Study of DPPG2-TSL-DOX Combined With Hyperthermia in Soft Tissue Sarcoma

Study Overview
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Brief Summary
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This study aims to explore a new therapeutic approach for advanced soft tissue sarcoma (STS) by investigating the safety, tolerability, and maximum tolerable dose (MTD) of DPPG2-TSL-DOX combined with regional hyperthermia (RHT) in patients who have been pre-treated with doxorubicin (DOX).

Detailed Description
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Considering that up to 40 percentage of patients with soft tissue sarcoma (STS) will develop metastatic disease and that for these patients overall survival (OS) ranges between 3.7 to 25 months it becomes clear that new therapeutic approaches for the treatment of advanced STS are urgently needed. Doxorubicin (DOX) is a cytotoxic compound that belongs to the class of anthracyclines. DOX has had market authorization since 1960s and is considered the most active chemotherapeutic drug for the treatment of STS. DPPG2-TSL-DOX is a novel formulation of DOX encapsulated in DPPG2-containing thermosensitive liposomes (TSL). Regional hyperthermia (RHT) with a tumor target temperature of ≥41.5 to ≤44 degree of Celsius combined with anthracycline-based chemotherapy has shown to improve survival in patients with localized high-risk STS. Treatment with DPPG2-TSL-DOX aims at combining the confirmed anti-tumor efficacy of anthracyclines in the treatment of locally advanced STS with RHT-triggered DOX release from circulating liposomes resulting in 10-15-fold higher local DOX concentrations in the tumor as observed in preclinical studies. DPPG2-TSL-DOX combined with RHT has been investigated in feline sarcoma at 1 mg/kg dose level resembling the clinically recommended dose level of standard DOX with considerably improved efficacy and better tolerability. The proposed study will characterize the safety and tolerability and, if applicable, the maximum tolerable dose (MTD) of DPPG2-TSL-DOX in combination with RHT in patients with advanced or metastatic STS who have been pre-treated with DOX but not assessed as refractory to DOX. An adapted 3+3 MAD study design with sentinel dosing and a starting dose of 20 mg/m^2 DPPG2-TSL-DOX is applied in this study to identify dose-limiting toxicities (DLTs) of DPPG2-TSL-DOX in combination with RHT.

Official Title
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Phase I Dose Escalation Study of 3-Weekly Intravenous DPPG2-TSL-DOX Combined With Regional Hyperthermia in Locally Advanced or Metastatic Soft Tissue Sarcoma

Conditions
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Sarcoma, Soft Tissue

Intervention / Treatment
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* Drug: DPPG2-TSL-DOX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at the time of consent ≥18 years Patient has provided written informed consent prior to any study-specific procedure Locally advanced (unresectable) or metastatic soft tissue sarcoma (STS) histologically diagnosed by local pathology review for which treatment with doxorubicin (DOX) monotherapy is appropriate, as confirmed by the investigator Pretreatment with DOX combination chemotherapy (DOX/ifosfamide, DOX/dacarbazine or other anthracycline combination therapies) provided at least stable disease was achieved. For patients who received DOX in an adjuvant setting, local recurrence free interval of > 6 months is required Progressive disease not suitable for surgery after only one further line of chemotherapy (including tyrosine-kinase inhibitor) if the regional hyperthermia (RHT) field targets the clinically relevant tumor manifestation/s (e.g., locally advanced or multifocal intraabdominal STS; diffuse metastatic STS in which RHT of a tumor manifestation [e.g., liver] is considered relevant although other systemic metastases are present that do not endanger the patient, as per the judgment of the investigator), or two or more further lines of chemotherapies (including TKI) for patients with metastatic STS and a tumor manifestation suitable for RHT All previous oncological treatments must have been completed ≥3 weeks (21 days) prior to the first dose of study treatment, ensuring a sufficient washout period Measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (Eisenhauer et al. 2009) Tumor accessible for RHT Left ventricular ejection fraction (LVEF) >50% (within 28 days prior to enrolment) Adequate hematologic, organ and coagulation function within 14 days prior to enrolment as assessed by local lab: Absolute neutrophil count (ANC) ≥1.5×10^9/L. Granulocyte-colony stimulating factor (G-CSF) cannot be administered within 2 weeks (14 days) prior to enrolment Platelet count ≥100×10^9/L Hemoglobin ≥9.0 g/dL. No transfusions are allowed within 2 weeks (14 days) prior to enrolment Serum creatinine ≤1.5 times upper limit of normal (ULN) Negative dipstick for proteinuria or if proteinuria ≥2+, then additional 24 h urine collection <1g protein/ 24 h Total bilirubin within ULN (except for patients with Gilbert's syndrome, who must have a total bilirubin <3 mg/dL) Alanine aminotransferase (ALT)/ Aspartate aminotransferase (AST) ≤3.0×ULN; if the liver has tumor involvement, AST and ALT ≤5.0×ULN are acceptable An adequate coagulation function as defined by international normalized ratio (INR) ≤1.5×ULN or prothrombin time ≤1.5×ULN, and partial thromboplastin time ≤1.5×ULN (unless receiving anticoagulant therapy). Patients receiving phenprocoumon are recommended to switch to low molecular weight heparin and should have achieved stable coagulation status prior to the first dose of study treatment Tubular excretion rate (TER) by Mercaptoacetyltriglycin-3 (MAG-3)-clearance ≥ TERLoLi (TERLoLi = 70% TERNorm) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 If female, must: Be not of child-bearing potential due to surgical sterilization (at least 6 weeks following surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by medical history or menopause Be a post-menopausal woman, defined as a woman meeting either of the following criteria: i. spontaneous amenorrhea for at least 12 months, not induced by a medical condition such as anorexia nervosa and not taking medications during the amenorrhea that induced the amenorrhea (for example, oral contraceptives, hormones, gonadotropin-releasing hormone, antiestrogens, selective estrogen receptor modulators [SERMs], or chemotherapy) ii. spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone level >40 mIU/mL Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use two medically acceptable methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1 percentage per year when used consistently and correctly beginning at screening, during trial participation, and until 6 months after last dose of study treatment. Also, partner of male participants, who is of childbearing potential must use a highly effective method of contraception during the same duration. At least 3 months' life expectancy in the investigator's assessment Exclusion Criteria: Progressive disease under previous treatment with anthracyclines Patients already enrolled in any clinical study involving an investigational product or medical device or have participated within the past 30 days in a clinical trial involving an investigational product or medical device History of another primary malignancy, with the exception of: curatively treated non-melanomatous skin cancer curatively treated cervical carcinoma in situ non-metastatic prostate cancer, or other primary non-hematologic malignancies that had been treated with curative intent, no known active disease, and no treatment administered during the last 3 years prior to enrolment that the investigator agrees will not affect the interpretation of study results or would be unsuitable for participation in the study Active fungal, bacterial and/or known viral infection including human immunodeficiency virus or viral (A, B, or C) hepatitis Resting heart rate of >100 bpm Uncontrolled intercurrent illness including, but not limited to, an ongoing/active infection - - Have a serious cardiac condition, such as: unstable angina pectoris angioplasty, cardiac stenting, or myocardial infarction within 6 months of enrolment valvulopathy that is severe, moderate, or deemed clinically significant arrhythmias that are symptomatic or require treatment Have a QTcF interval of >450 msec for males and >470 msec for females on screening electrocardiogram (ECG) utilizing Fridericia's correction Psychiatric illness or social situation that would limit compliance with study requirements. Any planned or required major surgery during the course of the study Pregnant or breastfeeding female Individuals who are institutionalized on a judicial or regulatory order

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: an adapted 3+3 multiple ascending dose (MAD) design with sentinel dosing
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV DPPG2-TSL-DOX<br>DPPG2-TSL-DOX (20 or 40 or 50 mg/m^2) + regional hyperthermia (RHT) 3 dose levels are planned in this study: dose level 1 will be receiving 20 mg/m^2 DPPG2-TSL-DOX dose level 2 will be receiving 40 mg/m^2 DPPG2-TSL-DOX dose level 3 will be receiving 50 mg/m^2 DPPG2-TSL-DOX Participants are to be treated with DPPG2-TSL-DOX infusion over 30 minutes and RHT every three weeks (one cycle = 21 days), receiving up to 6 cycles in total: In the first cycle (cycle 1), DPPG2-TSL-DOX application will be performed without RHT in all participants for safety precaution. In cycles 2-6, DPPG2-TSL-DOX will be applied in parallel with RHT. Dexrazoxane as cardioprotectant will be provided for participants overcoming a cumulative dose of 300 mg/m^2 DOX. | Drug: DPPG2-TSL-DOX<br>* DPPG2-TSL-DOX is a thermosensitive liposomal formulation of doxorubicin.<br>* Other names: Doxorubicin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD | Assessment of the maximum tolerated dose based on the adapted 3+3 method | End of study (up to 14 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) | Number of treatment-emergent AEs according to CTCAE 5.0 | End of study (up to 14 months) | 
| Serious Adverse Events (SAEs) | Number of treatment-emergent SAEs according to CTCAE 5.0 | End of study (up to 14 months) | 
| Laboratory abnormalities | Number of laboratory abnormalities | End of study (up to 14 months) | 
| Electrocardiogram (ECG) abnormalities | Number of participants with ECG abnormalities | End of study (up to 14 months) | 
| Echocardiogram (ECHO) abnormalities | Number of participants with ECHO abnormalities | End of study (up to 14 months) | 
| Renal toxicities | Number of participants with renal toxicities | End of study (up to 14 months) | 
| Area under the plasma concentration versus time curve (AUC) without RHT | AUC of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 2-3 (+/-3) in the study for each participant | 
| Peak Plasma Concentration (cmax) without RHT | cmax of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 2-3 (+/-3) in the study for each participant | 
| Time of Peak Plasma Concentration (tmax) without RHT | tmax of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 2-3 (+/-3) in the study for each participant | 
| Clearance (Cl) without RHT | Cl of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 2-3 (+/-3) in the study for each participant | 
| Mean Residence Time (MRT) without RHT | MRT of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 2-3 (+/-3) in the study for each participant | 
| Percent Injected Dose (%ID) without RHT | %ID of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 2-3 (+/-3) in the study for each participant | 
| Area under the plasma concentration versus time curve (AUC) with RHT | AUC of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 23-24 (+/-3) in the study for each participant | 
| Peak Plasma Concentration (cmax) with RHT | cmax of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 23-24 (+/-3) in the study for each participant | 
| Time of Peak Plasma Concentration (tmax) with RHT | tmax of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 23-24 (+/-3) in the study for each participant | 
| Clearance (Cl) with RHT | Cl of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 23-24 (+/-3) in the study for each participant | 
| Mean Residence Time (MRT) with RHT | MRT of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 23-24 (+/-3) in the study for each participant | 
| Percent Injected Dose (%ID) with RHT | %ID of DPPG2, non-liposomal DOX, liposomal encapsulated DOX and total DOX without RHT (cycle 1; 12 time points) | day 23-24 (+/-3) in the study for each participant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sarcoma, Soft Tissue, Doxorubicin/ IV + Liposomes, Doxorubicin