytometry Annals of the Rheumatic Diseases, 63 (7), 774-784 DOI: 10.1136/ard.2003.013029
This week, (10th February) the FDA's Oncologic Drugs Advisory Committee will be meeting to review the filings from Cell Therapeutics ($CTIC) and ChemGenix ($CXSPY) for pixantrone and omacetaxine, in relapsed refractory NHL and CML, respectively.
I've just taken a few minutes to read the briefing documents and here are my initial thoughts.
Cell Therapeutics, a Seattle based biotech company, are going to have a very tough morning on Wednesday in DC for the following reasons:
The pivotal study had a very poor accrual with only 140 out of 320 patients enrolled.
Substantial cardiac and hematologic toxicities.
Risk:benefit trade-offs are always going to be a question for debate in the third-line setting, but CTI may well have shot themselves in the foot by closing enrollment early. This led the FDA to raise an important questionabout the study and whether there was sufficient information:
"the level of evidence necessary to draw conclusions from this Phase 3 study and the reliability of these conclusions."
Ouch.
After recent trials and tribulations over studies in elderly patients with AML had problems with a placebo comparator, it was good to see that in PIX301, patients were randomized 1:1 to single agent pixantrone or the following choice of comparators:
Oxaliplatin
Ifosfamide
Vinorelbine
Etoposide (PO/IV)
Mitoxantrone
Gemcitabine (only at U.S. sites)
Rituximab (only at U.S. sites)
Patients were treated for up to 6 cycles.
However, perhaps the most damning part of the FDA briefing document is the impact of halting enrollment early:
"The pivotal trial, PIX301, was discussed at an End of Phase 2 meeting on October 8, 2003. At this meeting, FDA stated, “Accelerated approval could be based on an interim analysis of a surrogate endpoint with completion of the trial demonstrating an improvement on a clinical benefit endpoint (survival or symptom benefit).”
FDA recommended that the trial assess complete response and the duration of complete response. Subsequently, agreement was reached concerning a Special Protocol Assessment for PIX301.
On March 28, 2008, CTI notified the FDA of an early halt to enrollment for PIX301. The study was not stopped at a planned interim analysis and early study stopping invalidated the applicant’s Special Protocol Assessment."
Based on this history, I think CTI will have a tough time arguing for approval on the basis of a shortened 140 patient study. It is clear in the FDA's analysis that they do not believe statistical significance was reached for the key efficacy measures.
Meanwhile, ChemGenex, a biotech company based in Australia with an office in San Francisco, are applying for approval of omacetaxine (Omapro) as treatment of adults with chronic myeloid leukemia (CML) who have failed prior therapy with imatinib and have the Bcr-Abl T315I mutation.
Interestingly, the FDA had completely different concerns with this filing.
The main issue with omacetaxine was that a commercially available assay does not exist for the T315i mutation and the company apparently didn't submit any information on how they were going to address this going forward. It's one thing to have central labs and academic labs do testing for trials, but given the majority of CML patients are seen by community oncologists in the US, a commercial assay is crucial for enabling decisions to be made on when to start therapy if the T315i mutation appears.
I would be surprised if a such a test hasn't been considered, but we will see what happens at ODAC on Wednesday. Approval may possibly be delayed until one is made available.
There was so much new data presented at the recent American Society of Hematology (ASH) meeting in New Orleans that I'm still digesting it all!
Today, I thought it was time to summarise what's hot in lymphomas, in particular, NHL.
Non-Hodgkins lymphomas (NHL) are a heterogeneous group of diseases affecting white blood cells with distinct clinical, morphologic, immunohistochemical, and molecular subtypes as defined in the 2008 World Health Organization (WHO) classification (PDF download).
In Europe, the German and French NHL groups are very methodical in taking each new potential regimen and comparing it in a randomised trial to the current stand of care to determine which is better, whether that be in terms of safety, tolerability or efficacy. In New Orleans, a number of particularly interesting studies were presented for discussion in indolent NHL.
Impact on the current standard of care
One of the most interesting findings
was a realisation that the standard of care for non-Hodgkins lymphoma
(NHL) is likely changing soon with the new data on the
bendamustine-rituximab combination looking to overtake standard R-CHOP
in first line treatment of newly diagnosed patients.
At ASH, Mathias Rummel presented data on an upfront study of bendamustine plus rituximab (BR) versus R-CHOP in patients with indolent (slow growing) lymphoma. The study population included mostly patients with follicular lymphoma, which accounted for probably 50% or so of the population, but about 20% or so of the patients had mantle cell lymphoma and the remainder had other indolent lymphomas.
What was interesting about the results was the complete response rate significantly favoured BR, as did the progression-free survival. When looking at the safety profile, the two-drug regimen versus the five-drug R-CHOP regimen seemed to be associated with a far superior safety profile, with patients having much less neutropenic fever and all of the other associated hematologic toxicities seen in patients with R-CHOP.
When I interviewed Dr Owen O'Connor from the NYU Cancer Institute for Clinical Research about the data, he described the study as "potentially paradigm changing" in indolent lymphomas. This may well turn out to be an accurate conclusion clinically, although it should be noted that the BR regimen will inevitably cost more than R-CHOP.
A long standing issue that has been unaddressed in diffuse large B-cell lymphomas has been the debate on whether a shorter R-CHOP regimen over 14 days would lead to better results than the standard 21 day regimen. The Germans, lead by Dr Pfreundschuh and colleagues, have long suggested that accelerated CHOP-based chemotherapy was superior to classic or conventional R-CHOP21 therapy based on data from the RICOVER trial.
This year, a heated debate apparently broke out in the NHL oral session after the French presented data from the GELA trial, demonstrating that R-CHOP21 was superior to R-CHOP14, both in terms of safety and toxicity profile, as well as efficacy, presumably because the shorter regimen was associated with more adverse events. It should be noted that the French study inclusion criteria was for patients over 65, so these results may well be applicable to that specific population, where tolerability is very important.
W2W4 (Watch to watch for) in the future?
A walk round the poster sessions left me struck with how many interesting compounds are now being tested in NHL, after a bleak period of disappointing data. Such compounds included AT-101, a gossypol and Mcl-1 inhibitor, and ABT-263, a Bcl-2 inhibitor.
It is early days yet for determining true efficacy, but both compounds appear to have manageable tolerability in the phase I trials completed to date. The rationale for ABT-263 is probably strongest in follicular lymphoma given the t(14:18) translocation, which gives rise to constituitive overproduction of Bcl-2.
In the future, we may well see studies with either agent in combination with rituximab to determine if efficacy and tolerability can be further improved.
I missed the oral NHL sessions as they clashed with the CML sessions (more on that tomorrow), but a quick check of several experts who attended them brought the following additional suggestions of new agents in development in NHL from Novartis and Roche:
Use of mTOR inhibitors such as everolimus (Afinitor) in refractory Waldenström macroglobulinemia (WM), a rare, indolent non-Hodgkin lymphoma, was considered very interesting. The data showed that everolimus had high single-agent activity with an overall response rate of 70% and manageable toxicity in patients with relapsed WM, and offers a potential new therapeutic strategy for this patient group.
RO5072759 (GA101) is the first humanized and glycoengineered type II monoclonal anti-CD20 antibody to enter clinical trials and is being developed by Roche. In vitro data show RO5072759 exhibits increased antibody-dependent cytotoxicity and strongly enhanced cell death (apoptosis) compared to rituximab. The ORR in refractory NHL data presented in a phase I study at this meeting was 43%, with many of the patients being heavily pre-treated. RO5072759 is now being explored as a single agent in phase II in relapsed/refractory indolent/aggressive NHL and B-CLL and in combination with chemotherapy in a phase Ib study.
Conclusions
Overall, the bendamustine-rituximab data was probably one of the stories of the conference and will likely see take-up in favour of R-CHOP in first-line NHL given the efficacy and tolerability benefits. Trials are also ongoing in CLL, and thus if positive, we may well see some CLL patients being given with BR over fludarabine-based regimens such as FC and FCR in 2010.
