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                Resources for Information | Approved Drugs

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                        Oncology (Cancer) / Hematologic Malignancies Approval Notifications
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          FDA D.I.S.C.O.: First FDA approval of a CAR T-cell immunotherapyResources for Information | Approved Drugs FDA D.I.S.C.O.: First FDA approval of a CAR T-cell immunotherapy
  
  	
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*FDA medical oncologists discuss the first approval of a chimeric antigen receptor (CAR) T-cell immunotherapy.*

Sanjeeve Bala: Welcome back to the DISCO. Today’s Drug Information Soundcast in Clinical Oncology from FDA’s Oncology Center of Excellence discusses the recent approval of tisagenlecleucel, marketed as Kymriah.

Abhilasha Nair: Acute lymphoblastic leukemia is the most common type of malignancy in children in the United States, and the most common cause of cancer death. The B-cell precursor subtype occurs in about 80 to 85 percent of children with ALL. Therapy for acute lymphoblastic leukemia is traditional cytotoxic chemotherapy, including induction with standard four- or five-drug regimens, followed by consolidation and maintenance chemotherapy phases, along with intrathecal chemotherapy for CNS prophylaxis throughout the course of therapy. While curable in up to 90 percent of children diagnosed, patients with relapsed and refractory disease have few options, such as hematopoietic stem cell transplantation, if a remission can be achieved and a suitable donor is available.

AN: Hi, I’m Abhilasha Nair, a medical oncologist at the Oncology Center of Excellence at the FDA.

SB: And I am Sanjeeve Bala, a medical oncologist and acting clinical team leader at FDA. Tisagenlecleucel was approved for the treatment of patients up to age 25 with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse. This agent is the first CAR-T cell approved by the FDA, and the first gene therapy approved in the United States.

AN: Immunotherapy continues to change the landscape of oncology care. Sanjeeve, tell us more about this new technology, the CAR-T cell, an entirely new treatment approach for patients with cancer.

SB: Sure, Abhi. This is produced by taking a sample of a patient’s blood, isolating the T lymphocytes, and genetically engineering those T-cells to express a new chimeric receptor that recognizes CD19 on their B-cells, which means both on their leukemia cells as well as their normal B-cells. As we know, the job of the T-cell is to kill its target. So, the engineered T-cell should recognize and kill B-cells, including the malignant cells.

AN: Let’s talk about the chimeric receptor.

SB: It’s called chimeric, because the structure of the receptor is a fusion of the antigen recognition portion of an antibody with the intracellular signaling domain of a T-cell receptor plus additional intracellular costimulatory molecules that help activate the immune attack. In this case, the chimeric receptor recognizes CD19 on B-cells and expresses the intracellular domains of the 4-1-BB costimulatory molecule along with the T-cell receptor’s own. The genetically-engineered cells are allowed to replicate in culture prior to infusion back into the patient. This process is known as adoptive T-cell transfer, or adoptive cell therapy.

AN: So how is this different from a bone marrow transplant or other hematopoietic stem cell transplants?

SB: Basically, this approach does not replace a patient’s entire hematopoietic system, and instead attempts to augment the immune system by the addition of these engineered immune T-cells, which are not hematopoietic stem cells.

AN: Sanjeeve, let’s look at the application. What clinical data supported this approval?

SB: Tisagenlecleucel was approved based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 who had undergone prior stem cell transplantation. After manufacture of the T-cell product, patients were treated with lymphodepleting chemotherapy, followed optimally within two days by intravenous infusion of their modified T-cells.

AN: I think we need to hear about the efficacy data. It’s going to be a lot of numbers, especially because of the way patients with ALL are monitored post treatment, with bone marrow biopsies and peripheral blood counts.

SB: Right. So, of the 63 patients, central review confirmed remission in nearly 83 percent. This breaks down into 63 percent of the total who had complete remission, and 19 percent with complete remission with incomplete hematological recovery. All responders had no residual disease by flow cytometry. The median duration of remission was not reached on the study, with a range of 1.2 to more than 14 months at the time the study was reported.

AN: Let’s hear the safety information.

SB: This treatment can produce adverse reactions that may be unfamiliar to most prescribers, like cytokine release syndrome or CRS. Neurotoxicity was also noted, with encephalopathy manifesting as aphasia, confusion, and somnolence as well as headaches. Since the treatment targets all B-cells, both normal B-cells as well as the leukemia cells, the treatment can also cause hypogammaglobulinemia, which may increase infections. On the study, the rate of grade 3 or 4 adverse reactions was 84 percent. Some adverse reactions were severe, including fatal CRS-related sequelae. Because of the novel and serious safety profile of this treatment, the approval includes a Risk Evaluation and Mitigation Strategy, or REMS, and may only be administered at accredited sites. This also ensures that treating sites have immediate access to the anti-interleukin-6 antibody tocilizumab for the treatment of CRS. Detailed safety information is available in the prescribing information, which may be found on the FDA website.

AN: Sanjeeve, give us the three take-home points from this DISCO.

SB: Sure, Abhi. The three main take away points are: 1) Tisagenlecleucel is approved for the treatment of patients less than 25 years old with precursor-B cell ALL that is refractory to treatment or in second or later relapse. 2) This adoptive cell therapy delivers a patient’s own genetically-modified T-cells to kill B-cells, but patients typically require treatment with lymphodepleting chemotherapy prior to the CAR T -cell infusion. 3) The toxicity profile for this treatment is unique, and can include cytokine release syndrome and its sequelae, neurotoxicity, and the mentioned complications associated with B-cell depletion. Because of the safety profile, tisagenlecleucel is under a REMS with elements to assure safe use and can only be administered at certified sites.

SB: For a transcript with a link to the prescribing information and the multidisciplinary team of FDA experts who conducted the review, visit the FDA Oncology Center of Excellence DISCO website at www.fda.gov/DISCO.

AN: Thank you Sanjeeve. Are there other FDA oncology drug approvals that you would like to hear about? Leave us your questions and comments on Twitter @FDAOncology and as always, we welcome your feedback at our email address, FDAoncology@fda.hhs.gov. I’m Abhi Nair, thank you for tuning in to DISCO today.

SB: And until next time at the DISCO, I’m Sanjeeve Bala.

**Acknowledgements:**

This Drug Information Soundcast in Clinical Oncology was developed by Sanjeeve Bala, Abhilasha Nair, Kirsten B. Goldberg, and Richard Pazdur, of the Oncology Center of Excellence and the Office of Hematology and Oncology Products; and Maura O’Leary, of the Center for Biologics Evaluation and Research. Steven Jackson of the Division of Drug Information was the sound producer.

Members of the review committee for this Biologics License Application were:

Clinical: Maura O’Leary, MD; Donna Przepiorka, MD, PhD; Bindu George, MD; Tejashri Purohit-Sheth; Marc Theoret, MD; Jaspal Ahluwalia, MD; Dennis Cato; Hong Yang; Million Tegenge; Richard Forshee; Shiowjen Lee; Xue (Mary) Lin (clinical and statistical review), and Xiaobin Victor Lu, PhD, Chair of the Review Committee.

Clinical Outcome Assessment: Chao Liu; Justin C. Earp; Stacy Shord; Yaning Wang; Nam Atiqur Rahman; Nikunj Patel.

Chemistry, Manufacturing and Controls (CMC): Xiaobin (Victor) Lu, PhD; Andrew Byrnes, PhD; Kimberly Schultz, PhD; Elena Gubina, PhD; Tom Finn, PhD; Denise Gavin, PhD; Joan Johnson, MS; Randa Melhem, PhD; Ashley Burns, PharmD; Richard Heath Coats; Simleen Kaur; Cheryl Hulme; Marie Anderson, MS, PhD.

Pharmacology/Toxicology: Ying Huang, PhD

Clinical Pharmacology: Iftekhar Mahmood

Labeling: Dana Jones

Other Reviews: Jean Makie, Naomi Redd

                                                                                  Content current as of:
      02/23/2018
              
              
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						  OncologyResources for Information | Approved Drugs

          
                        Oncology (Cancer) / Hematologic Malignancies Approval Notifications
          Ongoing | Cancer Accelerated Approvals
          Verified Clinical Benefit | Cancer Accelerated Approvals
          Withdrawn | Cancer Accelerated Approvals
          Other | Cancer Accelerated Approvals


                        Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description
 
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