May 31, 2019
Kite and Humanigen Announce Clinical Collaboration to Evaluate Investigational Combination of Yescarta® (Axicabtagene Ciloleucel) with Lenzilumab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma
-- Phase 1/2 Multi-Center Clinical Trial to Begin Enrolling in Q4 2019 --
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GM-CSF has been identified, through clinical correlative analysis and preclinical modeling, as a potential key signal in the inflammatory cascade triggering toxicities associated with chimeric antigen receptor T (CAR T) cell therapy.1 Toxicities associated with CAR T therapy include neurologic toxicity and cytokine release syndrome (CRS). Emerging pre-clinical evidence suggests that lenzilumab inhibition of GM-CSF may have the potential to disrupt CAR T cell mediated inflammation without disrupting CAR T cell anti-tumor efficacy.
“CAR T therapy represents a significant advance in the way relapsed or
refractory large B-cell lymphoma is treated,” said
“Humanigen has pioneered the approach to neutralizing GM-CSF to improve
CAR T,” said
Yescarta was the first CAR T cell therapy to be approved by the
Lenzilumab, alone or in combination with other therapies such as
Yescarta, is investigational and has not been approved by the
U.S. Important Safety Information for Yescarta
BOXED WARNING:CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES
- Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
- Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
- Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS.
CYTOKINE RELEASE SYNDROME (CRS): CRS occurred in 94% of patients, including 13% with ≥ Grade 3. Among patients who died after receiving Yescarta, 4 had ongoing CRS at death. The median time to onset was 2 days (range: 1-12 days) and median duration was 7 days (range: 2-58 days). Key manifestations include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.
NEUROLOGIC TOXICITIES: Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks, with a median time to onset of 4 days (range: 1-43 days) and a median duration of 17 days. Grade 3 or higher occurred in 31% of patients. The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.
YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YESCARTAREMS.com or 1-844-454-KITE (5483).
HYPERSENSITIVITY REACTIONS: Allergic reactions may occur. Serious hypersensitivity reactions including anaphylaxis may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.
SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients, and in 23% with ≥ Grade 3. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.
PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade 3 or higher cytopenias not resolved by Day 30 following Yescarta infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after Yescarta infusion.
HYPOGAMMAGLOBULINEMIA: B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.
SECONDARY MALIGNANCIES: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.
ADVERSE REACTIONS: The most common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.
Gilead Forward-Looking Statement
This press release includes forward-looking statements, within the
meaning of the Private Securities Litigation Reform Act of 1995 that are
subject to risks, uncertainties and other factors, including Kite’s
ability to complete the Phase 1/2 study of Yescarta in combination with
lenzilumab in patients with relapsed or refractory DLBCL in the
currently anticipated timelines, or at all. In addition, there is the
possibility of unfavorable results from clinical trials involving this
combination, Yescarta and other investigational CAR T therapies.
Further, it is possible that the parties may make a strategic decision
to discontinue development of the investigational combination of
Yescarta and lenzilumab. All statements other than statements of
historical fact are statements that could be deemed forward-looking
statements. These risks, uncertainties and other factors could cause
actual results to differ materially from those referred to in the
forward-looking statements. The reader is cautioned not to rely on these
forward-looking statements. These and other risks are described in
detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended
Humanigen Forward-Looking Statement
This release contains forward-looking statements. Forward-looking
statements reflect management's current knowledge, assumptions, judgment
and expectations regarding future performance or events. Although
management believes that the expectations reflected in such statements
are reasonable, they give no assurance that such expectations will prove
to be correct and you should be aware that actual events or results may
differ materially from those contained in the forward-looking
statements. Words such as "will," "expect," "intend," "plan,"
"potential," "possible," "goals," "accelerate," "continue," and similar
expressions identify forward-looking statements, including, without
limitation, statements regarding our expectations for future development
of lenzilumab to help CAR-T therapy reach its full potential.
Forward-looking statements are subject to a number of risks and
uncertainties including, but not limited to, the risks inherent in
All forward-looking statements are expressly qualified in their entirety by this cautionary notice. You should not place undue reliance on any forward-looking statements, which speak only as of the date of this release. We undertake no obligation to revise or update any forward-looking statements made in this press release to reflect events or circumstances after the date hereof or to reflect new information or the occurrence of unanticipated events, except as required by law.
U.S. Prescribing Information for Yescarta, including BOXED WARNING, is available at www.kitepharma.com and www.gilead.com.
Yescarta is a registered trademark of
Sterner, R., Sakemura, R., Cox, M., Yang, N., Khadka, R., Forsman,
C.,… Kenderian, S. (2019). GM-CSF inhibition reduces cytokine release
syndrome and neuroinflammation but enhances CAR-T cell function in
xenografts. Blood : the official journal of the
American Society of Hematology, 133:697-709. doi: https://doi.org/10.1182/blood-2018-10-881722
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Source: Kite, a
Kite, A Gilead Company,Contacts:
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Shant Salakian, Media
Al Palombo, Investors
Chris Bowe, Media