Neoadjuvant pembrolizumab in high-risk thyroid cancers (NEPENTHE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Istituti Clinici Scientifici Maugeri In Forma Abbreviata Istituti Clinici Scientifici Maugeri O Anche Ics Maugeri O Maugeri S.p.A. Sb

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Otorhinolaryngologic Diseases [C09]

Trial duration

25 Oct 2023 → ongoing

Decision date (initial)

2025-01-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Merck & Co., Inc.

External identifiers

EU CT number

2024-519129-38-00

EudraCT number

2021-003524-32

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Activity of pembrolizumab as neoadjuvant treatment in high-risk TCs

Secondary objectives 3

1. Investigation of pembrolizumab escape mechanisms
2. Radiomics as a predictive tool of pembrolizumab activity
3. Differences in RAI-avidity and thyroiditis rate between experimental arm and control group

Conditions and MedDRA coding

thyroid cancers

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of differentiated thyroid carcinoma candidate to surgery not previously treated will be enrolled in this study
2. Patients with a risk > 20% for persistent/recurrent disease (Filetti S, 2019; Haughen BR 2017): primary tumor > 4 cm; multifocal papillary microcarcinoma with extra tumor extension (ETE) and known BRAF V600E mutation; clinical N1; gross ETE (macroscopic invasion of perithyroidal soft tissues); extranodal extension; expected incomplete tumour resection
3. OR Poorly differentiated carcinoma; Hurtle cell carcinoma
4. OR Patients with distant metastasis at diagnosis
5. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
6. Have measurable disease based on RECIST 1.1.
7. 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
8. Have adequate organ function as defined in the following table (Table 2) Specimens must be collected within 10 days prior to the start of study treatment.
9. Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 6 months (e.g. 5 terminal half-lives for pembrolizumab) after the last dose of study treatment and refrain from donating sperm during this period.
10. 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: a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3.b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 4 months after the last dose of study treatment.

Exclusion criteria 20

1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
2. 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).
3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization
4. 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.
5. 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 (eg, FluMist®) are live attenuated vaccines and are not allowed. Administration of killed vaccines is allowed.
6. 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.
7. 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.
8. 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 (eg, breast carcinoma or cervical cancer in situ that have undergone potentially curative therapy are not excluded).
9. 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
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
11. 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
12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
13. Has an active infection requiring systemic therapy
14. History of Human Immunodeficiency Virus (HIV) infection.
15. History of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority
16. Has a known history of active TB (Bacillus Tuberculosis).
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
19. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
20. Has had an allogenic tissue/solid organ transplant.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To investigate the behavior of exhausted CD8+ T in response to pembrolizumab in TCs and the relationships between T cell clusters. To this aim, “spatial-transcriptomic” sequencing will be performed in tumor tissues and will be paired to single-cell maps at peripheral level before and after pembrolizumab.

Secondary endpoints 1

1. Cancer immunotherapy aims to induce a durable human immune response in order to destroy tumour cells (Jacobson M, 2019). Biological mechanisms behind a prolonged immune response are still unknown. We hypothesize that the persistence of tumor-specific T-cell clones after the treatment of primary cancer, might contribute to a durable immune response as well as a better patients’ outcome. Single cell/spatial-transcriptomics sequencing will be applied to the blood samples collected after surgery and

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Istituti Clinici Scientifici Maugeri In Forma Abbreviata Istituti Clinici Scientifici Maugeri O Anche Ics Maugeri O Maugeri S.p.A. Sb

Sponsor organisation

Istituti Clinici Scientifici Maugeri In Forma Abbreviata Istituti Clinici Scientifici Maugeri O Anche Ics Maugeri O Maugeri S.p.A. Sb

Address

Via Salvatore Maugeri 4

City

Pavia

Postcode

27100

Country

Italy

Scientific contact point

Organisation

Istituti Clinici Scientifici Maugeri In Forma Abbreviata Istituti Clinici Scientifici Maugeri O Anche Ics Maugeri O Maugeri S.p.A. Sb

Contact name

Laura Locati

Public contact point

Organisation

Istituti Clinici Scientifici Maugeri In Forma Abbreviata Istituti Clinici Scientifici Maugeri O Anche Ics Maugeri O Maugeri S.p.A. Sb

Contact name

Laura Locati

Locations

1 EU/EEA country · 5 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 7 files

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

Application history

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