Trial of Lenvatinib Plus PembrolizumAb in Recurrent Gynecological Clear Cell Adenocarcinomas (LARA)

NCT04699071 | Unknown Phase 2

• 1 other identifier: GY01/05/20
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase II non-randomized, multi-center study. The primary end point of this study is the objective response rate (ORR) at 24 weeks, using response evaluation criteria for solid tumors (RECIST) 1.1 criteria, for the combination therapy of continuous daily oral lenvatinib with three-weekly intravenous pembrolizumab in patients with recurrent clear cell carcinoma of gynecological origin (CCGC). The statistical design is Simon's minimax two-stage design and the present study aims to complete stage 1 of the Simon's two-stage design.

Conditions

Adenocarcinomas; Recurrent Gynecological

Keywords

Lenvatinib; PembrolizumAb; gynecological; Adenocarcinomas

Outcome Measures

Primary Outcomes (3)

• objective response rate (ORR)

  the percentage of subjects with a confirmed CR or PR as per RECIST 1.1 criteria.

  4 years

• Progression-free survival

  time from enrolment to the first documented tumor progression, or death due to any cause whichever occurred first. PFS time of any living patient with no documented progression, or any patient starting other cytotoxic and/or cytostatic therapies, will be censored at the date of last evaluable disease assessment on-study. PFS time of patients with no evaluable disease assessment on-study will be censored at enrollment

  4 years

• Duration of response

  This will be measured from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented.

  4 years

Study Arms (1)

patients with recurrent clear cell carcinoma of gynecological origin (CCGC)

EXPERIMENTAL

Recurrent clear cell carcinoma of gynecological origin (ovarian and endometrial primary) after progression on chemotherapy.

Drug: pembrolizumab and lenvatinib

Interventions

pembrolizumab and lenvatinib DRUG

All patients will receive oral lenvatinib daily plus intravenous pembrolizumab 3-weekly. A cycle is 21 days. Allowances will be made for stepwise dose reductions of lenvatinib due to treatment-related toxicities. Toxicity will be assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, (CTCAE) Version 5.0. Patients are planned to continue therapy until disease progression, intolerable toxicity, or withdrawal of patient consent.

patients with recurrent clear cell carcinoma of gynecological origin (CCGC)

Eligibility Criteria

• Age: 21 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of recurrent CCGC (ovarian and endometrial primary), as evidenced by WT-1 negativity, will be enrolled in this study. For tumors with a mixed histology, at least 70% of the tumor must consist of clear cell carcinoma.
• \. Patients must have had at least one prior line of platinum-based chemotherapy in the course of their treatment paradigm. A maximum of 4 prior lines of systemic treatment regimens will be allowed and may include chemotherapy and biologics (prior immune checkpoint inhibitor treatment will not be permitted).
• \. Participants must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment.
• \. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR
• A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days after the last dose of study treatment.
• \. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
• \. Have at least 1 measurable lesion based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• \. Provision of an archived tumor tissue block (or at least 10 newly cut unstained slides) where such samples exist in a quantity sufficient to allow for analysis.
• \. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of allocation/randomization.
• \. Life expectancy exceeding 12 weeks.
• \. Have adequate organ function as defined in the following. Specimens must be collected within 10 days prior to the start of study treatment.
• Haematology i) Absolute neutrophil count (ANC) ≥1500/µL ii) Platelets ≥100 000/µL iii) Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
• Renal I) Creatinine OR Measured or calculatedb creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR
• ≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN

You may not qualify if:

• \. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication.
• \. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
• \. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation. Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. Withhold lenvatinib for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of lenvatinib after resolution of wound healing has not been established".
• \. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• \. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• \. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• \. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• \. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in-situ cancers.
• \. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
• \. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• \. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• \. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• \. Has an active infection requiring systemic therapy.
• \. Has a known history of Human Immunodeficiency Virus (HIV) infection.
• \. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as detectable HCV RNA) infection.

Sponsors & Collaborators

• National University Hospital, Singapore: lead

Study Sites (1)

National University Hospital

Singapore, Singapore

RECRUITING

Related Publications (3)

• del Carmen MG, Birrer M, Schorge JO. Clear cell carcinoma of the ovary: a review of the literature. Gynecol Oncol. 2012 Sep;126(3):481-90. doi: 10.1016/j.ygyno.2012.04.021. Epub 2012 Apr 21.

  PMID: 22525820 RESULT

• Brinton LA, Felix AS, McMeekin DS, Creasman WT, Sherman ME, Mutch D, Cohn DE, Walker JL, Moore RG, Downs LS, Soslow RA, Zaino R. Etiologic heterogeneity in endometrial cancer: evidence from a Gynecologic Oncology Group trial. Gynecol Oncol. 2013 May;129(2):277-84. doi: 10.1016/j.ygyno.2013.02.023. Epub 2013 Feb 26.

  PMID: 23485770 RESULT

• Ngoi NYL, Lee JY, Lim D, Thian YL, Lim YW, Chan JJ, Chay WY, Zhang Z, Gopinathan A, Lim SE, Low J, Ng J, Tong P, Lee YJ, Park J, Kim JW, Tan TZ, Zhu J, Tai BC, Choi CH, Kim BG, Tan DSP. Pembrolizumab plus lenvatinib in recurrent gynaecological clear cell carcinoma (LARA): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2026 Jan 15:S1470-2045(25)00662-X. doi: 10.1016/S1470-2045(25)00662-X. Online ahead of print.

  PMID: 41548565 DERIVED

MeSH Terms

Conditions

Adenocarcinoma

Interventions

pembrolizumab; lenvatinib

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Study Officials

• David Shao Peng Tan

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David Shao Peng Tan

CONTACT

6772 4661; David_SP_Tan@nuhs.edu.sg

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: combination therapy of continuous daily oral lenvatinib with three-weekly intravenous pembrolizumab in patients with recurrent clear cell carcinoma of gynecological origin (CCGC).

Study Record Dates

• First Submitted: January 5, 2021
• First Posted: January 7, 2021
• Study Start: February 18, 2021
• Primary Completion: January 1, 2024
• Study Completion: January 1, 2025
• Last Updated: October 21, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

SG (1)