Study to Assess the Safety, Tolerability and Efficacy of Lurbinectedin and Dostarlimab treatment in patients with endometrial cancer after disease progression to a previous treatment with Platinum-based Chemotherapy. LiDer trial

Prior treatment

• Active or untreated central nervous system (CNS) involvement. Treated CNS metastases must show radiographic stability (defined as no CNS progression for at least three weeks from post-radiotherapy brain scan to brain scan performed prior to study entry), and patients must be free of neurologic sign/symptoms secondary to the brain metastases or radiation therapy. Any steroid treatment must be completed ≥ 14 days before the first dose of study treatment.
• History of previous bone marrow and/or stem cell transplantation.
• Impending need for radiation therapy (e.g., painful bone metastasis).
• Live vaccines within 30 days prior to start of study treatment and while on treatment.

Other illness

• Carcinosarcoma (malignant mixed Műllerian tumor), leiomyosarcoma or other high-grade sarcomas, or endometrial stromal sarcomas.
• History of allergy or hypersensitivity to any of the study drugs or their excipients.
• History of other prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or in situ cervical cancer. Patients with other prior malignancies and no disease recurrence for three years are eligible.

Lab values

• Concomitant diseases/conditions: a) History or presence of unstable angina, myocardial infarction, congestive heart failure defined as abnormal left ventricular ejection fraction (LVEF) < 50% assessed by multiple-gated acquisition scan (MUGA) or equivalent by ultrasound (US), or clinically significant valvular heart disease within 12 months prior first study dose. b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. c) Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C. d) Active uncontrolled infection. Serious non-healing wound, ulcer or bone fracture. e) Diagnosis of immunodeficiency or receiving systemic steroids therapy (more than a daily dose of 10 mg of prednisone or equivalent per day) or any other form of immunosuppressive therapy within 14 days prior to the first study dose. f) Active autoimmune disease that required systemic treatment in the past two years (i.e., with disease-modifying agents, corticosteroids and immunosuppressive drugs). Patients with vitiligo or resolved childhood asthma/atopy are eligible, as well as patients who require intermittent use of bronchodilators or local steroid injections, patients with hypothyroidism stable on hormone replacement, patients with insulin-treated controlled type 1 diabetes or Sjögren’s syndrome. g) History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis or evidence of active pneumonitis on screening chest computed tomography (CT) scans. h) Known history of active tuberculosis (Mycobacterium tuberculosis). i) Ongoing treatment-requiring, non-neoplastic chronic liver disease of any origin. For hepatitis B, this includes positive tests for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR). For hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR. Patients taking hepatitis-related antiviral therapy within six months prior to the first study dose will also be excluded. j) Known human immunodeficiency virus (HIV) infection. k) Myopathy or any clinical situation that causes significant and persistent elevation of CPK (>2.5 x ULN in two different determinations performed one week apart). l) Limitation of the patient’s ability to comply with the treatment or follow-up procedures. m) Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study.
• Prior therapy with lurbinectedin, antibodies against programmed cell death protein-1 (PD-1), programmed death ligand-1 (PD-L1), programmed death ligand-2 (PD-L2), CD137, or cytotoxic T lymphocyte associated antigen-4 (CTLA-4).

Other

• Deficient mismatch repair (dMMR) EC locally determined by IHC
• Pregnant and breastfeeding women, but also female patients not using an effective contraception method.

• Voluntarily signed and dated written informed consent prior to any specific study procedure.
• Available tumor tissue blocks or unstained slides from a previous non-irradiated lesion. Note: slides to be freshly cut or cut within 6 months from time of use.
• Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤7 days before inclusion in the study): a) Platelet count ≥ 100 x 109/L, hemoglobin ≥ 10.0 g/dL and absolute neutrophil count (ANC) ≥ 1.5 x 109/L. CBC should be obtained without transfusion in the 4 weeks before obtaining sample. b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x the upper limit of normal (ULN), regardless of the presence of liver metastases. c) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ULN. d) International Normalized Ratio (INR) < 1.5 (except if patient is on oral anticoagulation therapy). e) Calculated creatinine clearance (CrCL) ≥ 30 mL/minute (using Cockcroft-Gault formula; APPENDIX 4). f) Creatine phosphokinase (CPK) ≤ 2.5 x ULN. g) Serum albumin ≥ 3.0 g/dL. Albumin infusion to fulfill the inclusion criterion is not allowed.
• Evidence of non-childbearing status for women of childbearing potential (WOCBP). Women must agree to use a highly effective contraceptive measure during the trial, and for at least six months after last study treatment dose. Acceptable methods of contraception include abstinence, intrauterine device (IUD), oral contraceptive, subdermal implant and/or double barrier. Fertile male partners of WOCBP patients should use condoms during treatment and for four months following the last investigational medicine product dose. Valid methods to determine childbearing potential, adequate contraception and requirements of WOCBP partners are described in APPENDIX 2.
• Age >18 years.
• Histologically or cytologically confirmed diagnosis of EC (endometrioid, clear cell, high grade serous, undifferentiated carcinoma or mixed histology).
• Proficient mismatch repair (pMMR) EC locally determined by immunohistochemistry (IHC).
• Radiologically confirmed disease progression after one prior platinum-based chemotherapy for advanced (FIGO Stage III/IVA) or recurrent disease (diagnosed as early-stage EC and after primary therapy relapse): a) Patients with disease progression < 1 year after completion of prior adjuvant or neoadjuvant platinum-based chemotherapy are eligible without further systemic treatment. b) Patients with disease progression ≥ 1 year after completion of prior adjuvant or neoadjuvant platinum-based chemotherapy, and not amenable to radiation/surgical cure, must receive one additional cytotoxic systemic treatment prior to enrolment in this study.
• Prior hormonal or biological therapies (e.g., targeted therapies, or other), but excluding immunotherapy, are allowed and do not count as lines of prior therapy.
• Eastern Cooperative Oncology Group (ECOG) PS score ≤1.
• Measurable disease according to RECIST v.1.1. Note: irradiated lesions may qualify as target lesions if progression has been clearly documented.
• At least three weeks since last prior anticancer treatment (including radiotherapy) and recovery to grade ≤ 1 from any adverse event (AE) related to previous anticancer treatment (excluding sensory neuropathy, anemia, asthenia and alopecia, all grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5.