Clinical trial NCT04585893: Safety and Efficacy of Rituximab for Treatment of Multicentric Castleman Disease in Malawi
Official title: LCCC 1950 - Rituximab for Multicentric Castleman Disease in Malawi, A Single-Arm Phase II Safety/Efficacy Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Multicentric Castleman Disease
Keywords: Multicentric Castleman Disease
MCD
HIV
Rituximab
single arm phase 2
safety and efficacy
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: Fogarty International Center of the National Institute of Health
First posted: 2020-10-14
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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).

Eligibility 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) 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).

Primary outcomes:
measure: the rate of total non-hematologic Grade ≥3 adverse events (AEs)
timeFrame: From the start of rituximab-based therapy to 12 weeks. (Up to 13 weeks)
Secondary outcomes:
measure: Characterization of MCD presentation in Malawi
timeFrame: Baseline - until 21 days
measure: Overall survival
timeFrame: 90 days, 1 year, and 2 years
measure: Event-free survival
timeFrame: 90 days, 1 year, and 2 years
measure: Efficacy of risk-adjusted treatment
timeFrame: At the end of the treatment, 12 weeks after start of the treatment
measure: Clinical Response Rate
timeFrame: At the end of the treatment, 12 weeks after start of the treatment
measure: Radiological Response Rate
timeFrame: At the end of the treatment, 12 weeks after start of the treatment
measure: Additional Safety
timeFrame: First day of the treatment through 12 weeks (Up to 13 weeks)
measure: The rate of Kaposi sarcoma exacerbation
timeFrame: Up to 2 years
measure: Quality of Life- patient-reported outcomes questionnaires
timeFrame: Baseline, week3, end of the treatment, 12 weeks, 6 months after the treatment, 24 months after the treatment, time of relapse.
measure: Change in hemoglobin measurement
timeFrame: Baseline, Day 15 and End of treatment (approximately 6 weeks)
measure: Change in platelet count measurement
timeFrame: Baseline, Day 15 and End of treatment (approximately 6 weeks)
measure: Change in C-reactive protein measurement
timeFrame: Baseline, Day 15 and End of treatment (approximately 6 weeks)
measure: Change in Kaposi sarcoma herpesvirus viral load measurement
timeFrame: Baseline, Day 15 and End of treatment (approximately 6 weeks)
Other outcomes:
Locations:
city: Lilongwe
country: Malawi
facility: UNC Project, Kamuzu Central Hospital
Study officials:
affiliation: University of North Carolina
name: Matthew Painschab, MD
role: PRINCIPAL_INVESTIGATOR
References: