This is a multi-centre, two-part, open-label, phase 1, first in human study of multiple ascending doses of RC220 bisantrene formulation alone and in combination with fixed dose doxorubicin to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) in adult patients with locally advanced unresectable or metastatic solid tumours where doxorubicin may be considered as a treatment option / or is indicated. The study will consist of two parts: Part 1 - This part involves a fixed-dose doxorubicin (60 mg/m2) tolerability lead-in period, followed by dose-escalating doses of IV RC220 alone, and in combination, with fixed dose doxorubicin, to determine the maximum tolerated combined dose (MTCD) of RC220 with doxorubicin to be evaluated in Part 2. This dose-expansion cohort will enrol patients with solid tumours that are anthracycline treatment naïve and for whom treatment with doxorubicin is indicated. The objective of Part 2 will be to confirm the safety and tolerability and evaluate the preliminary cardioprotective and anti-tumour efficacy of the maximum tolerated combined dose (MTCD) of RC220 with doxorubicin.
This study is an open-label, Phase 1 dose escalation trial with expansion cohort to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary cardioprotective and antitumor activity of RC220 in combination with doxorubicin in patients with advanced solid tumours. The study is divided into two parts: Dose escalation (Part 1), and dose expansion (Part 2). In Part 1(Dose Escalation), patients with locally advanced unresectable or metastatic solid tumours, where doxorubicin may be considered as a treatment option and/or is indicated will be enrolled. An initial fixed-dose doxorubicin (60 mg/m2) monotherapy 21-day cycle (cycle M1) will be conducted to confirm each patient's tolerability. Patients will be monitored for safety and tolerability, and samples will be collected for PK and PDx biomarker analysis. Patients who meet the safety and tolerability criteria during cycle M1 will proceed to the RC220 monotherapy lead-in 21-day cycle (cycle M2). Patients who are unable to tolerate 60 mg/m2 doxorubicin will not be eligible for the study, and those who received a doxorubicin containing regimen of ≥ 60 mg/m2 within 3 months prior to screening, may proceed directly to the RC220 monotherapy lead-in cycle. During Cycle M2, each patient in a dose cohort will receive an intravenous (IV) infusion of RC220 on Day 1 of the lead-in 21-day cycle. Upon confirmation of safety and tolerability to the RC220 dose, patients will continue to the combination cycle, where patients will receive IV RC220 (at the same dose) followed by IV doxorubicin on Day 1 of a 21-day cycle. New patients will be enrolled in each dose escalation cohort based on safety observed during the first 21 days of RC220 and doxorubicin combination treatment Cycle 1 until the MTCD is defined based on the recommendations of the Safety Review Committee (SRC). Patients will continue to be treated beyond the first combination cycle observation period until disease progression, unacceptable toxicity, withdrawal of consent or defined end of study, whichever occurs first. An interim analysis of Part 1 may be undertaken after the last patient in the dose escalation (Part 1) has completed their end-of-study visit. Part 2 of the study will evaluate the MTCD of RC220 in combination with doxorubicin in an exploratory expanded cohort of patients to assess the cardioprotective and anti-tumour efficacy in patients with solid tumours that are anthracycline treatment naïve and for whom treatment with doxorubicin is indicated.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
53
The assigned dose will be administered by intravenous infusion over 60 minutes.
60 mg/m2 administered by intravenous infusion over 10 minutes on Day 1 of the monotherapy lead-in cycle (M1) and on Day 1 of each 21-day combination cycle following administration of intravenous RC220
Gosford Hospital
Gosford, New South Wales, Australia
RECRUITINGCancer Care Foundation
Miranda, New South Wales, Australia
RECRUITINGWyong Hospital
Wyong, New South Wales, Australia
RECRUITINGQueen Mary Hospital
Hong Kong, Hong Kong
RECRUITINGPrince of Wales Hospital
Shatin, Hong Kong
RECRUITINGAsan Medical Centre
Seoul, South Korea
NOT_YET_RECRUITINGEwha Womans University MokDong Hospital
Seoul, South Korea
NOT_YET_RECRUITINGSamsung Medical Centre
Seoul, South Korea
NOT_YET_RECRUITINGSeverance Hospital, Yonsei University, Health System
Seoul, South Korea
NOT_YET_RECRUITINGPart 1. Incidence of dose limiting toxicities (DLTs)
Evaluated at each dose level RC220 combined with doxorubicin, as graded by National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) version 5.0.
Time frame: During the first cycle of RC220 and doxorubicin treatment (1-21 days)
Part 1 and Part 2. Treatment emergent adverse events (TEAE) and serious adverse events (SAEs),
This includes clinically significant changes in vital signs, physical examination, electrocardiogram, echocardiogram and clinical laboratory tests, as graded by NCI CTCAE v5.0.
Time frame: First dose up to 30 days post last combination dose (up to 12 months)
Part 1. Maximum tolerated combined dose (MTCD)
The MTCD is based on the incidence of Dose Limiting Toxicities (DLTs).
Time frame: After the first dose of RC220 and doxorubicin treatment cycle (1-21 days)
Part 1 and Part 2. Best Overall Response (BOR)
Percentage of patients with best confirmed overall response of clinical response (CR) or partial response (PR) (evaluated by the investigator according to RECISTv1.1) until the time of disease progression.
Time frame: Up to 12 months
Part 1 and Part 2. Duration of Response (DOR)
Defined as the time from the earliest date documented (CR or PR) (evaluated by the investigator according to RECISTv1.1) until disease progression or death (by any cause, in the absence of progression).
Time frame: Up to 12 months
Part 1 and Part 2. Progression Free Survival (PFS)
Defined as the time of first treatment until disease progression or death (by any cause, in the absence of progression).
Time frame: Up to 12 months
Part 2. Change from baseline in cardiac blood biomarker levels (hs-troponins and NT-proBNP), as measured by laboratory tests
Time frame: up to 12 months
Part 2. Change from baseline in 2D-echocardiogram measurements including GLS, LV volume, LV mass, transmitral flow, atrial volumes.
2D-echocardiograms are performed at specified timepoints. Each time a 2D-echocardiogram is performed, multiple measures will be collected, aggregated and reported on once by a single observer. Measures collected from each 2D-echocardiogram, and compared to baseline, include: * global longitudinal strain * left ventricular mass * left ventricular volumes * transmitral flow * left atrial volume
Time frame: Up to 12 months
Part 2. Change from baseline in cardiac magnetic resonance imaging (cMRI) cardiac function parameters (blood flow, global ventricular function, myocardial perfusion)
Each time a cMRI is performed, cMRI images are collected, assessed, compared and reported on in an aggregated manner by an independent cardiologist for changes in cardiac function measures (blood flow, global ventricular function, myocardial perfusion).
Time frame: Up to 12 months
Part 2. Change from baseline in functional volume of peak oxygen uptake (VO2 peak). Defined as the highest amount of oxygen consumed at peak exercise.
Time frame: Up to 12 months
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