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Rapid Response: Understanding the severity and implication of Juno's clinical hold announcement for JCAR015 on July 7th 2016 after 2 additional patient deaths in the ROCKET trial.Ticker(s): JUNO, NVS, KITE
Name: Dr Stephan Grupp - MD/ PhD
Institution: University of Pennsylvania
- Director of the Cancer Immunotherapy Frontier Program, director of Translational Research for the Center for Childhood Cancer Research and medical director of the Stem Cell Laboratory
- Has led a group that performed a nationwide clinical trial establishing antibody-based immunotherapy as the new standard for care in neuroblastoma.
- Has received several awards throughout his career and is a member of a number of professional organizations including the International Society for Cell Therapy, American Pediatric Society, American Society of Hematology, American Society of Blood and Marrow Transplantation and more
What is your initial reaction to the clinical hold disclosed by Juno?
The company said:
"The clinical hold was initiated after two patient deaths last week, which followed the recent addition of fludarabine to the pre-conditioning regimen."
What do you think was the reason that fludarabine was added? Was this done per a pretrial protocol or in response to an issue? Was this added to the pre-regimen after cyclophosphamide because it was perceived to be a higher risk?
What implications do think this development will have for other CAR-T therapies in development?
What timeline could we expect for the FDA to make a decision on Juno's
proposal? Would additional data most likely need to be generated or
could it be a relatively straightforward process. Essentially the FDA
says "Ok, it looks like we understand why fludarabine caused and issue
let's just go forward with cyclophosphamide."?
Neurotoxicity in fludarabine patients has evidence in the literature.
How much do these these studies calm fears over this issue?
Examples (Source from twitter user @Aiims1742)
Do you think the neurotoxicity seen with the JCAR015 flu-cy conditioning regimen is due to excessive Car-T mediated effects in the CNS, or more directly to neurotox effects of flu? If you think it is due to excessive kill off of normal Bcells and enhanced CAR-T proliferation, then why isn't this level of neurotoxicity seen with the KITE regimen? Lastly, since the co-stim signal of the JUNO construct is 4.1BB, which has been shown to enhance T cell persistence over CD28, the co-stim molecule in KITE's construct, could increased CART persistence explain the differences in toxicity between JUNO and KITE's CD19 CART toxicities?Added By: userd16bd1d0
Following the news of trials being put on hold, JUNO's management announced that they believe that fludarabine triggered cerebral edamas. However, some sources claim that there is no record of fludarabine being linked to cerebral edemas and that it is a compound used in a number of other CAR-T trials. Could you please comment on the likelihood of cerebral edemas being caused by fludarabine. Also, is there any indication that JCAR015 could have caused this condition?
Other companies that develop therapies based on CAR-T and use fludarabine do not seem to be worried about the problem JUNO encountered. For example KITE is firm on their ZUMA-1 trial and is not considering to pull out of it or resubmit application without fludarabine, in order to prevent situation experienced by JUNO. Is there any particular reason for such optimism and how do trials/therapy of JUNO's competitors differ from the one that was put on hold?
Given the recent challenges with JCAR015 and the poor durability reported with CTL019 do we understand what is driving the differences between agents? Is it going to take additional time to optimize generation 2+ agents and regimes? How does this impact KTE-019? Could this allow KTE-019 to be established as the near term leader in the space?Added By: userf9cca949
JUNO's management made a comment that this incident doesn't affect JUNO's development programs for other CD-19 directed CAR-T candidates. Could you please explain why this is the case and what are the differences between various development programs initiated by the company (e.g. JCAR017, JCAR015, JCAR014 etc.)?
Some companies heavily into bi-specific antibodies appear to have been doubling down on their statements about potential superiority to CAR-T after the recent Juno Therapeutics patient deaths. How realistic is it that bi-specific antibodies could hold the same CURATIVE promise as CAR-T? Do you view bi-specific antibodies as having long term potential superiority or are they more a potential short term compromise until safety issues of CAR-T are resolved?