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In the past, single agent and double agent regimens have been a mainstay in the treatment of multiple myeloma, yet the five year survival rate has remained steadfastly low around 3-4 years, on average. Typically, younger and fitter patients do better than elderly patients with a poorer performance status, yet the majority of new diagnoses are found in the elderly. Finding new treatment approaches is therefore a key imperative.
2009 has seen the advent of new triple, and even quadruple, combinations in an effort to improve efficacy and survival, hopefully not at the expense of increased side effects. Two of the most commonly used drugs, bortezomib and lenalidomide, for example, differ in their side effect profile with an increased
tendency to peripheral neuropathy and deep venous thrombosis,
respectively. New dosing regimens have begun to look at new strategies in the form of modified dosing regimens, which are potentially more patient friendly, without compromising efficacy.
Important trial results from two European groups at this American Society of Hematology (ASH) meeting, for example, demonstrated that a four
drug combination improved durable responses and progression-free survival in
elderly patients. Both studies showed that a
weekly schedule of bortezomib (Velcade) maintained efficacy with fewer toxic side effects (i.e. significantly decreased the incidence of grade 3-4 peripheral neuropathy) compared to the standard
twice weekly schedule.
In
newly diagnosed myeloma patients the combination of bortezomib with
melphalan-prednisone (VMP) has been previously shown to be superior to MP, while in relapsed-refractory patients the four drug combination bortezomib-melphalan-prednisone-thalidomide (VMPT) induced a high
proportion of complete responses (CR).
An Italian phase III study therefore looked at the four drug combination in the upfront setting and showed that induction therapy with a four drug combination of bortezomib,
melphalan, prednisone, and thalidomide (VMPT) followed by maintenance
therapy with bortezomib and thalidomide (VT) achieved superior response rates and PFS compared to VMP.
A Spanish study noted that previously in elderly patients with newly diagnosed myeloma, the VISTA
trial demonstrated that the combination of bortezomib plus
melphalan – prednisone (VMP) is significantly superior to MP alone.
However, it is unclear which agent is the optimal partner
for bortezomib: an alkylating agent or an immunomodulatory drug, so they set out to answer this critical question by comparing VMP to VTP, where T is thalidomide.
The results indicated that:
"1. Both modified induction schedules (VMP and VTP) are highly effective with similar ORR and CR rates, but a
clear different toxicity profile (more neutropenia, but less cardiac
toxicity and peripheral neuropathy with VMP)
2. Maintenance therapy with either VT and
VP markedly improve the quality of responses with a good safety
profile
3. The combination of these induction and
maintenance schedules seems to overcome the poor prognosis of high-risk cytogenetic abnormalities in elderly MM patients"
It should be noted that while melphalan causes more neutropenia, the cardiac toxicity seen with thalidomide is more difficult to manage, so the VMP combination is likely to be more suitable going forward in newly diagnosed elderly patients with myeloma.
One triple combination that garnered a lot of interest earlier this year at ASCO, was a trial looking at combining lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone (RVD) in relapsed or refractory myeloma patients, with overall response rates (ORR) of 69%, including 26% complete/near complete responses (CR/nCR) and manageable toxicities Anderson et al. ASCO 2009). The phase I portion of the study (Richardson et al. IMW 2009) found the maximum tolerated dose (MTD) of this combination in newly diagnosed myeloma patients to be lenalidomide (25 mg/day), bortezomib (1.3 mg/m2), and dexamethasone (20 mg). In all phase I patients, the ORR was 100%, including 31% CR, 9% nCR, and 75% very good PR (VGPR).
At this ASH meeting, we heard results reported for patients treated in the phase II portion of the study as conditioning prior to autologous stem cell transplantation (ASCT) by Dr Richardson, who concluded that:
"These phase II results suggest that RVD is a highly
effective combination, with a pre-ASCT ORR of 100% and high rates of CR/nCR, and encouraging time-to-event analyses to date. RVD
was well tolerated, with limited rates of grade 3 peripheral neuropathy and DVT/PE despite
prolonged use of bortezomib and lenalidomide."
