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

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ClinicalTrials.gov Identifier: NCT04585893
Recruitment Status : Recruiting
First Posted : October 14, 2020
Last Update Posted : August 16, 2021
Sponsor:
Collaborator:
Fogarty International Center of the National Institute of Health
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

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).

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : June 22, 2021
Estimated Primary Completion Date : August 2024
Estimated Study Completion Date : August 2026


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 Name: 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




Primary Outcome Measures :
  1. Rate of non-hematologic grade ≥3 adverse events [ Time Frame: 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).

  2. Treatment-related mortality rate [ Time Frame: 12 weeks ]
    Treatment-related mortality will be observed through twelve weeks from the start of rituximab-based therapy.


Secondary Outcome Measures :
  1. Characteristics of MCD presentation in Malawi [ Time Frame: 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.


  2. Overall survival rate [ Time Frame: 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.

  3. Event-free survival survival rate [ Time Frame: 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.

  4. Clinical response rate [ Time Frame: 90 days ]
    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).

  5. Radiologic response rate [ Time Frame: 90 days ]

    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.


  6. Frequency of all Adverse Events [ Time Frame: 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).

  7. Rate of Kaposi sarcoma exacerbation [ Time Frame: 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.

  8. Change in Multicentric Castleman disease symptom score [ Time Frame: 2 years ]
    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.

  9. Change in Quality of life PROMIS scores [ Time Frame: 2 years ]
    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.

  10. Change in hemoglobin measurement [ Time Frame: 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.

  11. Change in platelet count measurement [ Time Frame: 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.

  12. Change in C-reactive protein measurement [ Time Frame: 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.

  13. Change in Interleukin-6 measurement [ Time Frame: 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.

  14. Change in Interleukin-10 measurement [ Time Frame: 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.

  15. Change in Kaposi sarcoma herpesvirus viral load measurement [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)
      • 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).
  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 breast-feeding during therapy and for 30 days 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 30 days 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.
  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 30 days after the last dose of study therapy.

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) 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. >7 days of corticosteroids.
  8. Bilirubin >3 mg/dL.
  9. Creatinine clearance <30 ml/min by Cockcroft-Gault formula.
  10. ECOG performance status >3.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04585893


Contacts
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Contact: Matthew Painschab, MD 763 234 5055 matthew.painschab@unchealth.unc.edu

Locations
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Malawi
UNC Project, Kamuzu Central Hospital Recruiting
Lilongwe, Malawi
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Fogarty International Center of the National Institute of Health
Investigators
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Principal Investigator: Matthew Painschab, MD University of North Carolina
Additional Information:
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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04585893    
Other Study ID Numbers: LCCC 1950
K01TW011470 ( U.S. NIH Grant/Contract )
First Posted: October 14, 2020    Key Record Dates
Last Update Posted: August 16, 2021
Last Verified: August 2021

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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
Keywords provided by UNC Lineberger Comprehensive Cancer Center:
Multicentric Castleman Disease
MCD
HIV
Rituximab
single arm phase 2
safety and efficacy
Additional relevant MeSH terms:
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Castleman Disease
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Etoposide
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action