Itacitinib for the Treatment Steroid Refractory Immune Related Adverse Events Arising from Immune Checkpoint Inhibitors
Itacitinib for the Treatment Steroid Refractory Immune Related Adverse Events Arising from Immune Checkpoint Inhibitors
This phase II trial tests how well itacitinib works in in patients with immune related adverse events (irAEs) arising from immune checkpoint inhibitors (ICI) that do not respond to steroids (steroid refractory). Steroids are the usual treatment for these side effects. However, sometimes steroids do not improve or fix the side effects. Giving itacitinib may be effective in treating patients with known or suspected problems coming from ICIs, that do not resolve or improve with steroids, by reducing the patient's immune system response that can cause the irAEs.
Miscellaneous
Phase II
Adults
Mol. targeted/Immunotherapy/Biologics
Itacitinib
Johnson, Douglas
Local
Vanderbilt University
02-17-2023
Eligibility
18 Years
BOTH
NO
Inclusion Criteria:
>= 18 years of age at time of signing consent.
Participants must have signed and dated an Institutional Review Board/Independent Ethics Committee approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal participant care.
Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, biopsies, and other requirements of the study.
Subjects must have received at least one ICI therapy either as single agent(s) or in combination(s), including but not limited to nivolumab, ipilimumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, or avelumab.
Subjects must experience at least one Grade 2, 3 or 4 (CTCAE Version 5.0) toxicity/immune-related adverse event (irAE) attributed to immune checkpoint inhibitor (ICI) therapy as diagnosed by the patients study physician. This may be established by clinical, histological, or imaging criteria as defined below: * Symptoms must be attributed to an immune-related adverse event (irAE), with no infectious or alternative cause suspected by the patients study physician. * Subjects must be actively experiencing Grade 2+ irAE (at the time of screening) as broadly defined below: ** Cutaneous toxicity (including skin rash) ** Colitis/enteritis *** As defined by Grade 2+ diarrhea or Grade 2+ colitis (either or both conditions) ** Pneumonitis ** Arthritis ** Hepatitis *** As defined by Grade 2+ elevation in AST or ALT (either or both values elevated) ** Nephritis *** As defined by either Grade 2+ elevation in creatinine and/or proteinuria of at least 2+ on urinalysis attributed to ICI ** Myocarditis *** Given the vague nature of symptomatic myocarditis grading, troponin levels will be primarily used to grade myocarditis *** Troponin >2ng/ml *** Presumed diagnosis of myocarditis (myocardial infarction ruled out clinically) ** Myositis ***Defined as grade 2 myositis symptoms per CTCAE OR grade 2 elevations in creatinine kinase levels **Neurologic toxicity *** Encephalitis **** Neurologic symptoms consistent with encephalitis **** Lumbar puncture and infectious disease consult to rule out infectious etiologies if clinical suspicion for infectious causes *** Guillain Barre **** Magnetic Resonance Imaging (MRI) performed to rule out spinal cord compression **** Neurology consult to confirm diagnosis (or extremely high suspicion) *** Myasthenia Gravis **** MRI performed to rule out spinal cord compression and brain metastases **** Neurology consult to confirm diagnosis (or extremely high suspicion) ** Pericarditis ** Vasculitis ** Gastritis ** Other toxicities *** Other steroid refractory toxicities not listed in the above list may be included after discussion with the sponsor-investigator and may be included if meeting all other criteria. *** Note: Endocrine toxicities (including hypophysitis, hypopituitarism, hypothyroidism, thyrotoxicosis, immune checkpoint inhibitor-induced diabetes, and primary adrenal insufficiency) will NOT qualify for inclusion.
Subjects must have received oral or intravenous corticosteroids of at least 50mg per day prednisone equivalent dosing (approximately 1mg/kg daily) for >= 48 hours of therapy with worsening or lack of improvement to Grade 2.
Subjects may have been treated with additional immunomodulators (one or more) prior to study entry (e.g. infliximab, mycophenolate mofetil, intravenous immunoglobulin),provided such immunomodulators are discontinued prior to first dose of study therapy.
White blood cell >= 2.0 x 10^9/L
Absolute neutrophil count >= 1.5 x 10^9/L.
Platelet >= 75 x 10^9/L.
Hemoglobin >= 8.0 g/dL
Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) = 3 x Upper Limits of Normal (UNL) in subjects without hepatic metastases; AST and ALT = 5 x ULN in subjects with hepatic metastases, if AST/ALT elevation is NOT due to ICI-induced hepatitis ** Exception (without or with hepatic metastases): no limit for patients with ICI-induced hepatitis.
Total bilirubin = 2 x ULN not due to ICI-hepatitis (except subjects with Gilbert syndrome, where total bilirubin must be 3.0 mg/dL) * *Exception: no limit for patients with ICI-induced hepatitis.
Reproductive status: * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 7 days prior to the start of study treatment. * Women must not be breastfeeding. * WOCBP must agree to follow instructions for method(s) of contraception for the duration of study drug treatment and 60 days after the last dose of study treatment or longer if required based on prior immunotherapy received (for example, at least 4-5 months for nivolumab and pembrolizumab). * Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment and 60 days after the last dose of study drug or longer if required based on prior immunotherapy received. * Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements but still must undergo pregnancy testing as described in this section. * Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of contraception which have a failure rate of 1% when used consistently and correctly. WOCBP and men must agree to use adequate contraception (for example, hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of protocol treatment.
Exclusion Criteria:
Toxicity deemed by patients study physician to be primarily caused by another etiology (bacterial infection, other anticancer agents, etc.).
Ongoing serious infection requiring IV antibiotics.
Prior treatment with a JAK inhibitor within the past 8 weeks before first dose of protocol-indicated treatment.
Known HIV infection with CD4 count 200. (Testing not required by this study.)
History or current diagnosis of cardiac disease indicating significant risk of safety for participation in the study, such as uncontrolled or significant cardiac disease, including any of the following: * Recent myocardial infarction (within 6 months before first dose of protocol-indicated treatment). * New York Heart Association Class III or IV congestive heart failure. * Unstable angina (within last 6 months before first dose of protocol-indicated treatment). * Clinically significant (symptomatic) cardiac arrhythmias per judgment of patients study physician (e.g.,sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker). * Uncontrolled hypertension defined as blood pressure persistently above 160 systolic or 100 diastolic despite antihypertensive therapy.
Known allergies, hypersensitivity, or intolerance to any study medications or excipients.
History of solid organ transplant or allogeneic stem cell transplant with active graft versus host disease.
Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug/treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
>= 18 years of age at time of signing consent.
Participants must have signed and dated an Institutional Review Board/Independent Ethics Committee approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal participant care.
Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, biopsies, and other requirements of the study.
Subjects must have received at least one ICI therapy either as single agent(s) or in combination(s), including but not limited to nivolumab, ipilimumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, or avelumab.
Subjects must experience at least one Grade 2, 3 or 4 (CTCAE Version 5.0) toxicity/immune-related adverse event (irAE) attributed to immune checkpoint inhibitor (ICI) therapy as diagnosed by the patients study physician. This may be established by clinical, histological, or imaging criteria as defined below: * Symptoms must be attributed to an immune-related adverse event (irAE), with no infectious or alternative cause suspected by the patients study physician. * Subjects must be actively experiencing Grade 2+ irAE (at the time of screening) as broadly defined below: ** Cutaneous toxicity (including skin rash) ** Colitis/enteritis *** As defined by Grade 2+ diarrhea or Grade 2+ colitis (either or both conditions) ** Pneumonitis ** Arthritis ** Hepatitis *** As defined by Grade 2+ elevation in AST or ALT (either or both values elevated) ** Nephritis *** As defined by either Grade 2+ elevation in creatinine and/or proteinuria of at least 2+ on urinalysis attributed to ICI ** Myocarditis *** Given the vague nature of symptomatic myocarditis grading, troponin levels will be primarily used to grade myocarditis *** Troponin >2ng/ml *** Presumed diagnosis of myocarditis (myocardial infarction ruled out clinically) ** Myositis ***Defined as grade 2 myositis symptoms per CTCAE OR grade 2 elevations in creatinine kinase levels **Neurologic toxicity *** Encephalitis **** Neurologic symptoms consistent with encephalitis **** Lumbar puncture and infectious disease consult to rule out infectious etiologies if clinical suspicion for infectious causes *** Guillain Barre **** Magnetic Resonance Imaging (MRI) performed to rule out spinal cord compression **** Neurology consult to confirm diagnosis (or extremely high suspicion) *** Myasthenia Gravis **** MRI performed to rule out spinal cord compression and brain metastases **** Neurology consult to confirm diagnosis (or extremely high suspicion) ** Pericarditis ** Vasculitis ** Gastritis ** Other toxicities *** Other steroid refractory toxicities not listed in the above list may be included after discussion with the sponsor-investigator and may be included if meeting all other criteria. *** Note: Endocrine toxicities (including hypophysitis, hypopituitarism, hypothyroidism, thyrotoxicosis, immune checkpoint inhibitor-induced diabetes, and primary adrenal insufficiency) will NOT qualify for inclusion.
Subjects must have received oral or intravenous corticosteroids of at least 50mg per day prednisone equivalent dosing (approximately 1mg/kg daily) for >= 48 hours of therapy with worsening or lack of improvement to Grade 2.
Subjects may have been treated with additional immunomodulators (one or more) prior to study entry (e.g. infliximab, mycophenolate mofetil, intravenous immunoglobulin),provided such immunomodulators are discontinued prior to first dose of study therapy.
White blood cell >= 2.0 x 10^9/L
Absolute neutrophil count >= 1.5 x 10^9/L.
Platelet >= 75 x 10^9/L.
Hemoglobin >= 8.0 g/dL
Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) = 3 x Upper Limits of Normal (UNL) in subjects without hepatic metastases; AST and ALT = 5 x ULN in subjects with hepatic metastases, if AST/ALT elevation is NOT due to ICI-induced hepatitis ** Exception (without or with hepatic metastases): no limit for patients with ICI-induced hepatitis.
Total bilirubin = 2 x ULN not due to ICI-hepatitis (except subjects with Gilbert syndrome, where total bilirubin must be 3.0 mg/dL) * *Exception: no limit for patients with ICI-induced hepatitis.
Reproductive status: * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 7 days prior to the start of study treatment. * Women must not be breastfeeding. * WOCBP must agree to follow instructions for method(s) of contraception for the duration of study drug treatment and 60 days after the last dose of study treatment or longer if required based on prior immunotherapy received (for example, at least 4-5 months for nivolumab and pembrolizumab). * Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment and 60 days after the last dose of study drug or longer if required based on prior immunotherapy received. * Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements but still must undergo pregnancy testing as described in this section. * Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of contraception which have a failure rate of 1% when used consistently and correctly. WOCBP and men must agree to use adequate contraception (for example, hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of protocol treatment.
Exclusion Criteria:
Toxicity deemed by patients study physician to be primarily caused by another etiology (bacterial infection, other anticancer agents, etc.).
Ongoing serious infection requiring IV antibiotics.
Prior treatment with a JAK inhibitor within the past 8 weeks before first dose of protocol-indicated treatment.
Known HIV infection with CD4 count 200. (Testing not required by this study.)
History or current diagnosis of cardiac disease indicating significant risk of safety for participation in the study, such as uncontrolled or significant cardiac disease, including any of the following: * Recent myocardial infarction (within 6 months before first dose of protocol-indicated treatment). * New York Heart Association Class III or IV congestive heart failure. * Unstable angina (within last 6 months before first dose of protocol-indicated treatment). * Clinically significant (symptomatic) cardiac arrhythmias per judgment of patients study physician (e.g.,sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker). * Uncontrolled hypertension defined as blood pressure persistently above 160 systolic or 100 diastolic despite antihypertensive therapy.
Known allergies, hypersensitivity, or intolerance to any study medications or excipients.
History of solid organ transplant or allogeneic stem cell transplant with active graft versus host disease.
Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug/treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
