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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Vall D Hebron Institute Of Oncology

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

completed 25 Oct 2024

Decision date (initial)

2024-05-07

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pharmamar · GlaxoSmithKline (GSK)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Dose response, Safety

Phase I Stage:
• To determine the maximum tolerated dose (MTD) and the recommended dose for phase II studies (RD) of lurbinectedin in combination with dostarlimab in advanced/recurrent mismatch repair proficient (pMMR) endometrial cancer (EC) patients with disease progression after platinum-based chemotherapy.

Phase II Stage:
• To assess the efficacy of lurbinectedin in combination with dostarlimab in terms of confirmed tumor response rate according to the Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1 in advanced/recurrent pMMR EC patients with disease progression after platinum-based chemotherapy.

Secondary objectives 8

1. Phase I: • To characterize the safety profile and feasibility of this combination.
2. Phase I: • To characterize the pharmacokinetics (PK) of lurbinectedin and to detect major drug-drug PK interactions.
3. Phase I: • To obtain preliminary information on the clinical antitumor activity of this combination.
4. Phase I: • To conduct an exploratory pharmacogenomics (PGx) analysis substudy in tumor and blood samples from patients exposed to lurbinectedin and dostarlimab, to identify potential biomarkers of response and/or resistance to the combination of lurbinectedin and dostarlimab.
5. Phase II: • To confirm the safety profile and tolerability of the combination.
6. Phase II: • To further characterize the antitumor activity of the combination in terms of duration of response (DoR), clinical benefit (overall response rate [ORR] or stable disease [SD] lasting ≥ 3 months [12 weeks]), progression free survival (PFS), overall survival (OS), and mid- and long-term survival (OS at 6, 12, 18 and 24 months).
7. Phase II: • To characterize the PK of lurbinectedin and to detect major drug-drug PK interactions.
8. Phase II: • To conduct an exploratory PGx analysis substudy in tumor and blood samples from patients exposed to lurbinectedin and dostarlimab, to identify potential biomarkers of response and/or resistance to the combination of lurbinectedin and dostarlimab.

Conditions and MedDRA coding

Advanced/Recurrent Endometrial Cancer Patients with Disease Progression after Prior Therapy with Platinum-based Chemotherapy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1) Voluntarily signed and dated written informed consent prior to any specific study procedure.
2. 2) Age >18 years.
3. 3) Histologically or cytologically confirmed diagnosis of EC (endometrioid, clear cell, high grade serous, undifferentiated carcinoma or mixed histology).
4. 4) Proficient mismatch repair (pMMR) EC locally determined by immunohistochemistry (IHC).
5. 5) 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.
6. 6) 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.
7. 7) Eastern Cooperative Oncology Group (ECOG) PS score ≤1.
8. 8) Measurable disease according to RECIST v.1.1. Note: irradiated lesions may qualify as target lesions if progression has been clearly documented.
9. 9) 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.
10. 10) 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.
11. 11) 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.
12. 12) 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.

Exclusion criteria 11

1. 1) Deficient mismatch repair (dMMR) EC locally determined by IHC
2. 2) Carcinosarcoma (malignant mixed Műllerian tumor), leiomyosarcoma or other high-grade sarcomas, or endometrial stromal sarcomas.
3. 3) 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.
4. 4) History of previous bone marrow and/or stem cell transplantation.
5. 5) Impending need for radiation therapy (e.g., painful bone metastasis).
6. 6) History of allergy or hypersensitivity to any of the study drugs or their excipients.
7. 7) 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).
8. 8) Live vaccines within 30 days prior to start of study treatment and while on treatment.
9. 9) 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.
10. 10) 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.
11. 11) Pregnant and breastfeeding women, but also female patients not using an effective contraception method.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I Stage: Determination of MTD and RD: • The MTD will be the lowest dose level explored during dose escalation at which one third or more of evaluable patients experience a DLT during Cycle 1. • The RD will be the highest dose level explored during dose escalation at which less than one third of evaluable patients experience a DLT during Cycle 1.
2. Phase II Stage: The primary objective of this stage is to assess the antitumor activity of the lurbinectedin and dostarlimab combination in terms of ORR, defined as the percentage of evaluable patients with a confirmed response, either complete (CR) or partial (PR).

Secondary endpoints 4

1. • Safety: patients will be evaluable for safety if they have received at least one partial infusion of dostarlimab and lurbinectedin. AEs will be graded according to the NCI-CTCAE v.5 and coded using MedDRA dictionary version in force.
2. • Efficacy: antitumor activity of the combination will be evaluated in terms of: Progression-free survival (PFS) Duration of response (DoR) Clinical benefit Overall survival (OS) Mid- and long-term survival
3. • Pharmacokinetics: PK parameters will be evaluated in plasma by standard non-compartmental and/or population methods.
4. • Pharmacogenomics: the mutational status and the expression levels of potential predictive biomarkers of response and/or resistance to lurbinectedin and dostarlimab treatment will be analyzed from available tumor and blood samples obtained from all patients.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vall D Hebron Institute Of Oncology

Sponsor organisation

Vall D Hebron Institute Of Oncology

Address

Calle Natzaret 115

City

Barcelona

Postcode

08035

Country

Spain

Scientific contact point

Organisation

Vall D Hebron Institute Of Oncology

Contact name

Susana Muñoz

Public contact point

Organisation

Vall D Hebron Institute Of Oncology

Contact name

Susana Muñoz

Third parties 3

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications