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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.: FDA approval of moxetumomab pasudotox-tdfk for relapsed or refractory hairy cell leukemiaResources for Information | Approved Drugs FDA D.I.S.C.O.: FDA approval of moxetumomab pasudotox-tdfk for relapsed or refractory hairy cell leukemia
  
  	
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*FDA medical oncologists discuss the Sept. 13, 2018, approval of moxetumomab pasudotox-tdfk for the treatment of patients with relapsed or refractory hairy cell leukemia.*

Dr. Sanjeeve Bala: Welcome back to the DISCO, the FDA’s Soundcast in Clinical Oncology from the Oncology Center of Excellence. We are coming to you from Silver Spring, MD, and during our soundcasts, we discuss recent FDA approvals of cancer drugs and therapies. We hope this information will help you in better understanding these approvals and how new drugs and therapies are benefitting people fighting cancer. Today, we’ll be discussing the recent approval of moxetumomab pasudotox-tdfk for the treatment of patients with relapsed or refractory hairy cell leukemia.

I’m Dr. Sanjeeve Bala, a medical oncologist and clinical team leader at FDA, and I am joined by my colleague Dr. Abhi Nair, also a medical oncologist at the Oncology Center of Excellence here at the FDA. She’s going to start with some background on the disease.

Dr. Abhi Nair: Hi everyone. Thanks for joining us.

AN: Hairy cell leukemia is a rare and incurable malignancy in which malignant “hairy” B-cell lymphocytes accumulate in bone marrow and interfere with trilineage hematopoiesis. This results in extramedullary hematopoiesis with resultant symptomatic and sometimes massive splenomegaly. Treatment, when clinically indicated, starts with monotherapy with one of the purine nucleoside analogs, cladribine or pentostatin. Roughly 85% of patients will achieve a complete response from their initial treatment, which can be durable, with a median of 10 years. Upon recurrence, the malignancy may again be sensitive to treatment with cladribine or pentostatin, although subsequent remissions tend to be less durable. Moxetumomab pasudotox-tdfk is for adult patients with relapsed or refractory hairy cell leukemia who have had treatment with at least two prior systemic therapies, including at least one purine nucleoside analog.

SB: Moxetumomab pasudotox-tdfk was approved on September 13, 2018. That four-letter suffix “tdfk” denotes that this is an approval for a biologic product and is a new naming standard at FDA. The trade name for this CD22-directed therapy is Lumoxiti. It is composed of only the variable domains, or antigen-binding domains, from an anti-CD22 monoclonal antibody, so it’s not a full-length antibody. The heavy chain variable domain is fused to a shortened form of the pseudomonas exotoxin, PE38, that inhibits protein synthesis. After binding to CD22 on B-cells, the toxin payload modifies elongation factor 2, inhibits protein synthesis, and results in cell death. The dose is 0.04 mg/kg administered intravenously over 30 minutes on days 1, 3, and 5 of each 28-day cycle.

AN: Sanjeeve, let’s hear about the clinical trial that led to the approval.

SB: The evaluation of effectiveness of moxetumomab pasudotox-tdfk was primarily based on a single-arm, open-label study evaluating monotherapy with this agent in a heavily-pretreated population of 80 patients, all of whom had prior treatment with at least one round of a purine nucleoside analog. In the recurrent setting, about 75% of patients had also received off-label treatment with rituximab and 18% also had prior off-label treatment with a BRAF inhibitor.

AN: So, this is definitely a heavily pre-treated population. Tell us about the endpoints used in this single-arm trial.

SB: Yeah, they were heavily pre-treated, Abhi. The endpoint was the rate of durable complete response, defined as the overall response that meets blood, bone marrow, and imaging criteria for a complete response by a blinded independent central review, followed by a duration of hematologic remission of at least 180 days.

AN: With that defined endpoint, what were the results, Sanjeeve?

SB: The durable complete response rate was 30% as assessed by the blinded central review, and the median duration of response was not reached.

AN: For a patient population with an unmet medical need, that sounds like a meaningful possibility of benefit from this treatment. What were the overall safety findings?

SB: Abhi, there are important safety issues with moxetumomab pasudotox-tdfk attributed to the nature of the pseudomonas-derived toxin payload. The first is capillary leak syndrome.

AN: So, this is characterized by findings like fluid retention, including weight gain and hypotension, as well as hypoalbuminemia and increased hemoconcentration.

SB: Right, in the combined safety database of 129 patients in this application, capillary leak syndrome occurred in 34% of patients, with grade 3 or 4 symptoms in about 4% of treated patients, and usually but not uniformly occurring in the first 8 days of a treatment cycle. Another significant toxicity is hemolytic-uremic syndrome or HUS.

AN: And this is characterized by signs of hemolysis with schistocytes usually present in peripheral blood smear, acute onset or worsening thrombocytopenia, and renal injury.

SB: Yes. HUS occurred in 7% of patients, including 3% with grade 3 and 0.8% with grade 4 HUS. While most cases of HUS occurred within 9 days of infusion, they were reported on other days throughout the cycle. Because of the severity and potentially fatal consequences of these toxicities from treatment with moxetumomab pasudotox-tdfk, the prescribing information has a boxed warning to notify prescribers that vigilance is required for the early detection of these symptoms, with prompt management required to mitigate the potential severity of these toxicities. The prescribing information has additional important details regarding these and other toxicities associated with this treatment.

AN: Thanks, Sanjeeve. Why don’t you give us the three take-aways for this D.I.S.C.O.

SB: Sure, Abhi. Number one, moxetumomab pasudotox-tdfk is a new option for the treatment of adult patients with hairy cell leukemia who have relapsed or have become refractory to at least two prior systemic therapies, including treatment with a purine nucleoside analog. Number two, the prescribing information contains important safety information, including a boxed warning. And number three, prescribers must remain on the alert for the development of capillary leak syndrome or hemolytic uremic syndrome, which are rare but potentially significant toxicities from the treatment that require early intervention.

SB: You can find more detailed prescribing and safety information in the approved prescribing information, also available on the web at Drugs@FDA.

SB: For a transcript with links to an in-depth look at the FDA analysis, and the multidisciplinary team of FDA experts who conducted the review, visit the FDA Oncology Center of Excellence DISCO website at 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 the 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, Bindu Kanapuru, Kirsten B. Goldberg, and Richard Pazdur, of the Oncology Center of Excellence and the Office of Hematology and Oncology Products. Steven Jackson of the Division of Drug Information was the sound producer.

Members of the Multidisciplinary Review and Evaluation team for this New Drug Application were:

Nonclinical Reviewer: Matthew Thompson
Nonclinical Team Leader: Christopher Sheth
Clinical Pharmacology Reviewer: Guoxiang Shen
Pharmacometrics Reviewer: Jee Eun Lee
Pharmacometrics Team Leader: Lian Ma
Clinical Pharmacology Team Leader: Olanrewaju Okusanya
Clinical Reviewer: Bindu Kanapuru
Clinical Team Leader: Nicole Gormley
Statistical Reviewer: Jiaxi Zhou
Statistical Team Leader: Yuan Li Shen
Cross-Disciplinary Team Leader: Nicole Gormley
Division Director (DHOT) John Leighton
Deputy Division Director (OCP): Brian Booth
Deputy Division Director (OB): Thomas Gwise
Acting Deputy Division Director (DHP): Nicole Gormley
Office Director: Richard Pazdur

Further Information:

Drug Approval Package for LUMOXITI

                                                                                  Content current as of:
      11/29/2018
              
              
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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
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                        Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Short Description
 
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