What does this mean for Immunotherapy? FDA put a temporary hold on Juno’s JCAR015, Three Death of Celebral Edema in CAR-T Clinical Trial and Kite Pharma announced Phase II portion of its CAR-T ZUMA-1 trial
Reporters and Curators: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN
UPDATED on 8/9/2016 at noon EST
Kite steps up plans for leading CAR-T, putting pressure on Juno
By Ned Pagliarulo | August 8, 2016
UPDATED on 7/14/2016 at 7 AM
UPDATED AGAIN on 7/14/2016 at 3 PM
NIH clamps down on two labs, interrupting trial work by Kite’s star scientist
by John Carroll |
Apr 20, 2016 6:26am
The NIH has put a crimp in the clinical trial work of Steven Rosenberg, Kite Pharma’s star collaborator at the National Cancer Institute. The feds slammed the brakes on the production of experimental drugs at two of its facilities–including cell therapies that Rosenberg works with–after an internal inspection found they weren’t in compliance with safety and quality regulations.
he NIH’s statement follows a release from Kite–one of the leading biotechs involved in CAR-T work–over the weekend saying only that the NIH facilities were undergoing a “voluntary internal review” that required a halt in new patient enrollment for the NCI’s cell therapy trials until the review is completed. Lion Biotechnologies used the same reference to explain a suspension of its NCI studies on tumor-infiltrating lymphocytes.
The problems at the facilities were uncovered after a fungal infection was discovered last summer in vials of albumin that were manufactured for the NIH Clinical Center. That embarrassment triggered a wide ranging probe into NIH facilities that led to the recent suspension, though the feds provided no details on exactly what they found.
Juno’s treatment, known as JCAR015, was being tested in adults facing their third or fourth bouts with leukemia. Such patients have very poor odds of beating the cancer, which makes testing risky treatments acceptable.
Michel Sadelain, the scientist at Memorial Sloan Kettering Cancer Center in New York who originally developed the T cell treatment being tested by Juno, says he only learned of the deaths this week. He says the fatalities did not occur in New York but at other centers participating in the trial.
“We have not seen this particular complication in over 50 adult [leukemia] patients treated at MSK,” he says. “These new medicines are powerful and the field is still learning how to harness this power. I don’t think these events change in any way the long-term potential for engineered T cells.”
Juno Halts Cancer Trial Using Gene-Altered Cells After 3 Deaths
Juno halts its immunotherapy trial for cancer after three patient deaths
JULY 7, 2016
In Juno patient deaths, echoes seen of earlier failed company
JULY 8, 2016
After a deadly clinical trial, will immune therapies for cancer be a bust?
JULY 8, 2016
Hours after Juno CAR-T study deaths announced, Kite enrolls CAR-T PhII
Well That Was Quick! FDA Lets Juno Restart Trial With a New Combination Chemotherapuetic
FDA lets Juno restart cancer-treatment trial
The FDA halted Juno’s “Rocket” clinical trial after the company reported thattwo patients undergoing treatment had died. Juno determined the deaths resulted from swelling in the brain caused by a new drug that had been added to the treatment.
he trial seeks to treat patients with relapsed acute lymphoblastic leukemia by using engineered T-cells to attack cancer cells.
Juno added the chemotherapy drug fludarabine to the treatment plan as part of an early step that gets the patient’s body ready for the T-cell injection. Previously, Juno was using only cyclophosphamide in that part of the treatment.
Under an agreement with the FDA, Juno will continue the trial without fludarabine, using only cyclophosphamide instead.
The company’s stock price, which fell more than 30 percent after the clinical hold was announced, was trading up more than 26 percent to $35.25 in after-hours trading Tuesday.
So What Did this all mean for the CAR-T world? Is it end for CAR-T Therapies?
This, as I have posted before is a matter of pharmacovigilence, the part of drug development and premarketing trials and postmarketing analysis that deals with adverse events and safety
see post of FDA guidelines for CAR-T therapy here
The JUNO trial called for co-treatment with the drug fludarabine, and antimetabolite known, in some cases to promote a cytotoxic lysis syndrome and central nervous system complications. GRANTED these two side effects were deemed RARE however it appears that the addition of fludarabine pre CART therapy aggravated either the side effect of fludarabine pretreatment or a cytoxic lysis syndrome from CAR-T (an adverse event from CAR-T therapy as I had posted here INCLUDING REPORTS OF TWO DEATHS DURING THE MSK CAR-t TRIAL
see below for listing of fludarabine adverse events
Chemocare.com uses generic drug names in all descriptions of drugs. Fludara is the trade name for fludarabine. In some cases, health care professionals may use the trade name fludara when referring to the generic drug name fludarabine.
Drug type: Fludarabine is an anti-cancer (“antineoplastic” or “cytotoxic”) chemotherapy drug. This medication is classified as an “antimetabolite.” (For more detail, see “How this drug works” section below).
What this drug is used for:
- Treatment of chronic lymphocytic leukemia (CLL), including CLL that has not responded to or reoccurred after standard therapy.
- Salvage therapy for non-Hodgkin’s lymphoma and acute leukemias.
Note: If a drug has been approved for one use, physicians may elect to use this same drug for other problems if they believe it may be helpful.
How this drug is given:
- Fludarabine is given through a vein, intravenously, IV.
- The amount of fludarabine that you will receive depends on many factors, including your height and weight, your general health or other health problems, and the type of cancer or condition being treated. Your doctor will determine your dose and schedule.
Important things to remember about the side effects of fludarabine:
- Most people do not experience all of the side effects listed.
- Side effects are often predictable in terms of their onset and duration.
- Side effects are almost always reversible and will go away after treatment is complete.
- There are many options to help minimize or prevent side effects.
- There is no relationship between the presence or severity of side effects and the effectiveness of the medication.
- The side effects of fludarabine and their severity depend on how much of the drug is given. In other words, high doses may produce more severe side effects.
The following side effects are common (occurring in greater than 30%) for patients taking fludarabine:
- Low blood counts. Your white and red blood cells and platelets may temporarily decrease. This can put you at increased risk for infection, anemia and/or bleeding.
Nadir: Meaning low point, nadir is the point in time between chemotherapy cycles in which you experience low blood counts.
Onset: none noted
Nadir: 10-14 days
Recovery: 14-21 days
- Nausea and vomiting
- Poor appetite
These side effects are less common side effects (occurring in about 10-29%) of patients receiving fludarabine:
- Numbness and tingling of hands and feet
- Shortness of breath (see lung problems)
- Rash (see skin reactions
- Taste changes, metallic taste
Other side effects:
- Increased risk of infection (such as herpes, fungal infection, and Pneumocystis carinii) due to suppression of the immune system. Antibiotics are often given to prevent or protect from these infections while receiving fludaribine.
- Although rare at regular dosages, severe central neurotoxicity may be seen in high dose treatment. Symptoms such as weakness, agitation, confusion, seizures, and/or coma.
- Hemolytic anemia has rarely occurred in people receiving one or more cycles of fludarabine. Patients are monitored for this condition.
- Your fertility, meaning your ability to conceive or father a child, may be affected by fludarabine. Please discuss this issue with your health care provider.
- Tumor lysis syndrome may occur as a result of leukemia treatment. Tumor lysis syndrome occurs when large amounts of cancerous cells are rapidly killed by the therapy. These cells release uric acid, potassium and phosphorus into the blood stream. Tumor lysis syndrome can lead to kidney failure. Tumor lysis syndrome usually occurs within 24 – 48 hours of therapy. Care must be taken to prevent the development of tumor lysis syndrome. Your health care provider will prescribe plenty of fluids to keep you hydrated. You may be given a drug called allopurinol that blocks uric acid production. In some cases, your health care provider may prescribe other measures to lower your white blood count before therapy. Let your health care provider know immediately if you are unable to urinate. Your health care provider will monitor your progress carefully during therapy. This is rarely seen and most often in the setting of high tumor cell burden.