The data are summarised in the table below, based on all patients (n=35):
Patients
ORR, %
CR/nCR, %
≥VGPR, %
Response at cycle 4 (n=31)
78
12
12
Response at cycle 8(n=24)
100
33
67
Best response
100
54
69
Some of the most exciting new developments in myeloma could be found in both the oral and poster sessions.
A new generation proteasome inhibitor, carfilzomib (PX-171), has been generating consistent results in the bortezomib refractory setting. An ongoing phase II study presented at ASH looked at carfilzomib monotherapy in myeloma patients with relapsed or refractory disease following 1–3 prior therapies, ie a heavily pre-treated population. Updated data for the bortezomib-treated cohort were reported at ASH and the authors concluded that:
"18% ORR (CBR 30%) is notable for this steroid- and
anthracycline-sparing regimen. Single-agent carfilzomib is well tolerated, even
in patients with renal insufficiency, and both myelosuppression and peripheral neuropathy
are uncommon."
Carfilzomib was originally developed by Proteolix, who have just been acquired by Onyx. This should ensure more solid funding for the development of the phase III program, which looks promising in the relapsed, refractory setting.
Perifosine (Keryx) modulates Akt, and a number of other signal transduction pathways,
including the JNK and MAPK, all of which are associated with programmed cell death, cell growth, cell
differentiation and cell survival. Updated data from a phase I/II study in 84 patients who were heavily pre-treated with a median of 5 prior lines of therapy (range 1-13), showed that the overall response rate (ORR) was 41%, for the bortezomib relapsed group, 65%, and for the bortezomib refractory group, 43%.
Approximately 60% of patients
demonstrated progression (or stable disease (SD) for 4 cycles) at some point in their
treatment and received 20 mg dexamethasone, four times per week, in
addition to perifosine plus bortezomib. Responses occurred both with
patients taking perifosine in combination with bortezomib and with
patients receiving the combination plus dexamethasone. The ORR for the perifosine plus bortezomib arm was 25%, with an increase to 38% when dexamethasone was added. Survival data in the 73 evaluable patients was 6.4 months for PFS and 25 moths for overall survival (OS).
Another exciting new compound in development is MLN4924 from Millennium, the novel mechanism of which was recently described in detail (see article below) and was the also subject of a Nature article. The compound works very differently from proteasome inhibitors, which target the proteasome substrate. MLN4924 is involved with neddylation rather than direct ubiquination.
Neddylation activating enzyme (NAE) is the E1-activating enzyme for the ubiquitin-like protein Nedd8.
NAE catalyzes the first step in the neddylation cascade leading to
modification of cullin-based ubiquitin ligase activity. This results in
specific protein substrates, with important roles in cancer cell
survival, being targeted for degradation as shown the diagram below:
Source: Soucy et al., 2009
The end result is that MLN4924 inhibits neddylation by disrupting the cullin-RING ligase-mediated protein turnover, leading
to apoptotic death in human tumour cells by a new mechanism of action,
the deregulation of S-phase DNA synthesis.
A phase I dose escalation study in myeloma and NHL patients with MLN4924 was reported at ASH. The primary objectives were to determine the maximum
tolerated dose (MTD) and safety profile of MLN4924, as well as describe the
pharmacokinetics (PK) and pharmacodynamics (PD) in blood. Among the 22 patients enrolled to date, the median age was 65 years, 14 had myeloma and 8 had NHL.
The results showed that NEDD8-Cullin levels in peripheral blood myeloma cells (PBMCs) were inhibited and Nrf-2 target gene
transcripts in whole blood were higher vs. baseline after MLN4924
administration, which is indicative of NAE inhibition. Cdt-1 and Nrf-2 levels in skin increased above baseline following the
second dose of MLN4924, which is indicative of NAE inhibition in peripheral
tissue. These results are promising and provide early proof of concept for the role of neddylation in myeloma.
Overall, this was a good meeting on the myeloma front with lots of promise for triple and quadruple combinations, as well as new agents being developed in both the newly diagnosed and refractory settings that augers well for the future, both in terms of improved survival and also more tolerable regimens.
