Posted on March 11th, 2016
by Jeffrey Bacha
I imagine I speak for many in the GBM community when I say that the Celldex news earlier this week felt like getting punched in the gut – at least a bit. Yes, Celldex is “technically” a potential competitor to my company, but to have the wind knocked out of the sails of yet another therapy that we all hoped would give doctors and patients another tool in the sparse armamentarium to treat this most horrible of cancers hit home – again.
Perhaps unlike any other scientific field, the GBM community is united to work together – perhaps out of mutual frustration for the inability to make a difference for patients. Glioblastoma multiforme, or GBM, is among the most deadly of cancer diagnoses. It has largely been left behind in the huge leaps and bounds that have been made in the treatment of many tumors. The median survival of GBM patients today is about 15 months from diagnosis … a statistic that hasn’t changed in decades.
A cancer physician’s treatment “toolkit” is generally limited to surgical resection, radiotherapy and pharmaceutical therapy. In tumors of the central nervous system, such as GBM, this toolkit is limited to therapies that can penetrate the blood-brain-barrier (bbb). Most drugs are useless against GBM because they cannot reach the tumor. Approaches to circumvent the bbb, such as injecting drugs directly into the tumor bed following surgery have been met with limited success in GBM because of the tumor’s infiltrative nature. A drug that is injected into the site of the primary tumor cannot reach distant GBM cells – clinical experience tells us that can only be accomplished with systemic therapy.
The drugs in the GBM toolkit have been generally limited to cytotoxic alkylating agents such as nitrosoureas (CCNU, BCNU) and temozolomide. These drugs attack the tumor’s DNA at the O6 position of guanine resulting in base-pair mismatch or DNA strand breaks. Unfortunately, these all share a common liability associated with their mechanism. A naturally occurring DNA repair enzyme renders O6 alkylators ineffective in approximately 2/3 of GBM patients.
Tremendous investment has been made in new approaches. Recent efforts at new therapeutic modalities have included immunotherapy, vaccines, gene therapy and electromagnetic field therapy. All of these have shown promise in early GBM studies, but none have yet played out in controlled Phase III clinical trials. These elegant scientific approaches have shown limited utility in other cancers – sometimes with meaningful benefit in a subset of patients. Given this, why do we continue to be at first spellbound then heartbroken each time they advance in clinical trials for GBM – a most difficult to treat cancer?
The reason is hope.
GBM is, in fact, a rare cancer affecting just 15,000 patients in the United States each year. But, it strikes suddenly and steals life from most patients and their loved ones in only a few short months. GBM has made headlines with Beau Biden, Ted Kennedy, and Gary Carter’s deaths. It is such a scourge that any glimmer of hope – even from a competitor – grabs us because we in the field are committed to giving doctors new tools for their arsenal against GBM.
Avastin™, approved for recurrent GBM in 2009 has failed to demonstrate a survival benefit in controlled clinical trials.
Recently, the approval of the Optune™ a medical device that delivers electromagnetic waves to the brain has provided a new tool that improved median survival in newly diagnosed GBM patients by 4.9 months when added to the standard chemotherapy + radiation regimen.
An immunotherapy, ICT-107, is seeking a second wind after failing to meet the primary endpoint in its first Phase III clinical trial. In looking at the data, it appears that there may be a survival benefit by adding this immunotherapy to standard of care for the 1/3 of patients where available chemotherapy is effective. A new Phase III trial is focusing specifically on that population.
Still, at this point, the only drug treatments that have shown meaningful survival benefit are cytotoxic chemotherapies; however, as discussed above, the currently available chemotherapies lack efficacy in the majority of GBM patients.
At DelMar, we are focused on a new cytotoxic chemotherapy, VAL-083, that we believe will be game changing for the 2/3 of patients whose tumors express features that render currently available chemotherapy ineffective. VAL-083 demonstrated promising activity against GBM in prior human clinical trials sponsored by the United States National Cancer Institute. VAL-083 was eventually passed over for commercialization in favor of nitrosoureas primarily due to the status of its patent portfolio at the time.
A randomized Phase II clinical trial conducted at the Mayo Clinic during the NCI research era demonstrated a greater than 8 month survival benefit when VAL-083 was combined with radiotherapy versus radiation treatment alone. By comparison, temozolomide, the billion-dollar product that replaced the nitrosoureas as standard-of-care chemotherapy in GBM, demonstrated a survival benefit versus radiation alone of 2.5 months. We have also demonstrated that VAL-083’s unique anti-tumor mechanism is not subject to the same resistance mechanisms that plague drugs like temozolomide. Based on these facts, we initiated clinical trials focused initially on GBM patients who have failed all other available therapies.
We believe that VAL-083 as an active chemotherapy for the majority of the GBM population will provide a real paradigm shift in the treatment of GBM – especially in combination with other treatments such as immunotherapy, that that may become available in the future.
Again, we have hope.
In reality, Celldex’ drug, Rintegra® performed on par with its prior trials, but for some reason, the control arm had a much better than expected outcome. At the moment, “Why?” is a mystery. We are all rooting for Celldex’ subgroup analysis to shed light on this surprising outcome, and hopefully, we will gain new knowledge from their research – knowledge that we can use toward continuing the development of new treatments for GBM.
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