Therefore it appears that THE ISSUE IS ONE OF PHARMACOVIGILENCE. During the UPENN trial the first patient almost died from Cytotox Release Syndrome however as UPENN incorporated a pharmacovigilence aspect in their trial early on, this serious adverse event was caught early and alleviated. However there may still be safety issues which still need to be addressed with CAR-T as the field is still evolving. Perhaps Juno switching from fludarabine to cyclophophospamide might be better but more favorable and safer results have been found in other trials.
AND THE NEWS KEEPS COMING!
Updated 7/14/16 18 hours AFTER the Previous story broke!!
Note to Revised Remarks: (Chief Medical Officer Dr. Mark) Gilbert mistakenly said “three” cases out of 129 rather than “four” cases. The fourth case was a patient treated in the JCAR014 trial, which case occurred in a young adult patient with r/r ALL who received flu/cy preconditioning and a higher JCAR014 cell dose than is now used on that trial. This death was included in the data presented in an oral presentation at the American Society of Hematology meeting in December 2015 and included in Juno’s Annual Report on Form 10-K for the fiscal year ended December 31, 2015.
Note to Revised Remarks: As noted earlier in the question and answer session, the FDA also reported an instance of cerebral edema in its database outside of the JCAR015 trial. Juno does not know whether that instance is the same case of cerebral edema as Juno is aware of from the JCAR014 trial, or if it occurred on a trial for a non-Juno product candidate.
Juno triggered a rout among its investors last week when it stunned the market with news that its lead CAR-T drug, JCAR015, had killed three people in clinical studies, triggering a clinical hold of its pivotal study by the FDA. The company immediately blamed the recent addition of the chemo drug fludarabine to precondition patients for the cell therapy and offered to drop the drug. In one of the fastest responses by the FDA in the face of multiple patient deaths, the agency agreed and lifted the hold earlier this week.
The personalized brand of CAR-Ts that Juno, Kite, and Novartis have been developing extract immune cells from patients, re-engineer them with a chimeric antigen receptor and then inject them back into patients, equipped to swarm cancer cells. These new treatments are also known to trigger cytokine release syndrome, which forced a temporary pause in the experimental work a couple of years ago. But Juno believes that the way that fludarabine was used recently caused the neurotoxicity that triggered cases of cerebral edema tracked by investigators.
Not everyone was as quick as the FDA to buy into that theory, though, as several investigators note that fludarabine has been used regularly without evidence of cerebral edemas. In addition, rival Kite Therapeutics has used a low dose of fludarabine in its work and has no plans to change as it pursues its own pivotal work.
The FDA, though, is not explaining anything as of now, declining to answer some specific questions of mine.
“Cellular therapies, including Chimeric Antigen Receptor (CAR) T-Cell therapies, hold great promise in the treatment of serious and life-threatening diseases,” the agency said in a statement to Endpoints. “We therefore do everything possible to assist sponsors in advancing clinical development programs in an effort to bring promising therapies to patients. The FDA recognizes that investigational products intended to treat serious diseases also have the potential to pose risks to patients. To this end, the FDA constantly looks at the risk-benefit profile of experimental therapies and when we have concerns about the risks, we may place the clinical trials on hold.”
This now seems like a problem with the running of a clinical trial. As I mentioned early UPENN’s trials had an incident in the first patient, who was closely monitored during the whole course of therapy. They reported the SERIOUS ADVERSE EVENT PROMPTLY and dealt with it within 2 days! This is how pharmacovigilence should work. It appears that JUNO may not had a good pharmacovigilence procedures in place as this Fourth (which appeared to be First) death should have been immediately reported as a SERIOUS ADVERSE EVENT (SAE) to the FDA where prompt action could have been taken. Perhaps such an experimental biotherapy should be conducted as an open trial format with data sharing. I understand that companies don’t want to real time reporting of results and AE and SAE but for these type of biotherapies perhaps that is warranted at this stage.