ipilimumab

Ipilimumab is a medication used in the treatment of many types of cancers, mostly advanced or metastatic, either as a single agent or in combination with other medications. Ipilimumab is a type of targeted therapy that does not directly kill cancer cells, but targets and alters a specific cell mechanism that aids cancer cell proliferation. Ipilimumab works by enhancing the ability of body’s own immune system to fight against cancer cells.

Ipilimumab is a recombinant human monoclonal immunoglobulin G1 kappa (IgG1k) antibody designed to act against a specific T-cell protein that reduces the activity of T-cells against cancer cells. T-cells are immune cells that normally induce programmed death in damaged and mutated (cancer) cells. T-cell activity is up or down regulated by different cell mechanisms that stimulate or inhibit their activity. Ipilimumab works by blocking cell-signaling that inhibits T-cell activity, allowing T-cells to remain active and kill cancer cells.

T-cells are fully activated when protein molecules on T-cells known as major histocompatibility complexes (MHC) I and II receptors bind to tumor-associated antigens (TAA) that identify tumor cells, and CD28 receptors bind to CD80 and CD86 molecules on antigen-presenting cells (APCs). In response, another T-cell protein, cytotoxic T-lymphocyte antigen 4 (CTLA-4) gets upregulated, competes with CD28 and binds with greater affinity to CD80 and CD86, decreasing T-cell activity.

Ipilimumab binds to CTLA-4, the negative regulator of T-cell activity, and blocks its interaction with CD80 and CD86. Blocking CTLA-4’s interaction with CD80/CD86 reduces downregulation of T-cell response, amplifies activation and proliferation of T-cells, including tumor infiltrating T-effector cells, thus enhancing the immune system’s anti-tumor response.

Ipilimumab is administered as an intravenous infusion over 30 minutes. Ipilimumab is often used in combination with nivolumab, an IgG4 antibody that blocks the interaction of another protein molecule on T-cells, programmed death-1 (PD-1), with PD-L1 and PD-L2, which also inhibits T-cell activation. Ipilimumab may be used in combination with nivolumab as well as platinum-based chemotherapy in some cancers. The uses of Ipilimumab include the following:

FDA-approved:

Adult and pediatric patients 12 years and older:

• Melanoma: Unresectable or metastatic melanoma as monotherapy or in combination with nivolumab.
• Colorectal cancer: Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed after other treatments, in combination with nivolumab. This indication is under accelerated approval, contingent on verification of benefits in clinical trials. 

Adult:

• Melanoma: Adjuvant treatment of cutaneous melanoma in patients who have involvement of regional lymph nodes and have undergone complete resection, including total lymphadenectomy.
• Renal cell carcinoma (RCC): Previously untreated RCC in patients with intermediate or poor risk, in combination with nivolumab.
• Hepatocellular carcinoma: Treatment of patients previously treated with sorafenib, in combination with nivolumab. This indication is under accelerated approval, contingent on verification of benefits in clinical trials.
• Non-small cell lung cancer (NSCLC):
  • Metastatic NSCLC expressing PD-L1 (1% or higher) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with nivolumab.
  • Metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with nivolumab and 2 cycles of platinum doublet chemotherapy.
• Malignant pleural mesothelioma: Unresectable malignant pleural mesothelioma, as first-line treatment in combination with nivolumab.
• Esophageal cancer: Unresectable advanced or metastatic esophageal squamous cell carcinoma, as first-line treatment in combination with nivolumab.

Orphan Designation:

• Small cell lung cancer in adults

• Ipilimumab blocks T-cell inhibition and can cause immune-mediated severe or even fatal inflammatory reactions involving any organ or tissue. Monitor patients for signs and symptoms of immune-mediated reactions. In case of moderate reactions, withhold treatment, monitor the patient, and treat appropriately with corticosteroids. Discontinue permanently in case of severe or life-threatening reactions. Immune-mediated inflammatory adverse reactions may include the following:
  • Colitis, diarrhea and cytomegalovirus (CMV) infection/activation
  • Hepatitis
  • Dermatologic reactions including:
    • Rash
    • Bullous dermatitis
    • Exfoliative dermatitis
    • Stevens-Johnson syndrome
    • Toxic epidermal necrolysis
    • Drug rash with eosinophilia and systemic symptoms (DRESS)
  • Endocrinopathies including:
    • Hypophysitis
    • Hypopituitarism
    • Adrenal insufficiency
    • Hypogonadism
    • Thyroiditis
    • Hypothyroidism
    • Hyperthyroidism
    • Type I diabetes mellitus
    • Cushing’s syndrome
  • Pneumonitis
  • Nephritis and renal dysfunction
  • Neuropathies including meningitis, myelitis, demyelination, encephalitis, myasthenia gravis/myasthenic syndrome, nerve paresis, motor dysfunction and Guillain-Barre syndrome
  • Cardiovascular reactions including myocarditis, pericarditis, angiopathy, temporal arteritis and vasculitis
  • Eye conditions including blepharitis, scleritis, episcleritis, conjunctivitis, orbital myositis, iritis, and uveitis
  • Neurosensory hearing loss (hypoacusis)
  • Gastritis, duodenitis and pancreatitis
  • Arthritis, myositis, polymyositis, polymyalgia rheumatica and rhabdomyolysis
  • Erythema multiforme and psoriasis
  • Sarcoidosis
  • Blood disorders including aplastic anemia, cytopenias and eosinophilia
  • Histiocytic necrotizing lymphadenitis
  • Solid organ transplant rejection
  • Systemic inflammatory response syndrome
• Ipilimumab may cause severe infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions and discontinue for severe and life-threatening infusion reactions.
• In patients who receive donor (allogeneic) hematopoietic stem cell transplantation (HSCT) before or after ipilimumab therapy, serious and fatal graft-versus-host disease (GVHD) can occur, despite intervening therapy between HSCT and ipilimumab therapy.
  • Consider benefit and risks before initiating ipilimumab after HSCT.
  • Monitor patients closely for evidence of GVHD and intervene promptly.
• Ipilimumab can cause fetal harm. Apprise pregnant women of potential risk to the fetus and advise women of reproductive potential to use effective contraception during therapy and for 3 months following the last dose. 
• When used in combination with nivolumab, refer to prescribing information for additional risk information that applies to the combination use treatment.

Common side effects of ipilimumab include:

• Fatigue
• Weakness (asthenia)
• Fever (pyrexia)
• Rash
• Itching (pruritis)
• Dry skin
• Loss of skin color in patches (vitiligo)
• Hives (urticaria)
• Hair loss (alopecia)
• Swelling from fluid retention (edema)
• Headache
• Insomnia
• Dizziness
• Feeling unwell (malaise)
• Chills
• Influenza
• Influenza-like illness
• Diarrhea
• Colon inflammation (colitis)
• Nausea
• Vomiting
• Abdominal pain
• Constipation
• Dry mouth
• Oral inflammation (stomatitis)
• Swallowing difficulty (dysphagia)
• Gastritis
• Indigestion (dyspepsia)
• Intestinal perforation
• Inflammation of pancreas (pancreatitis)
• Decreased appetite
• Decrease in weight
• Musculoskeletal pain
• Joint pain (arthralgia)
• Joint inflammation (arthritis)
• Muscle disease (myopathy)
• Muscle inflammation (myositis, including polymyositis)
• Inflammatory arthritis of the spine (spondyloarthropathy)
• Polymyalgia rheumatica
• Muscle breakdown (rhabdomyolysis)
• Sjogren’s syndrome
• Nerve inflammation (neuritis)
• Foot drop (peroneal nerve palsy)
• Peripheral nerve disease (neuropathy)
• Autoimmune brain inflammation (encephalitis)
• Cough, including productive cough
• Shortness of breath (dyspnea)
• Exertional dyspnea
• Upper respiratory tract infection
• Pneumonia
• Aspiration pneumonia
• Lung inflammation (pneumonitis)
• Interstitial lung disease
• Blood clot in lungs (pulmonary embolism)
• Underactive thyroid (hypothyroidism)
• Overactive thyroid (hyperthyroidism)
• Adrenal insufficiency
• High blood pressure (hypertension)
• Low blood pressure (hypotension)
• Abnormal liver function
• Liver inflammation (hepatitis)
• Increase in liver enzymes AST and ALT
• High blood sugar (hyperglycemia)
• Increase in pancreatic enzymes lipase and amylase
• Increase in alkaline phosphatase (ALK)
• Increased creatinine levels
• Increase in bilirubin
• Increase in blood creatine phosphokinase (CPK)
• Electrolyte disturbances in blood including:
  • Low sodium (hyponatremia)
  • Low calcium (hypocalcemia)
  • High potassium (hyperkalemia)
  • Low calcium (hypocalcemia)
  • Low magnesium (hypomagnesemia)
  • Low potassium (hypokalemia)
• Blood disorders including:
  • Low red blood cell count (anemia)
  • Low lymphocyte immune cell count (lymphopenia)
  • Decrease in hemoglobin
  • Low platelet count (thrombocytopenia)
  • Low neutrophil immune cell count (neutropenia)
  • High eosinophil cell count (eosinophilia)
• Infusion-related reaction
• Blurred vision
• Inflammation of the uvea in the eye (uveitis)
• Rapid and irregular contraction of heart’s atrial chambers (atrial fibrillation)
• Inflammation of the heart muscle (myocarditis)
• Development of anti-ipilimumab antibodies

Less common side effects of ipilimumab include:

• Large intestinal ulcer
• Inflammation of the esophagus (esophagitis)
• Acute respiratory distress syndrome (ARDS)
• Kidney failure
• Systemic inflammatory syndrome (hemophagocytic lymphohistiocytosis)
• Graft-versus-host disease (GVHD)
• Solid organ transplant rejection
• Severe skin reactions including:
  • Exfoliative dermatitis
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis
  • Drug rash with eosinophilia and systemic symptoms (DRESS)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Injectable solution, single-dose

• 5 mg/mL (10 mL, 40 mL)

Adult:

Melanoma

Unresectable or metastatic melanoma

• Indicated for treatment of unresectable or metastatic melanoma in adults and children aged 12 years and above
• 3 mg/kg intravenous (IV) once every 3 weeks for a maximum of 4 doses  
• Combination with nivolumab
• Indicated in combination with nivolumab for unresectable or metastatic melanoma in adults
• Ipilimumab 3 mg/kg IV once every 3 weeks PLUS
• Nivolumab 1 mg/kg IV on the same day for maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier
• After completing 4 doses of combination therapy: Administer nivolumab 240 mg IV once every 2 weeks or 480 mg IV once every 4 weeks as a single agent until disease progression or unacceptable toxicity

Cutaneous Melanoma

• Indicated for adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes bigger than 1 mm who have undergone complete resection, including total lymphadenectomy
• 10 mg/kg IV once every 3 weeks for 4 doses followed by 10 mg/kg once every 12 weeks for up to 3 years  

Renal Cell Carcinoma

• Indicated in combination with nivolumab for patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma
• Ipilimumab 1 mg/kg IV once every 3 weeks following nivolumab on the same day for 4 doses  
• After completing 4 doses of combination therapy, continue nivolumab as a single-agent until intolerable toxicity or disease progression
• Also see nivolumab drug monograph for dose and continuation as monotherapy

Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

• Indicated in combination with nivolumab for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan
• Ipilimumab 3 mg/kg IV immediately following nivolumab 1 mg/kg IV on the same day, once every 3 weeks for 4 doses  
• After completing 4 doses of combination therapy, continue nivolumab as a single-agent until intolerable toxicity or disease progression
• Also see nivolumab drug monograph for dose and continuation as monotherapy

Hepatocellular Carcinoma

• Indicated in combination with nivolumab for hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib
• Ipilimumab 3 mg/kg IV immediately following nivolumab 1 mg/kg IV on the same day, once every 3 weeks for 4 doses  
• After completing 4 doses of combination therapy, continue nivolumab as a single-agent until intolerable toxicity or disease progression
• Also see nivolumab drug monograph for dose and continuation as monotherapy

Non-Small Cell Lung Cancer

Combination with nivolumab

• Indicated in combination with nivolumab for first-line treatment of metastatic non-small cell lung cancer (NSCLC) in adults whose tumors express PD-L1 (1% or higher) with no EGFR or ALK genomic tumor aberrations
• Nivolumab 360 mg IV once every 3 weeks, PLUS
• Ipilimumab 1 mg/kg IV once every 6 weeks  
• Continue until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression

Combination with nivolumab and platinum-based chemotherapy

• Indicated in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy, for first-line treatment of metastatic or recurrent NSCLC in adults with no EGFR or ALK genomic tumor aberrations
• Nivolumab 360 mg IV once every 3 weeks, PLUS
• Ipilimumab 1 mg/kg IV once every 6 weeks, PLUS  
• Histology-based platinum doublet chemotherapy once every 3 weeks for 2 cycles
• Continue until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression

Malignant Pleural Mesothelioma

• Indicated in combination with nivolumab for patients with unresectable malignant pleural mesothelioma, as first-line treatment
• Ipilimumab 1 mg/kg IV once every 6 weeks, PLUS
• Nivolumab 360 mg IV once every 3 weeks
• Continue in combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression

Esophageal Cancer

• Indicated for first-line treatment of unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) in combination with nivolumab
• 1 mg/kg IV once every 6 weeks plus nivolumab 3 mg/kg IV once every 2 weeks or 360 mg IV once every 3 weeks
• Continue until disease progression, unacceptable toxicity, or up to 2 years

Dosage Modifications

• Note: No dose reduction is recommended for adverse reactions

Renal impairment

• All severities: No dosage adjustment required

Hepatic impairment

• Mild (Total bilirubin [TB] above 1 to 1.5 times upper limit of normal [ULN] or aspartate aminotransferase [AST] above ULN): No dose adjustment required
• Moderate-to-severe (TB above 1.5 times ULN and any AST): Not studied; caution advised

Pneumonitis

• Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or lower (or equivalent) within 12 weeks of initiating steroids
• Grade 3 or 4: Permanently discontinue

Colitis

• Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or lower (or equivalent) within 12 weeks of initiating steroids
• Grade 3 or 4: Permanently discontinue

Hepatitis with no tumor involvement of the liver

• AST or alanine aminotransferase (ALT) increases to above 3 to 8 times ULN or total bilirubin increases to above 1.5 to 3 times ULN: Withhold therapy; resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or lower (or equivalent) within 12 weeks of initiating steroids
• AST or ALT increases to above 8 times ULN or total bilirubin increases to above 3 times ULN: Permanently discontinue

Hepatitis with tumor involvement of the liver

• Withhold therapy
  • Baseline AST or ALT 1 to 3 times ULN and increases to 5 to 10 times ULN
  • Baseline AST or ALT 3 to 5 times ULN and increases to 8 to 10 times ULN
  • Resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
  • Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or lower (or equivalent) within 12 weeks of initiating steroids
• Permanently discontinue
  • AST or ALT increases to above 10 times ULN or total bilirubin increases to above 3 times ULN

Endocrinopathies

• Grade 3 or 4: Withhold until clinically stable or permanently discontinue depending on severity

Nephritis with renal dysfunction

• Grade 2 or 3 increased blood creatinine: Withhold therapy; resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or lower (or equivalent) within 12 weeks of initiating steroids
• Grade 4 increased blood creatinine: Permanently discontinue

Exfoliative dermatologic conditions

• Suspected Steven Johnson Syndrome (SJS), toxic epidermal necrosis (TEN), or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Withhold therapy
• Confirmed SJS, TEN, or DRESS: Permanently discontinue

Myocarditis H4

• Grade 2, 3, or 4: Permanently discontinue

Neurologic toxicities

• Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade below 1) after corticosteroid taper
• Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg/day or lower (or equivalent) within 12 weeks of initiating steroids
• Grade 3 or 4: Permanently discontinue

Infusion-related reactions

• Grade 1 or 2: Interrupt or slow infusion rate
• Grade 3 or 4: Permanently discontinue

Dosing Considerations

Patient selection

• Patient selection should be based on PD-L1 expression
• Information on FDA-approved tests is available at: https://www.fda.gov/CompanionDiagnostics

Pediatric:

Unresectable or metastatic melanoma

• Indicated as a single agent or in combination with nivolumab in adults and children aged 12 years and above
• Children below 12 years: Safety and efficacy not established

Single agent

• Children 12 years and above: 3 mg/kg IV once every 3 weeks for a maximum of 4 doses

Combination with nivolumab

• Indicated in combination with nivolumab for unresectable or metastatic melanoma in adults and children aged 12 years and above
• Ipilimumab 3 mg/kg IV once every 3 weeks PLUS
• Nivolumab 1 mg/kg IV on the same day for maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier
• After completing 4 doses of combination therapy, administer nivolumab as a single agent
  • Children 12 years and above and weight below 40 kg: 3 mg/kg IV once every 2 weeks or 6 mg/kg IV once every 4 weeks until disease progression or unacceptable toxicity
  • Children 12 years and above and weight 40 kg and above: 240 mg IV once every 2 weeks or 480 mg IV once every 4 weeks until disease progression or unacceptable toxicity

Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

• Indicated in combination with nivolumab for patients aged 12 years and above with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan
• Children below 12 years: Safety and efficacy not established
• Children 12 years and above: 1 mg/kg IV once every 3 weeks following nivolumab on the same day; repeat for up to 4 doses or until intolerable toxicity or disease progression  
• Also see nivolumab drug monograph for dose and continuation as monotherapy

Dosage Modifications

Renal impairment

• All severities: No dosage adjustment required

Hepatic impairment

• Mild (TB 1 to 1.5 times ULN or AST above ULN): No dose adjustment required
• Moderate-to-severe (TB 1.5 times ULN and any AST): Not studied; caution advised

Interrupt or slow rate of infusion

• Grade 1 or 2 infusion-related reactions

Withhold

• Resume in patients with complete or partial resolution (Grade 0 or 1) after corticosteroid taper
  • Grade 2 colitis or diarrhea
  • Grade 2 pneumonitis
  • Grade 2 or 3 increased blood creatinine nephritis with renal dysfunction
  • Grade 2 neurological toxicities
  • Grade 2 myocarditis
• Resume when acute symptoms have resolved
  • Grade 2 to 4 hypophysitis
• Resume when AST/ALT returns to baseline
  • Hepatitis (AST or ALT 3 times to 5 times ULN or total bilirubin 1.5 times to 3 times ULN)

Withhold until specialist assessment

• Grade 2 exfoliative or bullous dermatologic conditions

Withhold if not clinically stable

• Grade 2 to 4 endocrinopathies

Permanently discontinue

• Grade 3 or 4 colitis or diarrhea
• Hepatitis (AST or ALT above 5 times ULN or total bilirubin above 3 times ULN)
• Grade 3 or 4 exfoliative or bullous dermatologic conditions
• Grade 3 or 4 pneumonitis
• Grade 4 increased blood creatinine
• Grade 3 or 4 myocarditis
• Grade 2 to 4 ophthalmologic that does not improve to Grade 1 within 2 weeks while receiving topical therapy or that requires systemic treatment
• Grade 3 or 4 neurological toxicities if signs of encephalitis or respiratory insufficiency due to neurological toxicity regardless of grade
• Grade 3 or 4 infusion-related reactions

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Ipilimumab has no known severe interactions with other drugs.
• Serious interactions of ipilimumab include:
  • axicabtagene ciloleucel
  • brexucabtagene autoleucel
  • ciltacabtagene autoleucel
  • idecabtagene vicleucel
  • lisocabtagene maraleucel
  • palifermin
  • selinexor
  • tisagenlecleucel
• Moderate interactions of ipilimumab include:
  • cholera vaccine
  • dengue vaccine
  • efgartigimod alfa
  • efgartigimod/hyaluronidase SC
  • ponesimod
  • rozanolixizumab
  • siponimod
  • ublituximab
  • vemurafenib
• Ipilimumab has no known mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There is insufficient information on use of ipilimumab in pregnant women, however, based on the drug’s mechanism of action and animal reproductive studies, ipilimumab can cause fetal harm if administered during pregnancy.
• The effects of ipilimumab are likely to be greater in the second and third trimesters of pregnancy.
• Women of pregnancy potential should use effective contraception during therapy and for 3 months following the last dose of ipilimumab.
• There is no information on the presence of ipilimumab in breastmilk, or its effects on milk production or the breastfed infant. Ipilimumab was excreted in monkey milk.
• Nursing mothers should not breastfeed while on treatment with ipilimumab and for 3 months following the last dose, because of the potential for serious adverse reactions in the breastfed infant.
• Report pregnancies to Bristol-Myers Squibb at 1-844-593-7869.

• While on ipilimumab treatment, contact your treating physician immediately if you:
  • Develop any symptoms of immune-related inflammatory reactions related to any organ system
  • Experience infusion reactions