Soucy, T., Smith, P., & Rolfe, M. (2009). Targeting NEDD8-Activated Cullin-RING Ligases for the Treatment of Cancer Clinical Cancer Research, 15 (12), 3912-3916 DOI: 10.1158/1078-0432.CCR-09-0343
Soucy, T., Smith, P., Milhollen, M., Berger, A., Gavin, J., Adhikari, S., Brownell, J., Burke, K., Cardin, D., Critchley, S., Cullis, C., Doucette, A., Garnsey, J., Gaulin, J., Gershman, R., Lublinsky, A., McDonald, A., Mizutani, H., Narayanan, U., Olhava, E., Peluso, S., Rezaei, M., Sintchak, M., Talreja, T., Thomas, M., Traore, T., Vyskocil, S., Weatherhead, G., Yu, J., Zhang, J., Dick, L., Claiborne, C., Rolfe, M., Bolen, J., & Langston, S. (2009). An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer Nature, 458 (7239), 732-736 DOI: 10.1038/nature07884
After the furore around Pfizer and figitumumab on Friday, this morning brought entirely different kind of news with Onyx Pharma seeking to purchase a small biotech based in South San Francisco called Proteolix. Regular readers of this blog will be familiar with previous notes on Proteolix's proteasome inhibitor, PR-171 or carfilzomib, which will potentially be a major competitor to Millennium's Velcade (bortezomib) if it is approved by the regulatory authorities.
Onyx already have sorafenib (Nexavar), on the market for several VEGF-mediated cancers such as renal cell cancer and hepatocellular (liver) carcinoma. They are under increasing competition from Pfizer's sunitinib (Sutent) in the same cancer types, as well as 4 other therapies recently approved in renal cancer, including Novartis's everolimus (Afinitor). It therefore makes sense to expand the product pipeline and replenish it with relatively late stage and interesting compounds.
There may be new phase II data in multiple myeloma and possibly even in non-Hodgins lymphoma (NHL) presented at the forthcoming American Society of Hematology (ASH) meeting in December and early data from the phase IIb trial is expected next year. Current therapies for myeloma are fairly effective, but are limited by neurotoxicity issues. It will be interesting to see if carfilzomib has an improved safety or efficacy profile based on the new data. The early data was very promising, but as with all R&D, larger scale clinical trials are always necessary to see what happens in a larger pool of patients and whether the responses are durable over time.
If the results hold up, then this could well be a good investment for Onyx, because it expands their pipeline with new agents and different tumour targets. It's also good to see the biotech companies getting smart about combining resources in terms of R&D and marketing muscle. Overall this deal looks a win-win for both parties.
While taking a break from pouring over Pharma market cap data, I checked out how the FDA ODAC meetings were going today.
This morning, Gloucester Pharma were slated first and many VC's and investors must have been a tad nervous after the two negative votes for Genzyme and Vion in AML yesterday. Gloucester recently announced $29M in series D financing to further the development of their HDAC inhibitor, romidepsin. Everyone needn't have worried, since the committee voted with 10 in favour and 1 abstained.
The discussion this morning focused on refractory CTCL, a rare form of non-Hodgkins Lymphoma (NHL). CTCL is caused by a mutation of T cells, unlike most non-Hodgkin's lymphomas which are generally of B-cell origin. The malignant T cells involve the skin, causing plaques, patches, erythroderma and/or tumors and can involve other organs, including the blood lymph nodes and viscera.
In the Phase 2B, international, multicenter registration study of romidepsin in patients with CTCL (n=96, intent-to-treat), patients refractory to prior therapy who received romidepsin had an overall response rate of 34% i.e. 33 out of 96 patients. This exceeded the primary endpoint of the study, which was a 15% improvement.
Overall, complete and partial responses were observed at all stages of disease. The median duration of response was 14.9 months. Despite the exclusion of steroid and antihistamine use, 63% of patients with moderate to severe pruritus at baseline experienced significant pruritus relief, a key indicator of clinical benefit. The most common adverse effects in clinical trials of romidepsin include fatigue, gastrointestinal disturbances and generally mild to moderate hematologic toxicity.
Currently, treatments for CTCL include Merck's Zolinza (vorinostat), the first HDAC (approved in 2006) for this indication, as well as Ontak (denileukin diftitox), approved in 1999, and Targretin (bexarotene), all of which were approved on the basis of single arm studies.
