Phase II multicentric study: efficacy evaluation of neo-adjuvant treatment associated with maintenance therapy by anti-PD1 immunotherapy on disease-free-survival (DFS) in patients with resectable mucosal melanoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17], Diseases [C] - Neoplasms [C04]

Trial duration

28 May 2018 → ongoing

Decision date (initial)

2024-06-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

MSD

External identifiers

EU CT number

2024-513027-16-00

EudraCT number

2017-001628-23

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The main objective will be to estimate the disease free survival (DFS) of patients with resectable mucosal melanomas treated by neo-adjuvant anti-PD1 (in combination or not with lenvatinib) followed by surgery, radiotherapy if indicated, and maintenance immunotherapy in order to compare it to historical DFS results of this kind of patients treated by surgery and radiotherapy. Our primary end-point will be disease-free survival at 2 years.

Secondary objectives 5

1. Evaluation of overall survival
2. Evaluation of loco-regional control
3. Evaluation of preoperative efficacy of neo-adjuvant therapy with pembrolizumab as monotherapy and in combination with lenvatinib (objective response by RECIST 1.1 and pathological response)
4. Evaluation of the safety and tolerability of pembrolizumab immunotherapy and combination of pembrolizumab immunotherapy with lenvatinib
5. Exploratory objectives : • Description of immunological and histological response to anti- PD1 on tumor samples removed by surgery (evaluating before and after treatment the expression of PD-L1 in tumor cells, the number of tumor infiltrating lymphocytes and characterization of their phenotype in frozen or formalin fixed paraffin embedded tumor tissue). • Study of prognostic value of tumoral expression of PDL1, of mutation load of the tumors and other immunologic biomarkers in the tumors of patients with mucosal melanomas treated with neo-adjuvant anti-PD1 immunotherapy. • To determine circulating lymphocyte subpopulations as well as soluble immune factors in the blood before and during treatment. (see 7.4 Translational research)

Conditions and MedDRA coding

Resectable mucosal melanomas

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Be willing and able to provide written informed consent/assent for the trial.
2. 2. Be >18 years of age on day of signing informed consent.
3. 3. Present with a resectable mucosal melanoma.
4. 4. Be eligible for surgical treatment (without any contraindications).
5. 5. Be eligible for adjuvant radiotherapy.
6. 6. Have measurable disease based on RECIST 1.1.
7. 7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.
8. 8. Have a performance status of 0 or 1 on the ECOG Performance Scale.
9. 9. Demonstrate adequate organ function as defined in table 1, all screening labs should be performed within 10 days of treatment initiation.
10. 10. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
11. 11. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
12. 12. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
13. 13. Patient affiliated to a social security system or beneficiary of the same
14. 14. Not having any contraindication for lenvatinib treatment

Exclusion criteria 35

1. 1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
2. 2. Has a metastatic disease.
3. 3. Has a non resectable melanoma.
4. 4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (except topical or inhaled steroids) or any other form of immunosuppressive therapy within 2 weeks prior to the first dose of trial treatment.
5. 5. Has a known history of active TB (Bacillus Tuberculosis)
6. 6. Hypersensitivity to pembrolizumab or any of its excipients.
7. 7. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to D1 of study treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
8. 8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks or 5 half-life times (whatever the shorter) prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. - Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
9. 9. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
10. 10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
11. 11. Has active autoimmune and/or immune mediated inflammatory 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.
12. 12. Has known history of, or any evidence of active, non-infectious pneumonitis.
13. 13. Has an active infection requiring systemic therapy.
14. 14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
15. 15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
16. 16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
17. 17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
18. 18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
19. 19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
20. 20. Has received a live vaccine within 30 days of planned start of study therapy.
21. 21. Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete wound healing
22. 22. Has a prior history of organ transplant including allogeneic stem cell transplant
23. 23. Has a LVEF below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
24. 24. Has an uveal melanoma
25. For the cohort B, patients must be excluded if one of the following additional criteria is met : 25. Uncontrolled blood pressure (Systolic BP>140 mmHg or diastolic BP >90 mmHg) in spite of an optimized regimen of antihypertensive medication
26. 26. Electrolyte abnormalities that have not been corrected
27. 27. 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
28. 28. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy
29. 29. 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.
30. 30. Subjects who have not recovered adequately from any toxicity from other anti- cancer treatment regimens and/or complications from major surgery prior to starting therapy. 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. 31. The participant has severe hypersensitivity (≥Grade 3) to lenvatinib and/or any of its excipients.
32. 32. Has presence of a gastrointestinal condition including malabsorption, gastrointestinal, anastomosis, or any other condition that might affect the absorption of lenvatinib.
33. 33. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
34. 34. Has clinically significant hemoptysis or significant tumor bleeding within 3 weeks prior to the first dose of study drug.
35. 35. Prolongation of QTcF interval to >480 ms

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Disease free survival, defined as the time between the inclusion in the trial and the date of the first event defined as local, regional, distant relapse or death whatever the cause.

Secondary endpoints 6

1. Overall survival (OS)
2. Locoregional control (Time to locoregional relapse, TTLRC)
3. Efficacy (Objective response, according to RECIST 1.1), after neoadjuvant therapy
4. Pathological response after neoadjuvant therapy
5. Acute toxicity (CTC-NCI V4)
6. Translational criteria o Ex vivo response to anti-PD1 o Prognostic value of biomarkers including PDL1 expression and mutational load o Variation of circulating lymphocytes (before–after treatment)

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Locations

1 EU/EEA country · 6 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

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