Phase I/II Randomized Study of LB-100 and Doxorubicin Versus Doxorubicin Monotherapy in Advanced Soft Tissue Sarcomas

Trial ID: 2024-510877-67-00
Protocol: Geis-74
Sponsor: Asoc Grupo Espanol De Investigacion En Sarcomas

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Diseases & Conditions

Soft tissue sarcoma

Objectives

The primary objective of this Phase I/II randomized trial is to determine the **maximum tolerated dose (MTD)** of LB-100 in combination with doxorubicin, which will be used as the recommended phase 2 dose (RP2D). This is crucial for establishing a safe and effective dosage regimen for further clinical evaluation. In Phase II, the primary objective is to comparatively evaluate the efficacy of the LB-100 plus doxorubicin combination versus doxorubicin alone, as measured by median **progression-free survival (PFS)**. This comparison is clinically relevant as it may demonstrate an improved therapeutic benefit of the combination therapy over the standard treatment.

Secondary objectives in Phase I include evaluating the safety profile, overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and quality of life. In Phase II, the secondary objectives are to evaluate the overall response rate (ORR), overall survival (OS), safety profile, and quality of life. These secondary objectives provide comprehensive insights into the treatment's impact on patient outcomes and its potential advantages over existing therapies.

Participants

The clinical trial involves **adult patients** diagnosed with advanced or metastatic soft tissue sarcomas, including undifferentiated pleomorphic sarcoma, leiomyosarcoma, and other specified sarcoma subtypes. Participants are both male and female, aged 18 years and older, with a confirmed diagnosis by central pathology review. The study population is required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have adequate organ function and meet specific laboratory criteria, such as an absolute neutrophil count of at least 1,200/mm³ and a platelet count of at least 100,000/mm³. The trial does not include vulnerable populations, and both genders are represented. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified, but participants must be naïve to previous anthracycline treatment. Key inclusion criteria include the provision of pre-treatment tumor tissue for central pathology review and the absence of pregnancy or nursing at study entry for females of childbearing potential.

Plans and Procedures

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the efficacy and safety of LB-100 in combination with **doxorubicin** versus doxorubicin alone in the treatment of advanced soft tissue sarcomas. The trial is divided into two phases: Phase I aims to determine the maximum tolerated dose (MTD) of LB-100 when combined with doxorubicin, while Phase II focuses on assessing the efficacy of the combination therapy compared to doxorubicin alone, as measured by median progression-free survival (PFS). The trial is expected to run from May 2023 to June 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and organ function. During this visit, informed consent will be obtained, and baseline assessments, including laboratory tests and imaging, will be conducted. Follow-up visits will occur regularly to monitor safety, assess treatment response, and adjust dosages as necessary. The end-of-study visit will involve final evaluations to determine the overall response and any long-term effects of the treatment.

The expected length of participant involvement varies between the two phases. In Phase I, participants will remain in the study until the MTD is established, while in Phase II, participants will continue until disease progression or unacceptable toxicity occurs. Conditions that may lead to early termination from the study include withdrawal of consent, non-compliance with study procedures, or adverse events that compromise participant safety. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the integrity and validity of the research findings.

Treatment

The clinical trial involves the administration of **LB-100**, a novel investigational drug, which is a **solution for infusion**. The active substance in LB-100 is **3-(4-methylpiperazine-1-carbonyl)-7-oxabiclo[2.2.1]heptane-2-carboxylic acid**, a chemical compound. LB-100 is administered **intravenously**. The primary objective in Phase I is to determine the maximum tolerated dose (MTD) of LB-100 when used in combination with doxorubicin, which will inform the recommended Phase II dose (RP2D). The dosing schedule and frequency of administration are determined based on the trial protocol, with careful monitoring of participant compliance and adverse effects.

The comparator treatment in this trial is **Doxorubicin**, marketed as **DOXORUBICINE TEVA 50 mg/25 ml, solution injectable**. Doxorubicin is a well-established chemotherapeutic agent used in the treatment of various cancers, including advanced soft tissue sarcomas. It is also administered **intravenously** in the form of an **injection**. The trial aims to evaluate the efficacy of the combination of LB-100 and doxorubicin versus doxorubicin alone, with the primary endpoint being median progression-free survival (PFS) in Phase II. The administration of doxorubicin follows standard dosing guidelines, and participant adherence to the treatment regimen is closely monitored throughout the study.

Efficacy

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. In Phase I, the primary endpoint is to determine the maximum tolerated dose (MTD) of LB-100 in combination with doxorubicin, which will be used as the recommended phase 2 dose (RP2D). This will be determined by assessing adverse events according to CTCAE v5.0, which will guide dose escalation or reduction based on dose-limiting toxicities. In Phase II, the primary endpoint is the evaluation of efficacy through **median progression-free survival (PFS)**, measured according to RECIST v1.1 criteria. PFS is defined as the time from randomization to disease progression or death from any cause.

Secondary endpoints include the overall response rate (ORR), overall survival (OS), safety profile, and quality of life. ORR is defined as the number of subjects achieving a complete or partial response, evaluated by central radiology review using RECIST v1.1 and Choi criteria. OS is measured as the time from enrollment to death from any cause, with censoring on the last known date of survival. The safety profile will be assessed through adverse events related to study drugs, detected via physical examinations and laboratory tests, and graded according to CTCAE v5.0. Quality of life will be evaluated using the EORTC QLQ-C30 questionnaire.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Phase I: The patient must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of the screening process. Procedures conducted as part of the patient’s routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.
Phase I: Age ≥ 18 years.
Phase I: Diagnosis of advanced/metastatic soft tissue sarcoma (undifferentiated pleomorphic sarcoma, leiomyosarcoma, myxoid and hypercellular myxoid liposarcoma, myxofibrosarcoma, NOS sarcoma, synovial sarcoma, fibrosarcoma, malignant peripheral nerve sheath tumor, epitheloid sarcoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma, angiosarcoma and high-grade uterine sarcomas (excluding those with BCOR or NTRK translocation)) confirmed by central pathology review.
Phase I: Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. If archive biopsy is not available or is older than 3 months, the patient must be willing to have a pre-treatment re-biopsy of primary or metastatic tumor (baseline biopsy) within 28 days prior to enrollment.
Phase I: Measurable disease according to RECIST v1.1 criteria.
Phase I: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
Phase I: The patient must be naïve of any previous treatment with anthracyclines (not even in adjuvant chemotherapy).
Phase I: Adequate organ, hepatic, renal, cardiac, and hematologic function.
Phase I: Laboratory tests as follows: • Absolute neutrophil count ≥ 1,200/mm³ • Platelet count ≥ 100,000/mm³ • Hg > 9 g/dL • Bilirubin ≤ 1.5 mg/dL • PT and INR ≤ 1.5 • AST and ALT ≤ 2.5 times ULN • Creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60 mL/min • Blood glucose < 150 mg/dL
Phase I: Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.
Phase I: Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment. Patients must not be pregnant or nursing at study entry.
Phase I: Women and men of reproductive potential must have agreed to use an effective contraceptive method during study treatment and for 3 months after the last dose of study drug.
Phase II: The patient must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of the screening process. Procedures conducted as part of the patient’s routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.
Phase II: Age ≥ 18 years.
Phase II: Diagnosis of advanced/metastatic soft tissue sarcoma (undifferentiated pleomorphic sarcoma or leiomyosarcoma) confirmed by central pathology review.
Phase II: Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. If archive biopsy is not available or is older than 3 months, the patient must be willing to have a pre-treatment re-biopsy of primary or metastatic tumor (baseline biopsy) within 28 days prior to enrollment.
Phase II: Measurable disease according to RECIST v1.1 criteria.
Phase II: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
Phase II: The patient must be naïve of any previous treatment with anthracyclines (not even in adjuvant chemotherapy).
Phase II: Adequate organ, hepatic, renal, cardiac, and hematologic function.
Phase II: Laboratory tests as follows: • Absolute neutrophil count ≥ 1,200/mm³ • Platelet count ≥ 100,000/mm³ • Hg > 9 g/dL • Bilirubin ≤ 1.5 mg/dL • PT and INR ≤ 1.5 • AST and ALT ≤ 2.5 times ULN • Creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60 mL/min • Blood glucose < 150 mg/dL
Phase II: Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.
Phase II: Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment. Patients must not be pregnant or nursing at study entry.
Phase II: Women and men of reproductive potential must have agreed to use an effective contraceptive method during study treatment and for 3 months after the last dose of study drug.

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Exclusion Criteria

Phase I: Diagnosis different from the elegible histological subtypes.
Phase I: Previous treatment with doxorubicin, epirubicin, idarubicin, and/or other anthracyclines or any other systemic therapy. The exception is previous systemic therapy for a previous neoplasm (see exclusion criteria 10), if this is controlled, as long as it did not include anthracyclines.
Phase I: Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE version 5.0 Grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= Grade 3).
Phase I: HBV and HCV serologies must be performed prior to inclusion. If HbsAg is positive it is recommended to reject the existence of replicative phase (HbaAg+, DNA VHB+). If these were positives the inclusion is not recommended, remaining at investigators’ discretion the preventive treatment with lamivudine. If a potential patient is positive for anti-HCV antibodies, presence of the virus should be ruled out with a qualitative PCR, or the patient should NOT be included in the study (if a qualitative PCR cannot be performed then patient will not be able to enter the study).
Phase I: Any of the following diseases/illnesses within the previous 6 months: • Myocardial infarction • Severe or unstable angina • Coronary or peripheral artery bypass graft • Cerebrovascular accident or transient ischemic attack (TIA) • Pulmonary embolism
Phase I: Evidence of a bleeding diathesis.
Phase I: Ongoing cardiac dysrhythmias > Grade 2.
Phase I: Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
Phase I: History of allergy to study drug components.
Phase I: History of another cancer with the exception of adequately treated basal cell carcinoma or in situ cervical cancer, or with a relapse-free interval longer than 3 years after treatment of the primary cancer with no substantial risk of recurrence.
Phase I: Presence of brain or central nervous system metastases at the time of enrollment.
Phase I: Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily taken.
Phase II: Diagnosis of any sarcoma different from undifferentiated pleomorphic sarcoma and leiomyosarcoma.
Phase II: Previous treatment with doxorubicin, epirubicin, idarubicin, and/or other anthracyclines or any other systemic therapy. The exception is previous systemic therapy for a previous neoplasm (see exclusion criteria 10), if this is controlled, as long as it did not include anthracyclines.
Phase II: Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE version 5.0 Grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= Grade 3).
Phase II: HBV and HCV serologies must be performed prior to inclusion. If HbsAg is positive it is recommended to reject the existence of replicative phase (HbaAg+, DNA VHB+). If these were positives the inclusion is not recommended, remaining at investigators’ discretion the preventive treatment with lamivudine. If a potential patient is positive for anti-HCV antibodies, presence of the virus should be ruled out with a qualitative PCR, or the patient should NOT be included in the study (if a qualitative PCR cannot be performed then patient will not be able to enter the study).
Phase II: Any of the following diseases/illnesses within the previous 6 months: • Myocardial infarction • Severe or unstable angina • Coronary or peripheral artery bypass graft • Cerebrovascular accident or transient ischemic attack (TIA) • Pulmonary embolism
Phase II: Evidence of a bleeding diathesis.
Phase II: Ongoing cardiac dysrhythmias > Grade 2.
Phase II: Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
Phase II: History of allergy to study drug components.
Phase II: History of another cancer with the exception of adequately treated basal cell carcinoma or in situ cervical cancer, or with a relapse-free interval longer than 3 years after treatment of the primary cancer with no substantial risk of recurrence.
Phase II: Presence of brain or central nervous system metastases at the time of enrollment.
Phase II: Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily taken.