A Prescription Drug User Fee Act (PDUFA) date of November 12, 2009 has
been set, so it looks likely that the FDA may well approve romidepsin for
treatment of cutaneous T-cell lymphoma (CTCL), including relief of pruritus, in patients who have received at least one prior systemic therapy before 2009 is out. Patients will then have a new therapy option once initial treatment has failed.
{Updated: please see the revision at the end of this post for correction}
Perception is a strange thing sometimes.
The other week Genmab, a Copenhagen based biotechnology company, announced positive results for their CD20 therapy, ofatumumab (Arzerra) in development for the treatment of NHL:
"Genmab A/S (Copenhagen:GEN – News) announced today positive top-line results from the Phase II study of Arzerra TM (ofatumumab) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in patients with previously untreated follicular non-Hodgkin's lymphoma (NHL).
A total of 58 patients were treated in the study. The overall response rate (ORR) in patients treated with 500 mg of ofatumumab (n=29) was 90%, including 24% complete remissions (CR), and 45% complete remissions/unconfirmed (CRu). In patients treated with 1000 mg of ofatumumab (n=29), the ORR was 100% including 38% CR, and 17% CRu."
Source: Genmab
Wow! 90% response rates are pretty much unheralded in a cancer trial, so I checked out their development partner, GSK, to see what they had to say:
"The overall response rate (ORR) in the 1000 mg treatment arm was 10%, including one complete response and 8 partial responses. In addition, 50% (43) of patients in the 1000 mg treatment arm had stable disease. The overall response rate in the total population was 11%."
A very different story or perhaps a different perspective from two partners seeing the same thing differently. The market reacted promptly and the news sent shares of the Danish biotech down 30 percent on August 18, as investors realized the negative clinical news meant Genmab will not receive an expected milestone payment from GSK related to this indication.
The partnership deal, among the most expensive licensing transactions of the time, promised milestones of over $1 billion. As far as I can tell, GSK paid $102 million in December 2006 in up-front cash and made an equity investment worth over three times that for exclusive rights to the compound, which is in trials for a variety of indications.
As for how the two companies managed to interpret the data differently, I'm not sure what went wrong there, but the difference between 90% and 10% is quite a lot by anyone's reckoning.
Still, an ODAC panel recommended that it should be approved earlier this year and the FDA is expected to make a final decision in October. The new trial data may well make it harder to either gain approval, or even if it does, make any headway against Genentech's Rituxan with those kind of response rates.
Watch this space, as they say, for the next instalment in the story.
{Update:}
Little did I know when I wrote this post the other day that there would indeed be a rapid revision to the story, courtesy of my own haste and folly!
The good folks at GSK kindly alerted me to the fact that the statements relate to two completely different studies, hence the difference in the data. Of course, this makes a big difference! My bad.
So, for clarity, here's what the data across three different trials actually shows:
407 Study – Front-Line Chronic Lymphocytic Leukemia (CLL)
In early August, results from a Phase II study of Arzerra in front-line CLL were announced. The study examined treatment of ofatumumab in combination with fludarabine and cyclophosphamide (O-FC) in previously untreated CLL patients.
The study added to the growing body of positive clinical evidence for Arzerra in CLL. Arzerra results in patients with CLL that were refractory to fludarabine and another CLL therapy, alemtuzumab, or refractory to fludarabine and had bulky lymph nodes were presented last year. These results became the basis of the first US and EU submissions for Arzerra in the first quarter of 2009. Approvals are still pending.
405 Study – Refractory Follicular non-Hodgkin’s Lymphoma (NHL)
In mid-August, the team also unblinded a study for Arzerra in rituximab refractory follicular NHL. Essentially, researchers were assessing the effectiveness of Arzerra in a very hard to treat from of NHL.
The patients evaluated in this study have a form of NHL that was refractory to rituximab –a standard NHL therapy that targets the same site on cancer cells (CD20) as Arzerra. Many patients in this study were also refractory to standard chemotherapy treatments
409 Study – Front-Line Non-Hodgkin’s Lymphoma (NHL)
The last study to be unblinded was a Phase II study in previously untreated patients with follicular NHL. Arzerra was evaluated in combination with a commonly used regimen called (CHOP) which includes cyclophosphamide, doxorubicin, vincristine and prednisone.
