Tocilizumab for KSHV-Associated Multicentric Castleman Disease

Overall clinical benefit response is defined as Complete Response (CR): Full resolution of all clinical symptoms and laboratory abnormalities (whether or not these are indicator abnormalities) probably or definitely attributable to MCD, lasting at least 3 weeks; and Partial Response (PR): At least 50% of the abnormalities probably or definitely attributed to KSHV-MCD must improve by the minimum amounts specified to attain PR. Only abnormalities present in a specific patient at baseline may count toward the achievement of a PR (e.g. if six of indicator abnormalities are present at baseline, at least three must meet the specified criteria to be considered a PR) assessed using a modified Kaposi sarcoma herpes virus-associated multicentric Castleman disease (KSHV- MCD) Clinical Benefit Response Criteria and the National Cancer Institute (NCI) KSHV-MCD criteria.

Time frame: every 2 weeks for up to 12 weeks

Cumulative plasma exposure of Atazanavir will be evaluated.

Time frame: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.

Population: This outcome measure was not done because either patients were not on the antiretroviral therapies Atazanavir, Efavirenz, Ritonavir, and Lopinavir and that the timed administration of ART and tocilizumab were not described in the protocol therefore not done.

Cumulative plasma exposure of Efavirenz will be evaluated.

Time frame: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.

Population: This outcome measure was not done because either patients were not on the antiretroviral therapies Atazanavir, Efavirenz, Ritonavir, and Lopinavir and that the timed administration of ART and tocilizumab were not described in the protocol therefore not done.

Cumulative plasma exposure of Lopinavir will be evaluated.

Time frame: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.

Population: This outcome measure was not done because either patients were not on the antiretroviral therapies Atazanavir, Efavirenz, Ritonavir, and Lopinavir and that the timed administration of ART and tocilizumab were not described in the protocol therefore not done.

Cumulative plasma exposure of Ritonavir will be evaluated.

Time frame: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.

Population: This outcome measure was not done because either patients were not on the antiretroviral therapies Atazanavir, Efavirenz, Ritonavir, and Lopinavir and that the timed administration of antiretrovirals (ART) and tocilizumab were not described in the protocol therefore not done.

Evaluate the effect of tocilizumab on the pharmacokinetics of antiretroviral agents that are cytochrome P3A4 (CYP3A4) substrates in patients with symptomatic Kaposi sarcoma herpes virus-associated multicentric Castleman Disease (KSHV-MCD).

Time frame: Cycle 1, Day 1 and Cycle 2-6 Day 1

Population: This outcome measure was not done because either patients were not on the antiretroviral therapies Atazanavir, Efavirenz, Ritonavir, and Lopinavir and that the timed administration of ART and tocilizumab were not described in the protocol therefore not done.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Time frame: Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.

Progression-free survival is defined as participants who progress or die by 4 months after the start of treatment with tocilizumab and tocilizumab /AZT/VGC.

Time frame: 4 months

A biochemical response is defined as a Complete Response (CR): Normalization of abnormalities attributed to MCD in the following labs: Complete blood count (CBC), Chem 20, C-Reactive protein (CRP), lasting 1 cycle (3-4 weeks depending on regimen); Partial Response (PR): 50% improvement in all labs abnormalities attributable to MCD, lasting 1 cycle (3-4 weeks depending on regimen), and was assessed by the National Cancer Institute (NCI) Kaposi sarcoma herpes virus-associated multicentric Castleman Disease (KSHV-MCD) Response Criteria.

Time frame: up to 12 weeks

Clinical response is defined as a Complete Response (CR): Full resolution of all signs and symptoms attributable to MCD, lasting 1 cycle (3-4 weeks depending on regimen; Symptom Free Disease (SFD:) Full resolution of all signs and symptoms attributable to MCD, not yet lasting 1 cycle (3-4 weeks depending on regimen); and Partial Response (PR): Improvement in at least 50% of signs and symptoms by at least 1 grade (NCI-Common Terminology Criteria for Adverse Events (CTCAE v4), with no increased MCD related increases, lasting 1 cycle (3-4 weeks depending on regimen) assessed by the National Cancer Institute Kaposi sarcoma herpes virus-associated multicentric Castleman disease (NCI KSHV-MCD) Response Criteria.

Time frame: up to 12 weeks

A radiographic response is defined as a Complete Response (CR): Normalization of all lymph nodes to \<1.5 cm in greatest transverse dimension, decrease to \< 1 cm of lymph nodes 1.1-1.5 cm at baseline (or 75% decrease in the sum of products of diameters (SPD)), Spleen \< 12 cm greatest dimension, no pleural effusions; Complete Response unconfirmed (CRu): Residual lymph node mass \>1.5 cm or splenomegaly \> 12 cm that has decrease by \>75% and does not change over one year; and Partial Response (PR): For lymph nodes, \>50% decrease in SPD of 6 dominant nodes, for spleen 50% decrease in longest transverse dimension assessed by the National Cancer Institute (NCI) Kaposi sarcoma herpes virus-associated multicentric Castleman Disease (KSHV-MCD) Response Criteria.

Time frame: up to 12 weeks

Here is the percentage of participants with \<Grade 3 non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. Grade 1 is mild and Grade 2 is moderate.

Time frame: each cycle, up to 6 years, 8 months and 24 days.

Here is the percentage of participants with Grade 3 or greater serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 3 is severe or medically significant, Grade 4 is life threatening, and Grade 5 is death.

Time frame: each cycle, up to 6 years, 8 months and 24 days.

The ACTG Criteria is defined as a Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), and Symptom Free Disease (SFD). The terms Improved (I), Stable (S), Mixed (M) Response, and Worse (W) are also used to further describe participants who have SD or PR.

Time frame: Baseline, week 7, and at off study visit, approximately 2 weeks following last study treatment for those with KS, up to 14 weeks.

Overall survival is defined as the percentage of participants alive at 4 months after the start of treatment with tocilizumab and tocilizumab /AZT/VGC.

Time frame: 4 months