“A phase II randomized non-comparative study, with NEOadjuvant plus adjuvant Therapy with combination or sequence of vemurafenib, cobImetinib, and atezolizuMab in patients with high-risk, surgically resectable BRAF mutated and wild-type Melanoma”

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Melanoma Onlus

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Oct 2020 → ongoing

Decision date (initial)

2024-09-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Roche S.p.A.

External identifiers

EU CT number

2024-516659-41-00

EudraCT number

2018-004841-17

ClinicalTrials.gov

NCT04722575

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To determine the pathologic complete response (pCR) rate

Secondary objectives 5

1. Recurrence-Free Survival (RFS)
2. Overall Survival (OS)
3. Pathological Overall Response Rate (pORR)
4. Safety
5. Biomarkers analyses

Conditions and MedDRA coding

high-risk, surgically resectable BRAF mutated and wild-type Melanoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Patients of either sex aged ≥18 years
2. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
3. Patients must have histologically or cytologically confirmed Stage IIIB/C/D resectable cutaneous melanoma. The definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumour Conference attended by melanoma medical and surgical oncology staff. Resectable tumours are defined as having no significant vascular, neural or bony involvement. Only cases where a complete surgical resection with tumour-free margins can safely be achieved are defined as resectable
4. All patients must have a BRAF V600E/K mutation status known
5. Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team
6. Patients must have measurable disease, defined by RECIST 1.1
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
8. Patients must have organ and marrow function as described
9. Absence of any psychological, familiar or social condition that may affect compliance with study protocol and scheduled follow-up
10. Female subjects of childbearing potential must have a negative pregnancy test result at baseline and must practice a reliable method of contraception for the total study duration plus 24 weeks after the last dose of experimental drugs.
11. Men who are sexually active with women of childbearing potential must practice a reliable method of contraception for the total study duration plus 24 weeks after the last dose of experimental drugs.

Exclusion criteria 24

1. No previous cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug
2. Prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, thyroid cancer (except anaplastic) or any cancer from which the patient has been disease-free for 2 years
3. Any major surgery within the last 3 weeks
4. Pregnancy and/or breast feeding or of childbearing potential and not practicing a reliable method of birth control
5. Unwillingness or inability to follow the procedures required in the protocol
6. Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity
7. Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at therapeutic levels
8. History of uncontrolled cardiovascular or interstitial lung disease and evidence or risk of retinal vein occlusion or central serous retinopathy
9. Subjects with conditions requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment
10. Prior BRAF or MEK targeted therapy; patients who have received prior interferon are eligible
11. History of retinopathy or any finding at ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular de generation
12. History of ocular/uveal/mucosal melanoma
13. Presence of any of the following risk factors for RVO: a) Uncontrolled glaucoma with intra-ocular pressures ≥ 21mmHg; b) Serum cholesterol ≥Grade 2; c) Hypertriglyceridemia ≥ Grade 2; d) Hyperglycaemia (fasting) ≥Grade 2
14. Correct QT interval > 450 msec to baseline, history of congenital long QT syndrome
15. Uncontrolled medical condition among which endocrine disorders (such as hypothyroidism, hyperthyroidism and diabetes mellitus)
16. Other severe medical or psychiatric conditions (e.g. depression) or abnormalities of laboratory tests that may increase the risk associated with study participation or the assumption of Vemurafenib, Atezolizumab and Cobimetinib, or that may interfere with the interpretation of study results, which in the judgment of the Investigator can make the patient not eligible for the study
17. Uncontrolled intercurrent illness, including but not limited to: ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, cerebrovascular accident or transient ischemic attack, pulmonary embolism, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
18. History of active primary immunodeficiency
19. Receipt of live attenuated vaccine within 30 days prior to the first dose. Note: enrolled patients should not receive live vaccine whilst receiving IMP and up to 30 days after the last dose of IMP.
20. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA- 4 antibody
21. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
22. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
23. History of testing positive for HIV or known AIDS
24. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary objective is to determine the pathologic complete response (pCR) rate. (Centrally/Independently determined). Pathologic complete response, which is defined as residual cancer burden 0.

Secondary endpoints 5

1. Recurrence-Free Survival (RFS) at 2-years, 3-years and at the end of the study. RFS defined as the time from randomisation to recurrence event (local or distant disease development, or death). For patients without events at the end of the study time will be censored at the date of last follow-up.
2. Overall Survival (OS) defined as the time from randomisation to death. For patients alive at the end of the study time will be censored at the date of last follow-up.
3. Pathological Overall Response rate (pORR) defined as the sum of pathologic complete responses (pCRs), near pathologic complete responses (near pCRs) and pathologic partial responses (pPRs).
4. Safety
5. To determine molecular and immunophenotypic changes in tumour and peripheral blood evaluating several biomarkers.

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Melanoma Onlus

Sponsor organisation

Fondazione Melanoma Onlus

Address

Via Mariano Semmola

City

Naples

Postcode

80131

Country

Italy

Scientific contact point

Organisation

Fondazione Melanoma Onlus

Contact name

Paolo Antonio Ascierto

Public contact point

Organisation

Fondazione Melanoma Onlus

Contact name

Paolo Antonio Ascierto

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 11 files

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

Application history

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