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US FDA Approves LUMOXITI™ (moxetumomab pasudotox-tdfk) for Certain Patients with Relapsed or Refractory Hairy Cell Leukemia

AZN | September 13, 2018

US FDA Approves LUMOXITI™ (moxetumomab pasudotox-tdfk) for Certain Patients with Relapsed or Refractory Hairy Cell Leukemia

Approval of LUMOXITI, a first-in-class medicine for hairy cell leukemia, marks first new treatment option for patients in over 20 years

AstraZeneca and MedImmune, its global biologics research and development arm, announced today that the US Food and Drug Administration (FDA) has approved LUMOXITI™ (moxetumomab pasudotox-tdfk) for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. LUMOXITI is not recommended in patients with severe renal impairment (CrCl ≤ 29 mL/min). The Phase III trial results demonstrated 75% (95% confidence interval [CI]: 64, 84) of patients receiving LUMOXITI achieved an overall response; 30% (95% CI: 20, 41) had a durable complete response.

Dave Fredrickson, Executive Vice-President, Global Head Oncology Business Unit, said: “Today’s FDA approval of LUMOXITI represents a significant milestone for people living with hairy cell leukemia, a rare blood cancer that can result in serious and life-threatening conditions. For patients, this approval provides the first FDA-approved medicine for this condition in more than 20 years.”

Robert J. Kreitman, MD, Senior Investigator, Head of Clinical Immunotherapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, and Principal Investigator of the Phase III clinical trial, said: “While many patients with hairy cell leukemia experience a remission with current treatments, 30% to 40% will relapse five to ten years after their first treatment. With subsequent treatments, durations of response diminish and toxicities accumulate, and few approved treatment options exist. Moxetumomab pasudotox represents a promising non-chemotherapeutic agent for HCL, addressing an unmet medical need for physicians and their patients.”

LUMOXITI was approved under FDA Priority Review. The approval is based on data from the Phase III single-arm, open-label ‘1053’ trial of LUMOXITI monotherapy in 80 patients who have received at least two prior therapies, including a purine nucleoside analog. The primary endpoint of the trial was durable complete response. Summary of key results from the trial, as determined by a blinded independent central review:


Efficacy Measure		Result %, (95% CI)
Durable Complete Response Rate^a,b		30% (20, 41)
Overall Response Rate^c		75% (64, 84)
Complete Response^d		41% (30, 53)
Partial Response^e		34% (24, 45)
Hematologic Remission^b		80%

^a		Durable complete response is defined as patients who achieved complete response with hematologic remission for a duration of more than 180 days
^b		Hematologic remission is defined as hemoglobin > 11g/dL, neutrophils > 1500/mm³, and platelets > 100,000/mm³ without transfusions or growth factor for at least 4 weeks
^c		Overall response rate is defined as best overall response of complete response or partial response
^d		Complete response is defined as clearing of the bone marrow of hairy cells by routine Hematoxylin and Eosin stain, radiologic resolution of preexisting lymphadenopathy and/or organomegaly, and hematologic remission
^e		Partial response is defined as ≥ 50% decrease or normalization (< 500/mm³) in peripheral blood lymphocyte count, reduction of pre-existing lymphadenopathy and/or organomegaly, and hematologic remission

The median time to hematologic remission was 1.1 months (range: 0.2 to 13). At data cut-off, the median duration of complete response was not yet reached after a median 16.7 months of follow-up.

Capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS), including life-threatening cases of each, have been reported among patients treated with LUMOXITI. In the combined safety database of 129 HCL patients treated with LUMOXITI, Grade 3 or 4 CLS occurred in 1.6% and 2% of patients, respectively. Grade 3 or 4 HUS occurred in 3% and 0.8% of patients, respectively.