Considering the use of a murine domain in JCAR015, how necessary is the intensive immuno-depletion offered by the flu/cy combination chemotherapy approach to achieve meaningful efficacy over alternative approaches such as biologics (CPIs, BsAbs etc)? It would appear to me that such a construct would be negatively impacted by the presence of non-malignant B-cells as well as CD8+ T-cells which can lead to inhibitory abs to the scFv domain or direct killing of the construct. However, bearing this in mind do you think the over depletion, if you will, coupled with the CD28 co-stim domain led to a far greater T-cell pop than is clinically necessary? In all, how do you see Juno, Kite, and other investigators balancing potent T-cell response while avoiding over activation leading to serious toxicity?
Without an efficent means of reversing the dose in the event of a sAE, due to the fact that this is a cell based living therapy, is there a clear pathforward to approval at this stage without the introduction of a safety switch (perhaps as Bellicum's approach)? From my prospective, with safety and manufacturing considerations is it likely that CAR-T will remain in 3rd line (or later) w.r.t hematologic malignancies until the technology is further improved, but would of course like a second opinion on how you see the SoC progressing.
Mechanistically, how does fludarabine cause neurotoxicity?Added By: user09bc613a
To put these two treatment-related deaths in perspective for this extremely sick patient population, can you tell us what percentage of Adult ALL patients die of treatment-related deaths based on current therapies in this refractory setting?Added By: jakstatgata
What is the expected median overall survival of the patient population enrolled in the ROCKET trial based on current standard of care?Added By: jakstatgata
Apart from increased regulatory scrutiny, what other impact do you think this event will have on the JCAR products, especially those in phase 3 trials currently?Added By: abir
How could this effect other pediatric ALL CAR therapy trials, like the one recently initiated by Cellectis?Added By: user09bc613a
why does the JCAR015
https://clinicaltrials.gov/ct2/show/NCT02535364state "one cycle of cytoreductive chemotherapy"
without specifying dose of Cy or Cy+Flu?
Is it possible one or more of the clinical trial sites gave an too large dose?
What is your preferred conditioning regimen (drugs and doses please)?
Don't we also have to blame on the DSMB and Regulators who certainly did not analyze the data from first dead patient correctly, since it seems there was a consensus about the fact 'the death was not treatment-related'? What do you think about what could have lead them to such a conclusion? Why not recommending a kind of 'dose-escalation' when adding something new impacting the immune system? How does DSMB work? Is it several people who vote with a majority rule or with unanimity to resume the trial? What is important to watch out in such a situation? Does doubt have a room?
In the CTL019 pediatric studies, what dose of fludarabine was used as preconditioning?Added By: user09bc613a
Hell will suicide technology prevent this kind of adverse eventAdded By: hwolfe8883
It is my understanding that the deaths were caused by brain swelling due to too much Cerebrospinal Fluid (CSF) being produced. While these deaths are tragic there is an other market where a drug that DOES increase CSF is needed.
My late wife Karen committed suicide due to Intracranial Hypotension due to Cerebrospinal Fluid (CSF) Leaks. A condition that is more common that many think (for example Actor George Clooney had/has a CSF Leak and considered suicide), yet is so unknown that some doctors argue the condition does not even exist.
Karen's Journal is now required reading at Duke School of Medicine. A local news paper report wrote this for the Sept. 8th 2014 cover story for the Derrick Newspaper: "Karen's first-hand account of her illness gave an honest, heart-wrenching depiction of what it is like to live with debilitating pain day-to-day."
Lets not let those lives lost in this drug trial be in vain and use what was learned to help those that do need more brain fluid. If anyone can help please contact me for more details on the condition of CSF Leaks.
What do you make of the fact that all 3 patients with cerebral edema were < 25 years old?
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- FDA has removed the clinical hold on the Phase II clinical trial of JCAR015 (known as the “ROCKET” trial) in adult patients with relapsed or refractory B cell acute lymphoblastic leukemia (r/r ALL) JUNO, CLLS, KITE, BLUE, ZIOP Occurred On: Jul 12, 2016
- Juno Therapeutics Reports Clinical Hold on the JCAR015 Phase II ROCKET Trial JUNO Occurred On: Jul 07, 2016