Primary Objective: To evaluate dose limiting toxicity and to determine the recommended phase 2 dose (RP2D) of pentamidine in combination with salvage chemotherapy with ifosfamide, carboplatin and etoposide (ICE) on a 3-weeks schedule in relapsed/refractory classical Hodgkin lymphoma (cHL). Secondary Objective: * To estimate the overall best treatment response at 5- and 16-weeks from study enrollment. Although the clinical benefit of these drugs in combination has not been established, offering this treatment may provide a therapeutic benefit. The patients will be carefully monitored for tumor response and symptom relief, in addition to safety and tolerability. * To estimate the duration of response to the proposed combined therapy. * To measure the protein of regenerating liver-3 (PRL-3) level of expression in patients at time of relapse. * To measure circulating biomarkers of response (soluble CD30 (sCD30), and thymus and activation-related chemokine (TARC)) in serum samples collected throughout treatment and inhibition of (pSTAT, pAKT) in peripheral blood mononucleated cells (PBMC). Exploratory Objective: * To measure cell-free messenger RNA (cfmRNA) in peripheral blood. * To measure cell-free DNA in peripheral blood
The primary objective of this Phase I study is to determine the maximum tolerated dose (MTD) of Pentamidine. A two-stage continual reassessment method (CRM) will be employed to determine dose escalation levels and the maximum tolerated dose (MTD) of Pentamidine. Specifically, a modified two-stage CRM will be employed with 2 patients per cohort at each dose level. The trial starts with an escalation design from the lowest dose (2 mg/kg) with a traditional 2+2 dose escalation method. After occurrence of the first DLT, dose assignment will be determined by the CRM (2 patients/per cohort) using empirical model with restrictions to avoid dose-skipping and escalation immediately after a toxicity outcome. A maximum of 12 patients will be enrolled into the trial during the escalation phase. Once the MTD is reached, an additional 4 patients will be treated at this dose. Thus, 6 or more patients will be treated at the MTD. The target DLT rate is 33% and the investigators choose to use 0.10, 0.20 and 0.33 as prior toxicity distribution. CRM simulations indicate optimal performance of this design with high dose recommendation probabilities (at least 48%) and more patients allocated to the correct dose
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
1
Pentamidine will be administered as an IV infusion on treatment day 1-3 of a 21-day cycle 3 cycles using 2, 3, and 4 mg/kg dose escalation schedules. Non-investigational agents will be administered as follows: Ifosfamide 5000 mg/m2, Carboplatin 5 area under curve (AUC), and Etoposide 100 mg/mg2.
University of Kentucky Markey Cancer Center
Lexington, Kentucky, United States
Maximum tolerated dose (MTD)
Dose limiting toxicity (DLT) for hematological and non-hematological toxicities will be graded using National Cancer Institute (NCI) CTCAE Version 5.0
Time frame: Up to 21 days
Determine Efficacy: best overall response
Individual best overall response at 5 and 16 weeks from enrollment, patients will be categorized as either a responder (complete response, partial response) versus nonresponders (stable disease, progressive disease).
Time frame: Up to 112 days
Define the Duration of Response
Duration of response as defined starting from the first occurrence of response until disease progression or death.
Time frame: Up to 112 days
Identify Immunohistochemistry Biomarkers
Immunohistochemistry staining of paraffin fixed tissue sample and peripheral blood will be done to assess the ability of pentamidine to inhibit its pharmacological target through PRL-3 expression.
Time frame: Up to 112 days
Polymerase Chair Reaction (PCR) analysis of Biomarkers
Digital PCR analysis of paraffin fixed tissue sample and peripheral blood will be done to assess PRL-3 expression and compare to the immunohistochemistry staining to determine the ideal testing modality for PRL-3 in cHL.
Time frame: Up to 112 days
Identify Phosphorylation Biomarkers
Pentamidine concentration/protein phosphorylation will be measured in PBMC and plasma samples collected throughout treatment.
Time frame: Up to 112 days
Identify sCD30 and TARC Biomarkers
Biomarkers: ELISA testing will be used to assess levels of sCD30 and TARC in serum samples collected prior to initiation of therapy and subsequent cycles.
Time frame: Up to 112 days
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