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

Sarcoma, Soft Tissue Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05858710
• Other study ID #: TS-DM-STS-101
• Secondary ID: 2020-005033-32
• Status: Recruiting
• Phase: Phase 1
• Start date: April 18, 2023
• Est. completion date: December 2024

Study information

• Verified date: October 2023
• Source: Thermosome GmbH
• Contact: Zuzana Haramiova, Dr., PhD.
• Phone: 06781285131
• Email: zuzana.haramiova[@]thermosome.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 9
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

1. 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

2. 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:

1. 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

2. Platelet count =100×10^9/L

3. Hemoglobin =9.0 g/dL. No transfusions are allowed within 2 weeks (14 days) prior to enrolment

4. Serum creatinine =1.5 times upper limit of normal (ULN)

5. Negative dipstick for proteinuria or if proteinuria =2+, then additional 24 h urine collection <1g protein/ 24 h

6. Total bilirubin within ULN (except for patients with Gilbert's syndrome, who must have a total bilirubin <3 mg/dL)

7. Alanine aminotransferase (ALT)/ Aspartate aminotransferase (AST) =3.0×ULN; if the liver has tumor involvement, AST and ALT =5.0×ULN are acceptable

8. 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:

1. 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

2. 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:

1. curatively treated non-melanomatous skin cancer

2. curatively treated cervical carcinoma in situ

3. non-metastatic prostate cancer, or

4. 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:

1. unstable angina pectoris

2. angioplasty, cardiac stenting, or myocardial infarction within 6 months of enrolment

3. valvulopathy that is severe, moderate, or deemed clinically significant

4. 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

Related Conditions & MeSH terms

• Hyperthermia
• Sarcoma
• Sarcoma, Soft Tissue

Intervention

Drug:
• DPPG2-TSL-DOX
DPPG2-TSL-DOX is a thermosensitive liposomal formulation of doxorubicin.

Locations

Country	Name	City	State
Germany	Helios Klinikum Berlin-Buch GmbH	Berlin
Germany	Klinikum der Universität München (KUM) Campus Großhadern	Munich

Sponsors (1)

Lead Sponsor	Collaborator
Thermosome GmbH

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Radiographic response	Radiographic response rates (CR, PR, SD, PD) and ORR (CR+PR) as assessed by RECIST 1.1	day 64 (+/-3) in the study for each participant and end of study (21 [+7] days after last study drug treatment)
Other	Radiographic local response	Radiographic local response rates (CR, PR, SD, PD) by Choi et al. 2007 assessed for target and non-target lesions in RHT field	day 64 (+/-3) in the study for each participant and end of study (21 [+7] days after last study drug treatment)
Other	Tumor temperatures (optional)	Specific tumor temperature parameters: Tmax, T90, T50, T20 and respective cumulative minutes	day 23, 44, 65, 86, 107 (+/-3) in the study for each participant
Primary	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	Adverse Events (AEs)	Number of treatment-emergent AEs according to CTCAE 5.0	End of study (up to 14 months)
Secondary	Serious Adverse Events (SAEs)	Number of treatment-emergent SAEs according to CTCAE 5.0	End of study (up to 14 months)
Secondary	Laboratory abnormalities	Number of laboratory abnormalities	End of study (up to 14 months)
Secondary	Electrocardiogram (ECG) abnormalities	Number of participants with ECG abnormalities	End of study (up to 14 months)
Secondary	Echocardiogram (ECHO) abnormalities	Number of participants with ECHO abnormalities	End of study (up to 14 months)
Secondary	Renal toxicities	Number of participants with renal toxicities	End of study (up to 14 months)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

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