IMP owner decision

Background:

Endometrial cancer is a prevalent gynecological malignancy, with a significant number of cases diagnosed at an advanced stage or recurring following initial treatment. Platinum-based chemotherapy represents a standard treatment option for these patients; however, disease progression often occurs, highlighting the need for novel therapeutic approaches. Lurbinectedin, a synthetic analog of marine alkaloid-derived compounds, and dostarlimab, a monoclonal antibody targeting PD-1, have demonstrated promising antitumor activity in various malignancies. This phase I-II clinical trial seeks to evaluate the safety, tolerability, and efficacy of combining lurbinectedin and dostarlimab in patients with advanced or recurrent endometrial cancer who have experienced disease progression following platinum-based chemotherapy.

Primary Objectives:

To determine the maximum tolerated dose (MTD) and recommended dose for further investigation of lurbinectedin and dostarlimab in combination therapy for advanced or recurrent endometrial cancer.

To assess the antitumor activity of lurbinectedin and dostarlimab combination therapy, measured by objective response rate (ORR), in patients with advanced or recurrent endometrial cancer.

Secondary Objectives:

To evaluate the safety and tolerability of lurbinectedin and dostarlimab combination therapy in patients with advanced or recurrent endometrial cancer.

To characterize the pharmacokinetic profile of lurbinectedin and dostarlimab when administered in combination therapy.

To explore pharmacogenomic biomarkers predictive of response and/or resistance to lurbinectedin and dostarlimab combination therapy in patients with advanced or recurrent endometrial cancer.

To assess progression-free survival (PFS), duration of response (DOR), clinical benefit rate (CBR), and overall survival (OS) in patients receiving lurbinectedin and dostarlimab combination therapy for advanced or recurrent endometrial cancer.

To investigate the impact of lurbinectedin and dostarlimab combination therapy on quality of life and symptom control in patients with advanced or recurrent endometrial cancer.

This study is a phase I-II clinical trial conducted to evaluate the safety, tolerability, and efficacy of lurbinectedin and dostarlimab combination therapy in patients with advanced or recurrent endometrial cancer. The trial follows a multicenter, open-label design and comprises two phases: a dose escalation phase (Phase I) and an expansion phase (Phase II). The primary endpoints include determining the maximum tolerated dose (MTD), recommended dose for further investigation, and objective response rate (ORR). Secondary endpoints encompass safety, pharmacokinetics, pharmacogenomics, progression-free survival (PFS), duration of response (DOR), clinical benefit rate (CBR), overall survival (OS), and quality of life assessments.

Study Treatments:

Lurbinectedin: Lurbinectedin is administered as a lyophilized powder for concentrate for infusion, reconstituted with sterile water for injection to achieve a concentration of 0.5 mg/mL. The initial dose for infusion is 2.6 mg/m^2, diluted in either 5% glucose solution or 0.9% sodium chloride solution. During Phase I, dose adjustments are based on body surface area calculated using the DuBois formula.

Dostarlimab: Dostarlimab is supplied in vials containing 500 mg at a concentration of 50 mg/mL. The recommended dose is a fixed dose of 500 mg administered intravenously over 30 minutes. Treatment cycles consist of administration on Day 1 of a 21-day cycle, with dostarlimab followed by lurbinectedin in combination therapy.

During the dose escalation phase (Phase I), a predefined dose escalation scheme is employed, starting with dose level (DL) -1 and progressing to DL1, DL2, and subsequent levels as per the protocol. Dose escalation is guided by the occurrence of dose-limiting toxicities (DLTs) and the determination of the MTD. Once the MTD is established, the expansion phase (Phase II) begins, wherein additional patients receive treatment at the recommended dose to further evaluate safety and efficacy outcomes.

Inclusion Criteria:

• Adult patients aged 18 years or older.
• Histologically confirmed advanced or recurrent endometrial cancer.
• Disease progression following prior platinum-based chemotherapy.
• Adequate organ function, including bone marrow, renal, and hepatic function.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Measurable disease per RECIST v.1.1 criteria.
• Availability of archival tumor tissue sample or willingness to undergo a tumor biopsy.
• Signed informed consent form.
• Life expectancy of at least 3 months.
• Willingness and ability to comply with study procedures and follow-up visits.
• Agreement to use effective contraception during the study period and for a specified duration thereafter if applicable.

Exclusion Criteria:

• Prior treatment with lurbinectedin or dostarlimab.
• Active autoimmune disease requiring systemic treatment.
• Symptomatic or untreated central nervous system metastases.
• History of interstitial lung disease or pneumonitis requiring steroids.
• Uncontrolled concurrent illness or medical condition.
• History of Grade ≥3 immune-related adverse events with prior immunotherapy.
• Pregnancy or breastfeeding.
• Concurrent treatment with other anticancer therapy.
• Prior treatment with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
• Concurrent treatment with corticosteroids exceeding a specified dose or duration.
• Participation in another clinical trial involving investigational therapy within a specified timeframe.
• Any other condition that, in the investigator's opinion, would compromise the patient's safety or interfere with the study conduct.