Phase II Lenvatinib and Pembrolizumab in Endocrine Resistant Breast Cancer With Letrozole

NCT05286437 | Recruiting Phase 2

• 1 other identifier: LaPemERLA
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase II study testing the combination of pembrolizumab with lenvatinib, a multi-kinase inhibitor that has activity against vascular endothelial growth factor receptors 1-3 (VEGFR1-3), fibroblast growth factor receptors 1-4 (FGFR1-4), ret protooncogene (RET), platelet-derived growth factor receptor-alpha (PDGFR-alpha) and KIT (a stem cell factor receptor), and letrozole, a non-steroidal aromatase inhibitor, in advanced hormone receptor (HR) positive human epidermal growth factor receptor 2 (HER2) negative breast cancer (BC) that has progressed on/after standard endocrine therapy.

Conditions

Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer

Keywords

Advanced Breast Cancer

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  The efficacy of Pembrolizumab, Lenvatinib and Letrozole. ORR is defined as the proportion of subjects who have best objective response (BOR) of CR or PR at the time of data cutoff.

  Up to 2 years.

Secondary Outcomes (4)

• Progression-Free Survival (PFS)

  Up to 3 years after End of Treatment (estimated).

• Duration of Response (DOR)

  Up to 3 years after End of Treatment (estimated).

• Clinical Benefit Rate (CBR)

  Up to 3 years after End of Treatment (estimated).

• Overall Survival (OS)

  Up to 3 years after End of Treatment (estimated).

Study Arms (1)

Intervention

EXPERIMENTAL

Oral lenvatinib + Intravenous (IV) pembrolizumab + Oral letrozole

Drug: Oral lenvatinib + Intravenous (IV) pembrolizumab + Oral letrozole

Interventions

Oral lenvatinib + Intravenous (IV) pembrolizumab + Oral letrozole DRUG

Lenvatinib and letrozole will be given orally (PO) daily from Day -14, while pembrolizumab will be administered intravenously during week 1 of each 6-weekly cycle from Cycle 1 Day 1 (C1D1), with daily lenvatinib and letrozole.

Intervention

Eligibility Criteria

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

You may qualify if:

• Male/female participants who are at least 21 years of age on the day of signing informed consent, with histologically or cytologically confirmed diagnosis of metastatic or locally advanced carcinoma of the breast not amenable to treatment with curative intent, will be enrolled in this study.
• Disease progression after treatment with at least 1 line of palliative endocrine therapy in the metastatic setting.
• There is no limit to the number of lines of prior palliative endocrine therapy.
• Prior targeted therapy in the locally advanced (recurrent or progressed) or metastatic setting, such as CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, is allowed with no limit to the number of lines of targeted therapy (prior lenvatinib is not allowed).
• Maximum of 1 line of palliative chemotherapy is allowed.
• A chemotherapy line in advanced disease is an anticancer regimen(s) that contains at least 1 cytotoxic chemotherapy agent and was discontinued due to progression. If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease progression then this regimen does not count as a "prior line of chemotherapy".
• Antibody-drug conjugate will be considered as cytotoxic chemotherapy in the assessment of the lines of treatment.
• ER positive and/or PgR positive breast cancer (based on most recent tumor biopsy or archived tumor specimen) according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, assessed locally and defined as at least 1% of tumor cells stained positive.
• HER2-negative tumor assessed locally and defined as meeting one of the following sets of criteria:
• HER2 IHC score of 0 or 1+
• HER2 IHC score of 2+ accompanied by a negative fluorescence, chromogenic, or silver in situ hybridization test indicating the absence of HER2 gene amplification
• HER2/CEP17 ratio of \< 2.0 based on the most recent tumor biopsy (or archived tumor sample).
• For women: postmenopausal or premenopausal/perimenopausal status, defined as follows: Postmenopausal, as defined by at least one of the following criteria:
• Age ≥ 60 years
• Age \< 60 years and ≥ 12 months of amenorrhea plus follicle-stimulating hormone (FSH) and plasma estradiol levels within postmenopausal range by local laboratory assessment, in the absence of oral contraceptive pills, hormone replacement therapy, or gonadotropin-releasing hormone agonist or antagonist

You may not qualify if:

• A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation. 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 (eg, CTLA-4, OX-40, CD137).
• Has received prior lenvatinib.
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (or 5 times the half-life, whichever is shorter) prior to allocation. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible.
• Subjects must have recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.
• 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 or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is 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.
• 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 known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• 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, lenvatinib, letrozole 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 (eg thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. Subjects with T3, free T3 or free T4 abnormalities at screening who are asymptomatic can be eligible, but will need to be monitored closely with correction of abnormalities as clinically indicated.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.

Sponsors & Collaborators

• National Cancer Centre, Singapore: lead
• MSD Pharma (Singapore) Pte Ltd: collaborator

Study Sites (1)

National Cancer Centre Singapore

Singapore, 169610, Singapore

RECRUITING

MeSH Terms

Interventions

lenvatinib; pembrolizumab; Letrozole

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Dr. Yoon-Sim YAP

  National Cancer Centre, Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dr. Yoon-Sim YAP

CONTACT

+65 63065912; yap.yoon.sim@singhealth.com.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

Study Record Dates

• First Submitted: March 9, 2022
• First Posted: March 18, 2022
• Study Start: February 15, 2023
• Primary Completion: December 31, 2025
• Study Completion (Estimated): December 31, 2027
• Last Updated: December 30, 2025

Record last verified: 2025-12

Locations

SG (1)