In the ‘1053’ trial of 80 patients, the most common Grade 3 or 4 adverse reactions (reported in at least ≥ 5% of patients) were hypertension, febrile neutropenia, and HUS. HUS was the most common adverse reaction leading to discontinuation (5%). The most common adverse reactions (≥ 20%) of any grade were infusion related reactions (50%), edema (39%), nausea (35%), fatigue (34%), headache (33%), pyrexia (31%), constipation (23%), anemia (21%), and diarrhea (21%). The most common laboratory abnormalities (≥ 20%) of any grade were creatinine increased, ALT increased, hypoalbuminemia, AST increased, hypocalcemia, hypophosphatemia, hemoglobin decreased, neutrophil count decreased, hyponatremia, blood bilirubin increased, hypokalemia, GGT increased, hypomagnesemia, platelet count decreased, hyperuricemia, and alkaline phosphate increased.

The recommended dose of LUMOXITI is 0.04 mg/kg administered as an intravenous infusion over 30 minutes on days 1, 3, and 5 of each 28-day cycle up to 6 cycles, disease progression, or unacceptable toxicity.

IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING

WARNING: CAPILLARY LEAK SYNDROME and HEMOLYTIC UREMIC SYNDROME

Capillary Leak Syndrome (CLS), including life-threatening cases, occurred in patients receiving LUMOXITI. Monitor weight and blood pressure; check labs, including albumin, if CLS is suspected. Delay dosing or discontinue LUMOXITI as recommended [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
Hemolytic Uremic Syndrome (HUS), including life-threatening cases, occurred in patients receiving LUMOXITI. Monitor hemoglobin, platelet count, serum creatinine, and ensure adequate hydration. Discontinue LUMOXITI in patients with HUS [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

WARNINGS AND PRECAUTIONS

Capillary leak syndrome (CLS), including life-threatening cases, has been reported among patients treated with LUMOXITI and is characterized by hypoalbuminemia, hypotension, symptoms of fluid overload, and hemoconcentration. In the combined safety database of HCL patients treated with LUMOXITI, CLS occurred in 34% (44/129) of patients, including Grade 2 in 23% (30/129), Grade 3 in 1.6% (2/129), and Grade 4 in 2% (3/129).

Most cases of CLS occurred in the first 8 days (range: 1 to 19) of a treatment cycle, however, cases have also been reported on other days throughout the cycle. The median time to resolution of CLS was 12 days (range: 1 to 53).

Monitor patient weight and blood pressure prior to each LUMOXITI infusion and as clinically indicated during treatment. Assess patients for signs and symptoms of CLS, including weight gain (increase in 5.5 pounds (2.5 kg) or ≥ 5% from Day 1 of current cycle), hypotension, peripheral edema, shortness of breath or cough, and pulmonary edema and/or serosal effusions. In addition, the following changes in laboratory parameters may help identify CLS: hypoalbuminemia, elevated hematocrit, leukocytosis, and thrombocytosis.

CLS may be life-threatening or fatal if treatment is delayed. Counsel patients to seek immediate medical attention should signs or symptoms of CLS occur at any time. Patients who develop CLS should receive appropriate supportive measures, including concomitant oral or intravenous corticosteroids, and hospitalization as clinically indicated. Withhold LUMOXITI for Grade 2 CLS until resolution, and permanently discontinue for Grade ≥ 3 CLS.

Hemolytic Uremic Syndrome (HUS), including life threatening cases, has been reported in patients treated with LUMOXITI and is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and progressive renal failure. In the combined safety database of HCL patients treated with LUMOXITI, HUS occurred in 7% (9/129) of patients, including Grade 3 in 3% (4/129) and Grade 4 in 0.8% (1/129).

Most cases of HUS occurred in the first 9 days (range: 1 to 16) of a treatment cycle, however, cases have also been reported on other days throughout the cycle. The median time to resolution of HUS was 11.5 days (range: 2 to 44). All cases resolved, including those who discontinued LUMOXITI.

Avoid LUMOXITI in patients with prior history of severe thrombotic microangiopathy (TMA) or HUS. Administer prophylactic intravenous fluids before and after LUMOXITI infusions. In Study 1053, patients with a platelet count ≥ 100,000/mm received low-dose aspirin on Days 1 through 8 of each 28-day cycle for prophylaxis of thrombosis.

Monitor blood chemistry and complete blood counts prior to each dose and on Day 8 of each treatment cycle. Monitoring mid-cycle is also recommended. Consider the diagnosis of HUS in patients who develop hemolytic anemia, worsening or sudden onset of thrombocytopenia, increase in creatinine levels, elevation of bilirubin and/or LDH, and have evidence of hemolysis based on peripheral blood smear schistocytes.

The events of HUS may be life-threatening if treatment is delayed with increased risk of progressive renal failure requiring dialysis. If HUS is suspected initiate appropriate supportive measures, including fluid repletion, hemodynamic monitoring, and consider hospitalization as clinically indicated. Discontinue LUMOXITI in patients with HUS.

Renal Toxicity has been reported in patients treated with LUMOXITI therapy. In the combined safety database of HCL patients treated with LUMOXITI, 26% (34/129) reported adverse events of renal toxicity, including acute kidney injury (2.3%), renal failure (2.3%), renal impairment (1.6%), serum creatinine increased (17%), and proteinuria (8%). Grade 3 acute kidney injury occurred in 1.6% (2/129) of patients.

Based on laboratory findings, during treatment, serum creatinine increased by two or more grades from baseline in 22% (29/129) of patients, including increases of Grade 3 in 1.6% (2/129) of patients. At the end of treatment, serum creatinine levels remained elevated at 1.5- to 3-times the upper limit of normal in 5% of patients. Patients who experience HUS, those ≥ 65 years of age, or those with baseline renal impairment may be at increased risk for worsening of renal function following treatment with LUMOXITI.

Monitor renal function prior to each infusion of LUMOXITI, and as clinically indicated throughout treatment. Delay LUMOXITI dosing in patients with Grade ≥ 3 elevations in creatinine, or upon worsening from baseline by ≥ 2 grades.

Infusion Related Reactions occurred in patients treated with LUMOXITI, and were defined as the occurrence of any one of the following events on the day of study drug infusion: chills, cough, dizziness, dyspnea, feeling hot, flushing, headache, hypertension, hypotension, infusion related reaction, myalgia nausea, pyrexia, sinus tachycardia, tachycardia, vomiting, or wheezing. In Study 1053, infusion related reactions occurred in 50% (40/80) of patients, including Grade 3 events in 11% (9/80) of patients. The most frequently reported infusion related events were nausea (15%), pyrexia (14%), chills (14%), vomiting (11%), headache (9%), and infusion related reaction (9%).

Infusion related reactions may occur during any cycle of treatment with LUMOXITI. Premedicate with antihistamines and antipyretics prior to each LUMOXITI dose. If a severe infusion related reaction occurs, interrupt the LUMOXITI infusion and institute appropriate medical management. Administer an oral or intravenous corticosteroid approximately 30 minutes before resuming, or before the next LUMOXITI infusion.

Electrolyte Abnormalities: In the combined safety database of HCL patients treated with LUMOXITI, electrolyte abnormalities occurred in 57% (73/129) of patients with the most common electrolyte abnormality being hypocalcemia occurring in 25% of patients. Grade 3 electrolyte abnormalities occurred in 14% (18/129) of patients and Grade 4 electrolyte abnormalities occurred in 0.8% (1/129) of patients. Electrolyte abnormalities co-occurred in the same treatment cycle with CLS, HUS, fluid retention, or renal toxicity in 37% (48/129) of patients.

Monitor serum electrolytes prior to each dose and on Day 8 of each treatment cycle. Monitoring mid-cycle is also recommended.

ADVERSE REACTIONS

Most common non-laboratory adverse reactions (≥ 20%) of any grade were infusion related reactions (50%), edema peripheral (39%), nausea (35%), fatigue (34%), headache (33%), pyrexia (31%), constipation (23%), anemia (21%), and diarrhea (21%). The most common Grade 3 or 4 adverse reactions (reported in at least ≥ 5% of patients) were hypertension, febrile neutropenia, and HUS.
Most common laboratory abnormalities (≥ 20%) of any grade were creatinine increased, ALT increased, hypoalbuminemia, AST increased, hypocalcemia, hypophosphatemia, hemoglobin decreased, neutrophil count decreased, hyponatremia, blood bilirubin increased, hypokalemia, GGT increased, hypomagnesemia, platelet count decreased, hyperuricemia, and alkaline phosphate increased.
Adverse reactions resulting in permanent discontinuation of LUMOXITI occurred in 15% (12/80) of patients. The most common adverse reaction leading to LUMOXITI discontinuation was HUS (5%). The most common adverse reaction resulting in dose delays, omissions, or interruptions was pyrexia (3.8%).

SPECIFIC POPULATIONS

Pregnancy: There are no available data on LUMOXITI use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Advise pregnant women of the potential risk to a fetus.
Lactation: Advise women not to breastfeed.
Geriatric Use: Exploratory analyses suggest a higher incidence of adverse reactions leading to drug discontinuation (23% versus 7%) and renal toxicity (40% versus 20%) for patients 65 years of age or older as compared to those younger than 65 years.

Please see complete Prescribing Information, including Boxed WARNING, Patient Information (Medication Guide), and Instructions for Use

NOTES TO EDITORS

About Hairy Cell Leukemia

Hairy cell leukemia (HCL) is a rare, chronic, and slow-growing leukemia in which the bone marrow overproduces abnormal B cell lymphocytes. HCL can result in serious conditions, including infections, bleeding and anemia. Approximately 1,000 people are diagnosed with HCL in the US each year. HCL accounts for up to 3% of all adult leukemias. While many patients initially respond to treatment, 30% to 40% will relapse five to ten years after their first treatment. With no established standard of care and very few treatments available, there remains significant unmet medical need for people with relapsed or refractory HCL.

About LUMOXITI

LUMOXITI™ (moxetumomab pasudotox-tdfk, formerly CAT8015 or HA22) is a CD22-directed cytotoxin and a first-in-class treatment in the US for adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. LUMOXITI is not recommended in patients with severe renal impairment (CrCl ≤ 29 mL/min). It comprises the CD22 binding portion of an antibody fused to a truncated bacterial toxin; the toxin inhibits protein synthesis and ultimately triggers apoptotic cell death. LUMOXITI has been granted Orphan Drug Designation by the FDA for the treatment of HCL.

About the ‘1053’ Phase III Trial

The ‘1053’ trial is a single-arm, multicenter Phase III clinical trial assessing the efficacy, safety, immunogenicity and pharmacokinetics of moxetumomab pasudotox monotherapy in patients with relapsed or refractory HCL who have received at least two prior therapies, including one purine nucleoside analog. The trial was conducted in 80 patients across 34 sites in 14 countries. The primary endpoint was durable complete response (CR), defined as CR with hematologic remission (blood count normalization) for >180 days. Secondary outcome measures included overall response rate, relapse free survival, progression-free survival, time to response, safety, pharmacokinetic and immunogenic potential.

Early discovery of moxetumomab pasudotox was led by Dr. Ira Pastan and colleagues at the National Cancer Institute (NCI). The collaboration between NCI and MedImmune, AstraZeneca’s global biologics research and development arm, is an example of how scientific partnerships can lead to important advances for cancer patients.

About AstraZeneca in Hematology

Leveraging its strength in oncology, AstraZeneca has established hematology as one of four key oncology disease areas of focus and is accelerating development of a broad portfolio of potential blood cancer treatments. AstraZeneca and Acerta Pharma, its hematology research and development center of excellence, received US FDA approval for the first medicine in this franchise in 2017.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in hematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

About MedImmune

MedImmune is the global biologics research and development arm of AstraZeneca, a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of small molecule and biologic prescription medicines. MedImmune is pioneering innovative research and exploring novel pathways across Oncology, Respiratory, Cardiovascular, Renal & Metabolic Diseases, and Infection and Vaccines. The MedImmune headquarters is located in Gaithersburg, Md., one of AstraZeneca’s three global R&D centers, with additional sites in Cambridge, UK and South San Francisco, CA. For more information, please visit www.medimmune.com.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.