Safety and Efficacy of Rituximab for Treatment of Multicentric Castleman Disease in Malawi

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of first-line, risk-stratified Rituximab-based Multicentric Castleman Disease (MCD) treatment in Malawi in a single-arm, phase II clinical trial. This study also aims to compare the cost-effectiveness of first-line Rituximab treatment for MCD in Malawi to chemotherapy.

Detailed Description
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This study aims to determine the safety and efficacy of first-line, risk-stratified rituximab-based MCD treatment in Malawi in a single-arm, phase II clinical trial. The investigators will enroll 27 subjects with newly diagnosed or previously treated MCD (who have not previously received rituximab) requiring treatment (B symptoms or hemoglobin <10 g/dL). Subjects will be treated with four weekly doses of rituximab. High-risk subjects (defined as patients with Eastern Cooperative Oncology Group (ECOG) performance status >2 or hemoglobin <8 g/dL) will also receive etoposide chemotherapy. Subjects will be followed for one year for toxicity and two years for survival. The primary outcome will be safety, defined as the frequency of ≥Grade 3 treatment-related Common Terminology Criteria for Adverse Events (AEs). Secondary outcomes will be event-free survival (death, progression, or development of NHL) and 1- and 2-year overall survival (OS). The investigators also aim to compare the cost-effectiveness of first-line rituximab treatment for MCD in Malawi to chemotherapy (using the investigators' historical controls).

Official Title
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LCCC 1950 - Rituximab for Multicentric Castleman Disease in Malawi, A Single-Arm Phase II Safety/Efficacy Trial

Conditions
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Multicentric Castleman Disease

Intervention / Treatment
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* Drug: Rituximab
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed or previously treated subjects with KSHV-associated MCD that is pathologically confirmed by characteristic histologic features and latency-associated nuclear antigen (LANA) positivity by Immunohistochemistry (IHC). Age is greater than or equal 18 years old at time of consent. Can provide informed consent. HIV-infected or HIV-uninfected. If HIV-infected, must be on or willing to start antiretroviral therapy including lamivudine or tenofovir. Willing to comply with study visits. MCD treatment indicated based on the presence of a symptomatic MCD flare, defined as the presence of each of the following three criteria: Fever (subjective or objective) Lymphadenopathy or hepatosplenomegaly At least one of the following signs or symptoms attributable to MCD by the local study investigator: Weight loss >5% Malaise Anemia (Hemoglobin <10 g/dL) within the past 4 weeks Thrombocytopenia (Platelets <100 x 103/mL) NOTE: If only two of the three criteria are present, but the provider feels treatment is indicated for a symptomatic MCD flare, this will be allowed after communication with the study principal investigator (PI). Subjects with low hemoglobin within the past 4 weeks that have since received a blood transfusion are still eligible for participation. The subject's pre-transfusion hemoglobin value will be considered when determining risk classification. Females of childbearing potential must have a negative urine pregnancy test within three days prior to registration. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Documentation of postmenopausal status must be provided. Females must agree to abstain from breastfeeding during therapy and for 6 months after the completion of therapy. Females of childbearing potential must be willing to abstain from heterosexual activity or to use two forms of effective methods of contraception from the time of informed consent until 12 months after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, a barrier method plus a hormonal method, or an intrauterine device that meets <1% failure rate for protection from pregnancy in the product label. Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 6 months after the last dose of study therapy. More than 7 days without corticosteroid use prior to starting the treatment. Exclusion Criteria: Symptomatic, extensive-stage KS (T1 by the AIDS Clinical Trials Group (ACTG) staging system; T1 includes ulceration or edema from KS, raised or non-hard palate oral lesions, or any visceral involvement) requiring urgent treatment, to avoid potential rituximab-induced KS worsening. Previous rituximab use for MCD. Second active malignancy requiring systemic therapy. If HIV negative and a) hepatitis B virus surface antigen positive or b) a combination of HepB core antibody positive and HepB surface antibody negative (indicative of chronic infection) unless on tenofovir or lamivudine. All HIV-infected patients must be on tenofovir or lamivudine as part of the inclusion criteria. Active infection requiring systemic therapy. Treatment with any investigational drug within 28 days prior to registration. More than 7 days of corticosteroids immediately prior to enrollment. If the subject is taking corticosteroids for more than 7 days, they require a 7 day washout period before enrollment. Bilirubin >3 mg/dL. Creatinine clearance <30 ml/min by Cockcroft-Gault formula. ECOG performance status >3. Pregnant or breastfeeding (Note: Breast milk cannot be stored for future use while the mother is being treated in the study).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm Rituximab<br>The safety and efficacy of first-line rituximab will be assessed through a risk-stratified rituximab-based Multicentric Castleman disease (MCD) The planned sample size is 27 adult patients accrued at a rate of 10 patients annually. High-risk patients (defined as patients with ECOG performance status >2 or hemoglobin <8 g/dL) will receive four weekly doses of rituximab (375 mg/m2) and etoposide (100 mg/m2). Low-risk patients will receive the same dose of rituximab (four weekly doses at 375 mg/m2) alone. | Drug: Rituximab<br>* 375 mg/m^2 administered via IV infusion weekly for four weeks. Administered via slow IV infusion, starting at 50mg/hr and increasing by 50mg/hr every 30 minutes to a maximum infusion rate of 400mg/hr.<br>* Other names: Rituxan;Drug: Etoposide<br>* Subjects with high-risk disease will receive 100 mg/m^2 etoposide weekly for four weeks administered over one hour via IV infusion after completion of rituximab<br>* Other names: VP-16;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the rate of total non-hematologic Grade ≥3 adverse events (AEs) | Safety will be assessed as the rate (percentage) of total non-hematologic Grade ≥3 adverse events (AEs) and treatment-related mortality. AEs will be evaluated using National Cancer Institute's Common Terminology Criteria for Adverse Events version 5 (CTCAE v5). The CTCAE grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). | From the start of rituximab-based therapy to 12 weeks. (Up to 13 weeks) | 
| Characterization of MCD presentation in Malawi | Characterization of Multicentric Castleman disease (MCD) presentation in Malawi will be summarized using baseline demographics and laboratory values. Descriptive statistics (means, median, variability measure for continuous variables, rates, and proportion for binary variables) will be performed. | Baseline - until 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival is the measure of time from the first treatment day to the date of death for any cause. Subjects who have not had an event will be censored at the date of the last assessment documenting the subject was alive. | 90 days, 1 year, and 2 years | 
| Event-free survival | Event-free survival is the measure of time after treatment during which no sign of cancer (refractory disease, relapse, non-Hodgkin lymphoma development, or death ) is found. | 90 days, 1 year, and 2 years | 
| Efficacy of risk-adjusted treatment | The efficacy of risk-adjusted treatment will be defined as the clinical response rate which is the resolution of presenting signs/symptoms that defined the Multicentric Castleman disease (MCD) attack. MCD attack/flare is defined as the presence of each of the following three criteria: 1) Fever (subjective or objective), 2) Lymphadenopathy or hepatosplenomegaly, 3) At least one of the following signs or symptoms attributable to MCD by the local study investigator: a) Weight loss >5%, b) Malaise, c) Anemia (Hemoglobin <10 g/dL), and d) Thrombocytopenia (Platelets <100 x 10^3/uL). | At the end of the treatment, 12 weeks after start of the treatment | 
| Clinical and Radiological Response Rate | Clinical and Radiological Response Rate will be defined as the percentage of subjects without relapse defined using chest radiography, abdominal sonography, and physical exam for gross lymphadenopathy. Response criteria for lymph node response will be Complete response (CR)- the disappearance of all evident disease; Partial response (PR)-at least a 50% decrease in target lesions with no increase in non-target lesions, Stable disease (SD)- Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD); PD- the appearance of a new lesion or at least a 50% increase in lesion size. | At the end of the treatment, 12 weeks after start of the treatment | 
| Additional Safety | Additional Safety will be defined as all Adverse Events occurred. AEs will be evaluated using National Cancer Institute's Common Terminology Criteria for Adverse Events version 5 (CTCAE v5). | First day of the treatment through 12 weeks (Up to 13 weeks) | 
| The rate of Kaposi sarcoma exacerbation | The rate of Kaposi sarcoma exacerbation will be determined by symptomatic or clinical (dermatologic or visceral organ) exacerbation of the disease. All disease flares will be biopsy confirmed whenever possible. | Up to 2 years | 
| Quality of Life- patient-reported outcomes questionnaires | Quality of Life- patient-reported outcomes (PRO) questionnaires will be assessed by the Patient-Reported Outcomes Measurement Information System Global Health Survey (PROMIS Global-10). The survey includes 10 items about mental and physical health rated on Likert scales ranging from 1 to 5, with higher scores indicative of better health. | Baseline, week3, end of the treatment, 12 weeks, 6 months after the treatment, 24 months after the treatment, time of relapse. | 
| Change in hemoglobin measurement | Hemoglobin will be measured in grams per deciliter (g/dL) at baseline, day 15, and end-of-treatment. Differences will be compared by paired t-test. | Baseline, Day 15 and End of treatment (approximately 6 weeks) | 
| Change in platelet count measurement | Platelet count will be measured in microliters (µl) at baseline, day 15, and end-of-treatment. Differences will be compared by paired t-test. | Baseline, Day 15 and End of treatment (approximately 6 weeks) | 
| Change in C-reactive protein measurement | C-reactive protein (CRP) will be measured in milligrams per milliliter (mg/mL) at baseline, day 15, and end-of-treatment. Differences will be compared by paired t-test. | Baseline, Day 15 and End of treatment (approximately 6 weeks) | 
| Change in Kaposi sarcoma herpesvirus viral load measurement | Kaposi sarcoma herpesvirus (KSHV) viral load will be measured in copies per milliliter (copies/mL) at baseline, day 15, and end-of-treatment. Differences will be compared by paired t-test. | Baseline, Day 15 and End of treatment (approximately 6 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multicentric Castleman Disease, MCD, HIV, Rituximab, single arm phase 2, safety and efficacy