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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Multicentric Castleman Disease
• Intervention / Treatment: Drug: Rituximab; Drug: Etoposide

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 Type: Interventional
• Enrollment (Estimated): 27
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Matthew Painschab, MD; Phone Number: 763 234 5055; Email: matthew.painschab@unchealth.unc.edu

Study Locations

• Malawi
  • Lilongwe, Malawi
    • Recruiting
    • UNC Project, Kamuzu Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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).
2. Age is greater than or equal 18 years old at time of consent.
3. Can provide informed consent.
4. HIV-infected or HIV-uninfected.
5. If HIV-infected, must be on or willing to start antiretroviral therapy including lamivudine or tenofovir.
6. Willing to comply with study visits.

7. MCD treatment indicated based on the presence of a symptomatic MCD flare, 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:

      • 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.

8. 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.

9. Females must agree to abstain from breastfeeding during therapy and for 6 months after the completion of therapy.
10. 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.
11. 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.
12. More than 7 days without corticosteroid use prior to starting the treatment.

Exclusion Criteria:

1. 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.
2. Previous rituximab use for MCD.
3. Second active malignancy requiring systemic therapy.
4. 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.
5. Active infection requiring systemic therapy.
6. Treatment with any investigational drug within 28 days prior to registration.
7. 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.
8. Bilirubin >3 mg/dL.
9. Creatinine clearance <30 ml/min by Cockcroft-Gault formula.
10. ECOG performance status >3.
11. Pregnant or breastfeeding (Note: Breast milk cannot be stored for future use while the mother is being treated in the study).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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.

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborators: Fogarty International Center of the National Institute of Health
• Investigators: Principal Investigator: Matthew Painschab, MD, University of North Carolina

Publications and helpful links

Helpful Links

• UNC Lineberger Comprehensive Cancer Center Website Homepage

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2021
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: September 10, 2020
• First Submitted That Met QC Criteria: October 9, 2020
• First Posted (Actual): October 14, 2020

Study Record Updates

• Last Update Posted (Actual): May 30, 2023
• Last Update Submitted That Met QC Criteria: May 25, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: HIV; Rituximab; MCD; safety and efficacy; Multicentric Castleman Disease; single arm phase 2
• Additional Relevant MeSH Terms: Immune System Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Castleman Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Etoposide; Rituximab
• Other Study ID Numbers: LCCC 1950; K01TW011470 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No