Trial Exploring Combined Neoadjuvant Therapy With Pembrolizumab/Lenvatinib + Adjuvant Pembrolizumab in Pat. With NSCLC

Studien-Informationen Einschlusskriterien Studien-Rationale Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT04875585

Studienbeginn:
Mai 2021

Letztes Update:
24.08.2022

Wirkstoff:
neoadjuvant therapy with Pembrolizumab/Lenvatinib, Adjuvant Treatment Phase

Indikation (Clinical Trials):
Lung Neoplasms, Carcinoma, Non-Small-Cell Lung

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Medical University Innsbruck

Collaborator:
Merck Sharp & Dohme LLC

Studienleiter

Georg Pall, Dr.
Principal Investigator
Georg.Pall@i-med.ac.at

Kontakt

KKS Innsbruck
Kontakt:
Phone: +43 0512 09003
Phone (ext.): 70086
E-Mail: kks-regulatory@i-med.ac.at» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

Medical University Innsbruck
6020 Innsbruck
AustriaRekrutierend» Google-Maps

Studien-Informationen

Detailed Description:

In Tyrol lung cancer is the fourth most incident cancer in women and the second most in men

(1). Mortality related to lung cancer is highest in both sex groups, which supports the huge

unmet medical need for improved lung cancer therapies in the near future (2). In very recent

years, many novel therapies have entered the clinical scene, particular for treatment of

non-small cell lung cancer (NSCLC) and many of those drugs target the tumor microenvironment

(TME) (3-6). Both, anti-angiogenic-treatment (AAT) and immunotherapy target the TME and have

been successfully established as standard therapeutic options in NSCLC (6-9). Recent

preclinical studies strongly suggest that AAT and immune-checkpoint-inhibitors act

synergistically and first clinical studies also proved an acceptable safety profile (6, 10,

11).

However, response and therapeutic efficacy of these approaches is still limited to certain

subgroups of patients and therefore the search for biomarker(s) predicting response and/or

toxicity for improved patient selection is of utmost importance. This knowledge would

definitely allow a more rational and efficient clinical use of these compounds. Neoadjuvant

"window of opportunity" trials may offer an important way of answering relevant translational

research questions related to optimized (biomarker-driven) patient selection, as they allow

sequential tissue sampling during diagnostic work-up and subsequently (after neoadjuvant

therapy) upon surgical tumor resection. Most studies investigating immunotherapy

combinational approaches mainly focused on the characterization of the immune cell

compartment, while the influence on the vascular network as well as on their mutual

regulation, particularly in case both compartments are targeted in parallel, has not

sufficiently been addressed.

Standard neoadjuvant therapy is a mainstay of combinational chemotherapy with high toxicity

and complication rates (12, 13). Several recent early clinical trials have shown promising

pathologic response rates and good tolerability with neoadjuvant immune-checkpoint antibody

therapy (14-16). Recently, neoadjuvant immune-checkpoint antibody monotherapy (ICA) with the

PD-1 blocking monoclonal antibody Nivolumab showed high pathological response rates and good

tolerability (14).

Adjuvant treatment with immune-checkpoint-inhibitors has been shown to be effective and safe

in the treatment of early stage melanoma (17, 18). In NSCLC prospective randomized trials

with the aim of recapitulating these beneficial effects are ongoing. A high medical need in

the adjuvant therapy setting is to select the optimal candidates for therapy and

liquid-biopsies drawn during adjuvant treatment offer important opportunities for patients

selection: (i) the kinetics of cell-free tumor-DNA (ct-DNA) can be used to monitor remission

status and potentially early sense later overt clinical relapse (19-22); (ii) longitudinal

assessment of patient-specific tumor alterations may predict therapy recurrence (iii)

together with measurements of immune cell populations ct-DNA kinetics might gain insights

into the dynamics within the TME during a prolonged period of checkpoint-blockade. Combining

these informations might lead to a better understanding of potentially beneficial

neo-/adjuvant treatment effects finally leading to relapse-prevention.

The present phase II investigator-initiated trial (IIT) investigates the efficacy of the

neoadjuvant combination therapy of the PD-1 inhibitor Pembrolizumab with the antiangiogenic

kinase inhibitor Lenvatinib (primary endpoint: major pathological response) and how this

therapy shapes the TME. Furthermore, the disease kinetics and the effects on cellular and

soluble immune-biomarkers will be monitored during an additional adjuvant treatment-phase

with Pembrolizumab via liquid-biopsies, multi-dimensional flow cytometry and cytokine

quantification. In total 33 patients with early stage NSCLC will be included in this trial.

