Pembrolizumab in combination with lenvatinib in patients with recurrent, persistent, metastatic or locally advanced vulvar cancer not amenable to curative surgery or radiotherapy (PIERCE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AGO Research GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Jun 2025 → ongoing

Decision date (initial)

2025-02-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

MSD Sharp & Dohme GmbH

External identifiers

EU CT number

2024-515646-16-00

ClinicalTrials.gov

NCT05903833

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To evaluate the efficacy of lenvatinib + pembrolizumab in terms of objective response rate (ORR).

Secondary objectives 3

1. To evaluate the efficacy of lenvatinib + pembrolizumab in terms of overall ORR, disease control rate (DCR), duration of response (DOR), overall survival (OS), progression free survival (PFS), time to first subsequent therapy (TFST), time to second subsequent therapy (TSST)
2. To evaluate the efficacy of lenvatinib + pembrolizumab in terms of quality of life
3. To evaluate the safety and tolerability of lenvatinib + pembrolizumab

Conditions and MedDRA coding

Recurrent, persistent, metastatic or locally advanced vulvar cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Signed written informed consent obtained prior to initiation of any study-specific procedures and treatment as confirmation of the patients awareness and willingness to comply with the study requirements.
2. Female patients who are at least 18 years of age on the day signing informed consent
3. Histologically confirmed locally advanced, recurrent, persistent and/or metastatic VSCC not amenable for salvage surgery or definitive (chemo)radiation (additive palliative radiotherapy for symptom control is allowed)
4. ≤2 previous lines of chemotherapy for recurrent or metastatic disease
5. Measurable disease (investigator assessed RECIST 1.1). Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
6. Eastern cooperative oncology group (ECOG) performance status of 0-1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
7. No pregnancy (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]), no breastfeeding, and at least one of the following conditions applies: a) Not a woman of childbearing potential (WOCBP) as defined in APPENDIX 3 OR b) A WOCBP who agrees to follow the contraception and pregnancy testing recommendations for investigational medicinal products (IMPs) with demonstrated or suspected human teratogenicity/ fetotoxicity in early pregnancy of the CTFG-guideline in APPENDIX 3 during the treatment period and for at least 4 months after the last dose of study treatment. In addition to the described highly effective oral/transdermal contraception methods a barrier method must be used. A WOCBP should not become pregnant during the treatment and for at least 4 months after the last dose of study treatment.
8. Available archival tumor tissue sample and/or newly obtained core or excisional biopsy of a tumor lesion ideally not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides
9. Adequate organ function as defined in Table 3. Specimens must be collected within 10 days prior to the start of study treatment.

Exclusion criteria 39

1. Non squamous cell histology
2. Contraindications regarding treatment with pembrolizumab: allergy or hypersensitivity to pembrolizumab or one of the components.
3. Contraindications regarding treatment with lenvatinib: allergy or hypersensitivity to lenvatinib or one of the components or: a. Pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula b. Radiographic evidence of major blood vessel infiltration
4. Bradyarrhythmia
5. Arterial dissection/aneurysm
6. Long QT Syndrome
7. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 12 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at screening
8. History or evidence of major thrombotic (e.g. symptomatic pulmonary embolism) or hemorrhagic disorders within 6 months prior to day 1, cycle 1. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe haemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
9. Allogenic tissue/solid organ transplant.
10. Diagnosis of immunodeficiency
11. 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.
12. History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years (time requirement does not apply for definitively treated early endometrial cancer (FIGO IA/B), in-situ carcinomas [e.g. breast, cervix, bladder], or basal or squamous cell carcinoma of the skin).
13. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.
14. Active CNS metastases and/or carcinomatous meningitis. Patients 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
15. History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
16. Major active infection requiring systematic therapy.
17. Has active hemoptysis within 3 weeks prior to the first dose of study intervention or tumor bleeding within 2 weeks prior randomization
18. Known history of Human Immunodeficiency Virus (HIV) infection
19. History of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
20. Known history of active TB (Bacillus tuberculosis).
21. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
22. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
23. Pregnancy
24. Breastfeeding
25. 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).
26. Systemic use of corticosteroids or immunosuppressive drugs prior start of study treatment (see EC 11.)
27. Antiarrhythmics of classes Ia and III and other QT-interval prolongation drugs
28. Prior systemic anti-cancer therapy including investigational agents within 4 weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] prior to allocation.
29. Prior radiotherapy within 2 weeks of start of study intervention. Patients must have recovered from 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.
30. Not recovered adequately from any toxicity from other anti-cancer treatment regimens and/or complications from major surgery prior to starting therapy. Note: 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.
31. Administration of a live, attenuated vaccine within 30 days prior first dose of study drug.
32. Uncontrolled blood pressure (Systolic BP >140 mmHg or diastolic BP >90 mmHg) in spite of an optimized regimen of antihypertensive medication.
33. Change of anti-HTN (hypertension) medical regimen within 1 week prior to randomization
34. Prolongation of corrected QT interval (QTc interval) >480 ms
35. Left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).
36. Electrolyte abnormalities that have not been corrected.
37. Subjects having >1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is <1 g/24 hours.
38. Prior enrolment on a clinical study evaluating pembrolizumab and lenvatinib for a carcinoma, regardless of treatment received.
39. 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. Note: Patients 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Efficacy of lenvatinib + pembrolizumab in terms of objective response rate (ORR). ORR will be defined as the proportion of patients with PR or CR within 24 weeks starting with the first study treatment. Tumor responses will be assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Secondary endpoints 3

1. ORR for whole trial duration. DCR=proportion of pts with PR/CR/SD for 8 weeks. DOR=time from response until 1st PD or death, whichever occurs first. OS=time from therapy start to death. PFS=time from therapy start to PD or death, whichever occurs first. TFST=time from therapy start until start of 1st subsequent therapy or death whichever occurs first. TSST=time from therapy start until start of 2nd subsequent therapy or death whichever occurs first. Tumor response assessed by INV per RECIST 1.1.
2. Quality of life is measured by patient reported outcome instruments EORTC QLQ-C30 and QLQ-VU34.
3. Events according to common terminology criteria for adverse events (CTCAE Version 5.0), dose reductions, delays or interruptions.

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AGO Research GmbH

Sponsor organisation

AGO Research GmbH

Address

Kaiser-Friedrich-Ring 71

City

Wiesbaden

Postcode

65185

Country

Germany

Scientific contact point

Organisation

AGO Research GmbH

Contact name

Study Office

Public contact point

Organisation

AGO Research GmbH

Contact name

Study Office

Third parties 4

Locations

1 EU/EEA country · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 13 files

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

Application history

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