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

Sponsor

UNC Lineberger Comprehensive Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04585893

Collaborator

Fogarty International Center of the National Institute of Health (NIH)

Enrollment

Location

Arm

61.3

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multicentric Castleman Disease	Drug: Rituximab Drug: Etoposide	Phase 2

Detailed Description

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

27 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 22, 2021

Anticipated Primary Completion Date :

Aug 1, 2024

Anticipated Study Completion Date :

Aug 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single Arm Rituximab 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 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. Other Names: Rituxan Drug: Etoposide 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 Other Names: Toposar VP-16

Arm

Intervention/Treatment

Experimental: Single Arm Rituximab

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

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.

Other Names:

Rituxan

Drug: Etoposide

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

Other Names:

Toposar

VP-16

Outcome Measures

Primary Outcome Measures

Rate of non-hematologic grade ≥3 adverse events [12 weeks]
Using National Cancer Institute's Common Terminology Criteria for Adverse Events, the rate (percentage) non-hematologic Grade ≥3 adverse events (AEs) (CTCAE version 5.0) will be assessed through twelve weeks from the start of rituximab-based therapy. 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).
Treatment-related mortality rate [12 weeks]
Treatment-related mortality will be observed through twelve weeks from the start of rituximab-based therapy.

Secondary Outcome Measures

Characteristics of MCD presentation in Malawi [21 days, at study entry]
Basic demographics and baseline laboratory values will be summarized using descriptive statistics (i.e., means, medians, and variability measures for continuous variable; rates and proportions for binary variables). Collected at study entry. Screening assessments to be completed within 21 days prior to study enrollment.
Overall survival rate [2 years]
Overall survival will be assessed at 90 days, one year, and two years from the start of treatment and will be described using Kaplan-Maier methods.
Event-free survival survival rate [2 years]
Event-free survival will be defined as the rate of refractory disease, relapse, non-Hodgkin lymphoma development or death and will be assessed at 90 days, one year, and two years from the start of treatment and will be described using Kaplan-Maier methods.
Clinical response rate [12 weeks]
Clinical response rate at end of treatment and 90 days from treatment initiation (clinical response defined as resolution of presenting signs/symptoms that defined the Multicentric Castleman disease (MCD) attack) without relapse at 90 days. 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).
Radiologic response rate [12 weeks]
Radiologic response rate is the percentage of patients without relapse at end of treatment and 90 days from treatment initiation. Chest radiography and abdominal sonography will be used for staging. Per Revised response criteria for gross lymphadenopathy, response will be evaluated via complete survey of lymph nodes with measurements and physical assessment of other palpable masses with measurements. Response criteria for lymph node response will be as follows: Complete response (CR)- disappearance of all evident disease; Partial response (PR)-at least 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- appearance of a new lesion or at least a 50% increase in lesion size.
Frequency of all Adverse Events [12 weeks]
Using National Cancer Institute's Common Terminology Criteria for Adverse Events, additional safety assessment will be graded by CTCAE v 5.0 through twelve weeks from the start of therapy. 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).
Rate of Kaposi sarcoma exacerbation [2 years]
Kaposi sarcoma (KS) exacerbation will be defined as new symptoms attributed to KS or clinically evident exacerbation of dermatologic or visceral disease. All disease flares will be biopsy confirmed whenever possible.
Change in Multicentric Castleman disease symptom score [Baseline, week 3, week 5, week 12, 6 months and 24 months]
Quality of life will be assessed at baseline, 4 weeks, 12 weeks, and 6 months after treatment and at the time of any relapse by patient-reported outcomes using the Multicentric Castleman disease symptom score (MCD-SS). The MCD-SS lists 10 symptoms which are graded on a scale: Did not experience (0); Very mild (2); Mild (4); Moderate (6); Severe (8); Very Severe (10). The mean score of the ten items is calculated and a higher score indicates more severe symptoms.
Change in Quality of life PROMIS scores [Baseline, week 3, week 5, week 12, 6 months and 24 months]
Quality of life will be assessed at baseline, 4 weeks, 12 weeks, and 6 months after treatment and at the time of any relapse by patient-reported outcomes questionnaires: 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.
Change in hemoglobin measurement [Baseline, Day 15 and End of treatment (approximately 6 weeks)]
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.
Change in platelet count measurement [Baseline, Day 15 and End of treatment (approximately 6 weeks)]
Platelet count will be measured in microliters (µl) at baseline, day 15, and end-of-treatment. Differences will be compared by paired t-test.
Change in C-reactive protein measurement [Baseline, Day 15 and End of treatment (approximately 6 weeks)]
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.
Change in Interleukin-6 measurement [Baseline, Day 15 and End of treatment (approximately 6 weeks)]
Interleukin-6 (IL-6) will be measured at baseline, day 15, and end-of-treatment. Differences will be compared by paired t-test.
Change in Interleukin-10 measurement [Baseline, Day 15 and End of treatment (approximately 6 weeks)]
Interleukin-10 (IL-10) will be measured at baseline, day 15, and end-of-treatment. Differences will be compared by paired t-test.
Change in Kaposi sarcoma herpesvirus viral load measurement [Baseline, Day 15 and End of treatment (approximately 6 weeks)]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).

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 breast-feeding 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, or 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.
At least 7 days without corticosteroid use prior to start of 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) 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 subject is taking corticosteroid 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 on the study).