The scientific program provides a comprehensive mapping of the TME prior to and after

neoadjuvant intervention using various single cell analysis platforms to depict the

composition of the TME. Consecutively collected plasma and blood probes will be analysed and

correlated with routine response assessment, TME patterns and the clinical endpoints.

In conclusion, the present phase II study aims for identification of potential biomarkers and

biomarker combinations relevant for combination therapy of immunotherapy and anti-angiogenic

agents in early stage NSCLC.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Male/female participants ≥18 years of age

2. Histologically confirmed primary diagnosis of resectable NSCLC, stages IA3-IIIA (max.

single station N2).

3. Measurable disease based on RECIST 1.1.

4. Male participants must agree to use a contraception as detailed in Appendix 3 of this

protocol during the treatment period and for at least 120 additional days after the

last dose of study treatment and refrain from donating sperm during this period.

5. Female participants are eligible to participate if not pregnant (see Appendix 3), not

breastfeeding, and at least one of the following conditions applies:

1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR

2. 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.

6. Written informed consent provided

7. ECOG performance status of 0 to 1

8. Adequate organ function. Specimens must be collected within 14 days prior to the start

of study treatment.

Exclusion Criteria:

1. A woman with child-bearing potential (WOCBP) who has a positive urine pregnancy test

within 72 hours prior to inclusion (see Appendix 3). If the urine test is positive or

cannot be confirmed as negative, a serum pregnancy test will be required.

2. Uncontrolled blood pressure (systolic BP>160mmHg or diastolic BP >95mmHg) despite an

optimized regimen of antihypertensive medication.

3. Significant cardiovascular impairment: history of congestive heart failure greater

than New York Heart Association (NYHA) Class II, unstable angina, myocardial

infarction or stroke within 6 months of the first dose of study drug, and/or cardiac

arrhythmia requiring medical treatment at screening.

4. History of prolonged QT syndrome, or family member with prolonged QT syndrome

5. QTc interval >490 msec when 3 consecutive ECG values are averaged

6. Bleeding and/or thrombotic disorders and/or subjects at risk for severe hemorrhage.

The degree of tumor invasion/infiltration of major blood vessels should be considered

because of the potential risk of severe hemorrhage associated with tumor

shrinkage/necrosis following Lenvatinib therapy.

7. 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.

8. Patient 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).

9. Patient has received prior systemic anti-cancer therapy for the newly diagnosed NSCLC

including investigational agents.

10. Patient has received prior radiotherapy for the newly diagnosed NSCLC.

11. Patient 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.

12. Patient 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 treatment.

Note: 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.

13. Diagnosis of immunodeficiency and/or patient 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.

14. Known additional malignancy that is progressing.

15. Known history of severe (≥Grade 3) allergic or hypersensitivity reactions to

Pembrolizumab or Lenvatinib and/or any of their excipients.

16. Known 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.

17. History of (non-infectious) pneumonitis that required steroids or has current

pneumonitis.

18. Active infection requiring systemic therapy.

19. Infection with Human Immunodeficiency Virus (HIV).

20. Infection with Hepatitis B and/or Hepatitis C

21. Known psychiatric or substance abuse disorders that would interfere with cooperation

with the requirements of the trial.

22. Patient has received prior surgery therapy for the newly diagnosed NSCLC.

23. 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.

Studien-Rationale

Primary outcome:

1. Major pathological response after neoadjuvant immunotherapy in combination with angiogenesis inhibition (Time Frame - 2 years):
Number of Participants Reaching a Major Pathological Response after Short Course Neoadjuvant Treatment with Pembrolizumab/Lenvatinib.

Secondary outcome:

1. Radiologic response according to RECIST/iRECIST (Time Frame - 2 years)

2. Surgical resection rate (Time Frame - 2 years)

3. Disease free survival at 1, 2, 3 and 5 years (Time Frame - 5 years)

4. Overall survival at 1, 2, 3 and 5 years (Time Frame - 5 years)

5. Capturing of the Toxicity of a neoadjuvant/adjuvant treatment (Time Frame - 5 years):
Capturing of the Toxicity of a Neoadjuvant Treatment with Pembrolizumab/Lenvatinib and Adjuvant Pembrolizumab (Common Toxicity Criteria).

Geprüfte Regime

neoadjuvant therapy with Pembrolizumab/Lenvatinib:
Neoadjuvant therapy for 6 weeks
Surgery:
surgical resection of primary tumor and lymph-node-dissection.
Adjuvant Treatment Phase:
Adjuvant treatment with 15 cycles of Pembrolizumab

Quelle: ClinicalTrials.gov

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