Nirogacestat in Patients With Kaposi Sarcoma

ConditionsAIDS-Related Kaposi Sarcoma Skin Kaposi Sarcoma

Trial statusNot yet recruiting

Trial phasePhase 2

Trial typeInterventional

Biological sexAll

Age18+

SponsorAIDS Malignancy Consortium

About this trial

This phase II trial studies how well nirogacestat works in treating patients with skin Kaposi sarcoma (KS). Several anti-cancer drugs work well in treating KS, but there is no treatment that cures KS. Nirogacestat binds to a protein called gamma secretase, which blocks the activation of other proteins called Notch receptors. Blocking these proteins may help keep tumor cells from growing and may kill them. Nirogacestat is a type of gamma secretase inhibitor. Nirogacestat may be effective in shrinking the size of KS lesions and reducing the spread of lesions.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Biopsy-proven KS involving skin with or without visceral involvement either newly diagnosed or refractory to or intolerant of one or more prior therapies.

Patients must have cutaneous lesion(s) amenable to six total biopsies (minimum size of biopsy to be 4 mm), either six lesions > 4 mm or one large lesion measuring 20 mm that can undergo serial biopsy, and at least five additional lesions measurable for assessment with no improvement over the past month.

Hemoglobin ≥ 8 g/dL (within three months prior to study entry)

Absolute neutrophil count (ANC) ≥ 1,000 cells/mm^3 (within three months prior to study entry)

Disqualifiers

Concurrent, acute, active opportunistic infection other than oral thrush or genital herpes within 14 days of enrollment.

Patients for whom front-line cytotoxic therapy is indicated (i.e., symptomatic visceral or pulmonary KS or symptomatic KS impairing functional status).

Concurrent neoplasia requiring cytotoxic therapy.

Anti-neoplastic treatment for KS (including chemotherapy, radiation therapy, local therapy including topical 5-FU, biological therapy, or investigational therapy) within four weeks of study entry.

Trial design

Design model

Single group

Treatments tested in this trial

Biospecimen Collection
Procedure/Surgery
Undergo collection of blood
Chest Radiography
Procedure/Surgery
Undergo chest X-ray
Computed Tomography
Procedure/Surgery
Undergo CT
Nirogacestat
Drug
Given PO
Skin Biopsy
Procedure/Surgery
Undergo skin biopsy

Treatment groups

28 Participants

are divided into 1 treatment group

Group A: Treatment (nirogacestat)Experimental treatment 5 interventions

Trial outcomes

Primary outcomes

Overall response rate (ORR)

The ORR will be estimated for each dose group and for all groups combined. The 95% confidence intervals will be constructed for the ORR.

Time frame

Up to 5 years after completion of study treatment

Secondary outcomes

Incidence of adverse events (AEs)

The AEs will be tabulated by type, grade, and attribution.

Time frame

Up to 5 years after completion of study treatment

Duration of the response (DOR)

Non-responders will be excluded in DOR analysis. Participants who begin treatment but drop out prior to the first post-baseline response assessment will be considered non-responders. The Kaplan-Meier method will be used to describe the DOR for all treated participants. The proportional hazards model will be used to evaluate the association of HIV status and pretreatment status on the DOR.

Time frame

From the first date on which a partial response or complete response is documented until progression or death due to any cause, assessed up to 5 years after completion of study treatment

Cumulative proportion of study participants still in response

Will be estimated using the point estimate and the 95% confidence interval using Greenwood's formula for the standard error of the Kaplan-Meier estimate.

Time frame

At 1 year

Blood biomarkers

Will assess the effect of nirogacestat on blood biomarkers such as CD4+ and CD8+ T, CD19+, cell number, HIV and Kaposi sarcoma-associated herpesvirus virus load. The analysis of variance will be used to evaluate the changes from entry to 4 or 12 weeks in CD4 and CD8 cell counts and percentages and levels of plasma-associated HIV-1 ribonucleic acid (RNA). Descriptive statistics for biomarkers will be reported using mean, standard deviation, median, and range. Linear regression analysis and correlation coefficient analysis will be performed to examine the association between change from baseline in a specific biomarker and study covariates.

Time frame

Up to 5 years after completion of study treatment

Other outcomes

Tumor-associated Kaposi sarcoma-associated herpesvirus (KSHV) latent and lytic gene expression

Will assess the effect of Nirogacestat on tumor-associated KSHV latent and lytic gene expression. To evaluate the relationship between clinical response and quantitative measures of KSHV/human herpesvirus (HHV)-8 and HIV viral load, these measures will be tested to determine if they are normally distributed. If the data does not meet the assumptions of normality, the data will be transformed for analysis purposes. Analysis of variance will be used to assess the relationship between qualification of baseline levels of KSHV/HHV-8, HIV viral load, and response. Spearman rank correlation analysis will be used to evaluate the relationship between the qualification of baseline KSHV/HHV-8, HIV viral load and time to progression, and response duration.

Time frame

Up to 5 years after completion of study treatment

Activation of Notch target genes and Notch regulatory genes

Will assess effects of Nirogacestat on activation of Notch target genes and Notch regulatory genes.

Time frame

Up to 5 years after completion of study treatment

Tumor-associated endothelial-mesenchymal transition

Will assess effects of Nirogacestat on tumor-associated endothelial-mesenchymal transition. Endothelial-mesenchymal transition will be assessed from scRNAseq. The following markers will be measured. Endothelial markers decreasing over time: CDH5 (VE-cadherin), PECAM1 (CD31), VWF (von Willebrand Factor), TEK (TIE2); Mesenchymal markers increasing over time: ACTA2 (a-SMA), VIM (vimentin), S100A4 (FSP-1), FN1 (Fibronectin); Master regulators of EMT increasing over time: SNAI1 (Snail), SNAI2 (Slug), TWIST1, ZEB1, ZEB2, LEF1.

Time frame

At the end of Cycle 1 (each cycle is 28 days)

Peak plasma of Nirogacestat in KS patients

For pharmacokinetic analysis, 20 samples will be used (10 from responders and 10 from non-responders) to estimate peak plasma level.

Time frame

Cycle 1 pre-dose, 0.5, 1.5, and 3 hours post-first dose and Cycle 2 day 1, pre-dose (one cycle=28 days)

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

AIDS Malignancy Consortium

Lead sponsor

National Cancer Institute (NCI)

Collaborator

Source ClinicalTrials.gov

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