A Study of Rituximab or Tocilizumab for Cancer Patients that Develop Immunotherapy-Related Side Effects Requiring Prolonged Steroid Use

Inclusion Criteria

• Patients with histologically confirmed advanced solid tumors that develop immune-related adverse events (irAEs) secondary to treatment aimed to enhance the anti-tumor immune response (i.e. immune checkpoint inhibitors). Diagnostic evaluation of irAEs conducted by a consenting investigator, such as the treating medical oncologist or toxicity-specific subspecialist (e.g. rheumatologist, dermatologist), supporting therapeutic rationale for either rituximab or tocilizumab-based therapy or if evidence-based indications exist and summarized below: * Dermatologic (bullous pemphigoid, pemphigus vulgaris, lichenoid and maculopapular rash) * Neurologic (autoimmune encephalitis) * Hematologic (immune thrombocytopenia, autoimmune hemolytic anemia) * Rheumatologic (rheumatoid arthritis, psoriatic arthritis) * Renal (autoimmune nephritis) * Pulmonary (pneumonitis) * Cardiac (autoimmune myocarditis) * Other system for which there is precedent in clinical literature for using either rituximab or tocilizumab as determined by medical oncologist or toxicity-specific subspecialist
• Steroid-dependent or steroid refractory, defined as: * Patients with increased irAE severity (i.e., increase in stage in any organ system or any new organ involvement) after 3 days (d) of primary treatment with prednisone ≥ 0.5 mg/kg/d (or equivalent) * Patients with irAE that has not improved (i.e., decrease in grade in at least 1 involved organ system) after 7 d of primary treatment with prednisone ≥ 0.5 mg/kg/d (or equivalent) * Patients who previously began corticosteroid therapy ( ≥ 0.5mg/kg/d prednisone) for treatment of a particular irAE syndrome but develop new irAE in another organ system * Patients who cannot tolerate a corticosteroid taper (i.e. begin corticosteroids at 0.5-1mg/kg/d, demonstrate response, but progress when >= 50% decrease from the initial starting dose of corticosteroids is achieved)
• Be willing and able to provide written informed consent/assent for the trial. In cases of partial impairment, impairment that fluctuates over time, or complete impairment due to dementia, stroke, traumatic brain injury, developmental disorders (including mentally disabled persons), serious mental illness, and delirium, a subject may be enrolled if the subject’s legally authorized representative consents on the subject’s behalf
• Be ≥ 18 years of age on day of signing informed consent
• Female subject of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential should be willing to use contraception, or abstain from heterosexual activity for the course of the study and through 12 months after last dose of rituximab or 3 months after last dose of tocilizumab. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Males must practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for 6 months after last dose of rituximab, 180 days even if he has undergone a successful vasectomy
• Vaccinations must be completed 4 weeks prior to the first treatment with rituximab or must not be taken at least 6 months after the last dose of chemotherapy. Non-live vaccines may be given during rituximab treatment; however, patients may experience reduced response rates. The safety of live vaccines has not been studied during cancer treatment and their use is not recommended unless otherwise advised by the oncologist. Subject must be vaccinated with the pneumococcal vaccine at least 4 weeks prior to initiation of therapy, unless subject was vaccinated within 5 years of study entry. If vaccination occurred greater than 5 years prior to study entry, the subject must be revaccinated at least 4 weeks prior to initiation of therapy
• Absolute neutrophil count >= 1,000/mcL
• Platelets >= 100,000
• Hemoglobin >= 7.0 g/dL (without transfusion in past 2 weeks). Note: Patients with cytopenias (e.g immune thrombocytopenia, autoimmune hemolytic anemia) clinically consistent with irAE will be eligible at the discretion of principal investigator. Patients with hematological values below those stated will not receive tocilizumab
• Aspartate transaminase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine transferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2 x institutional upper limit of normal
• Creatinine clearance of >= 30 mL/min. Creatinine clearance (CrCl) should be calculated at screening using the Cockcroft-Gault formula
• Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) performance scale

Exclusion Criteria

• Current participation in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
• Diagnosis of immunodeficiency or is receiving systemic immunosuppressive therapy other than steroids prior to the first dose of trial treatment
• Treatment with a non-biologic immunosuppressive or immune-modulating drug (e.g. methotrexate, azathioprine, mycophenolate, cyclosporine, hydroxychloroquine, penicillamine, intravenous immune globulin [IVIg]) within 4 weeks prior to treatment. An exception may be made in the case of standard of care immunomodulators (for example IVIg used to treat myasthenia gravis), where the treating physician is concerned for acute decompensation should the immunomodulator be stopped * Note: Patients who previously received treatment with either rituximab or tocilizumab may receive treatment with the alternative agent after discussion with the treating physician and/or the principal investigator
• Treatment with other immune-modulating biologic agents (e.g TNF-alpha inhibitors) within 4 weeks prior to treatment initiation * Note: Patients continuing treatment with immune checkpoint inhibitors (CPI) therapy will be eligible at the discretion of the treating physician and/or the principal investigator though CPI therapy must not be administered within 7 days of either investigational agent
• History of anaphylaxis or IgE-mediated hypersensitivity to murine proteins or any component of rituximab or tocilizumab History of allergic reactions attributed to compounds of similar chemical or biologic composition to either rituximab or tocilizumab
• History of human immunodeficiency virus (HIV) infection or other immunodeficiency
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• History of chronic viral hepatitis, alcoholic or metabolic liver disease. Carriers of hepatitis B and patients with a history of hepatitis B infection or positive serology are excluded in situations where the potential benefit is determined to justify the risk of possible hepatitis B reactivation, which can be fatal. Patients with positive serology should have viral DNA levels checked a gastrointestinal consultation obtained. If treated with rituximab, such patients should be closely monitored for clinical and laboratory signs of active hepatitis B virus (HBV) infection and for signs of hepatitis throughout their study participation
• Central nervous system (CNS) metastases, with the following exception: * Subjects who have previously-treated CNS metastases, are asymptomatic, and have no requirement for steroids in the management of CNS disease (steroids for irAEs are allowed) at least 14 days prior to first dose of study drug ** Note: Subjects with carcinomatous meningitis or leptomeningeal spread are excluded regardless of clinical stability
• History of or current positive purified protein derivative tuberculin skin test (PPD) ( > 5 mm induration, regardless of Bacille Calmette Guerin [BCG] vaccine administration), or positive QuantiFERON-tuberculosis (TB) Gold In-Tube Test (QuantiFERON), or historical chest x-ray unless completion of treatment has been documented for active TB, latent TB (a positive test, a negative chest x-ray, and no symptoms or risk factors), unless one month of prophylaxis has been completed prior to inclusion, an indeterminate QuantiFERON unless followed by a subsequent negative PPD or negative QuantiFERON as well as a consultation with and clearance by local infectious disease (ID) department
• If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Transplanted organs (except corneas with transplant performed > 3 months prior to screening)
• Active infection, including opportunistic infections, requiring systemic therapy within the past 2 weeks
• A deep space infection within the past 2 years (including, but not limited to meningitis, epiglottitis, endocarditis, septic arthritis, fasciitis, abdominal or pleural abscess, or osteomyelitis)
• Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective institutional review board (IRB) approval (by chair or designee) is given allowing exception to this criterion for a specific subject
• New York Heart Association Classification III or IV heart disease
• Breastfeeding is not permitted during treatment and for 6 months after the last dose of rituximab or 3 months after the last dose of tocilizumab
• Preexisting central nervous system demyelinating or seizure disorders
• History of diverticulitis, diverticulosis requiring antibiotic treatment, or other symptomatic lower gastrointestinal (GI) conditions that might predispose to perforations