My sincere apologies for the confusion, readers; that's the first and last time I will post in a hurry with pressures of work. Sometimes it is better to post something at leisure and get the facts right than repent in haste. We all make mistakes sometimes, a correction is an appropriate action to take.
A big thank you to Greg at GSK for providing the correct information on the three studies. These guys rock for fast and timely help!
A new study published in the American Journal of Hematology Oncology by the Children's Oncology Group demonstrated that the ABVE-PC regimen provided high efficacy and reduced the cumulative doses of chemotherapy and radiation:
"Between 1997 and 2001, 216 eligible patients younger than 22 years with intermediate- or high-risk HL were treated with ABVE-PC. The median time from the beginning of the first cycle to the end of the third cycle was approximately 8.7 weeks, and time to completion of the fifth cycle was approximately 16 weeks. Rapid early response was documented in 63% of patients. Dose densities were greater than those of the most commonly used regimens, but cumulative doses were significantly lower, especially in the rapid responders."
For years, patients have been treated with the standard of care, ie MOPP or ABVD regimens, but while these approaches lead to excellent survival rates, they often result in long-term effects from toxicity, including infertility, second malignancy, and cardiopulmonary toxicity. Doctors hope to be able to cure the cancer while reducing the risk of long term effects on patients with the new 6 drug combination, although it will take a while before the true effects are known.
This new approach consists of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide and while not a walk in the park, as the first four chemotherapies are fairly toxic themselves, it may represent a potential improvement for children with NHL over existing options.
Schwartz, C., Constine, L., Villaluna, D., London, W., Hutchison, R., Sposto, R., Lipshultz, S., Turner, C., deAlarcon, P., & Chauvenet, A. (2009). A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate and high risk Hodgkin lymphoma: the results of P9425 from the Children's Oncology Group Blood DOI: 10.1182/blood-2008-10-184143
There have been a number of interesting early phase compounds with new data being reported at American Society of Hematology (ASH) meeting this weekend, some of these will be described over the next few days.Seattle Genetics has a number of monoclonal antibodies in development for the treatment of hematologic malignancies. One of them,SGN-35, is an antibody conjugate that targets CD-30 cells and hence is being evaluated in CD-30 positive malignancies such as Hodgkins Lymphoma. There was an interesting poster published here (PDF) at the ASH meeting.
Lintuzumab is a humanized monoclonal antibody that targets the CD33 antigen, which is expressed on a number of hematologic malignancies, including AML, myelodysplastic syndromes (MDS) and several myeloproliferative disorders. Seattle Genetics recently reported data from a completed phase Ia dose-escalation clinical trial of lintuzumab demonstrating multiple complete responses at well-tolerated doses. In addition to the phase IIb clinical trial, the company is also conducting a phase Ib trial of single-agent lintuzumab in patients with AML or MDS and a phase I trial of lintuzumab in combination with Revlimid(R) (lenalidomide) for advanced MDS.
The Independent Data Monitoring Committee (IDMC) has now completed a pre-specified safety review of data from the ongoing phase IIb trial of lintuzumab (SGN-33) in combination with low-dose cytarabine chemotherapy for older patients with acute myeloid leukemia (AML).
After review of the collected data, the IDMC did not identify any safety concerns and has recommended that the trial continue per the protocol. This interim assessment was based upon a planned evaluation of safety data from the first 50 percent of patients randomized in the study who received at least one dose of treatment. The company has completed approximately two-thirds of the total target enrollment of 210 patients, and expects to report data in the first half of 2010.
Another drug from the same company, SGN-40 (dacetuzumab), is being tested b-cell lymphomas (PDF of poster) and multiple myeloma and was snapped up early by Genentech in a licensing deal in 2007. Seattle Genetics also has a monoclonal antibody in development for autoimmune diseases (SGN-70 and SGN-75), which target CD70. The latter is in preclinical development at present.
It should be an interesting company to watch out for.
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