A phase-2 clinical trial of regorafenib in patients with pretreated advanced melanoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

UZ Brussel

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

Trial duration

3 Oct 2022 → ongoing

Decision date (initial)

2024-09-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Kom Op Tegen Kanker

External identifiers

EU CT number

2024-514087-11-02

EudraCT number

2022-001291-34

ClinicalTrials.gov

NCT05370807

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To estimate the anti-tumor activity of regorafenib treatment when added to a BRAF-/MEK-inhibitor combination in patients with advanced pretreated BRAF V600-mutant melanoma at the time of progression on a BRAF-/MEK-inhibitor therapy or for patients who have interrupted this therapy for at least 12 weeks.

Secondary objectives 6

1. To determine the disease control rate (DCR) of regorafenib when added on to a BRAF-/MEK-inhibitor combination (cohort-B) or of regorafenib treatment when combined with encorafenib/binimetinib (cohort-C) in patients with advanced pretreated BRAF V600-mutant melanoma.
2. To determine the intracranial and extracranial response rate separately in patients with melanoma brain metastases
3. To estimate the progression-free survival (PFS) and overall survival (OS) of study patients
4. To document the incidence and severity of adverse events in study patients.
5. To estimate the duration of response of study patients
6. Health-Related Quality of Life (HRQOL)

Conditions and MedDRA coding

Melanoma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. ≥ 18 years of age
2. Signed written informed consent
3. Histologically confirmed advanced melanoma that is either stage III (locoregionally metastatic, unresectable) or stage IV (distant metastatic, unresectable)
4. Subjects must have failed prior systemic treatment with immune checkpoint inhibitors, including: CTLA-4 blocking immune checkpoint inhibitors (ipilimumab or other experimental anti-CTLA-4 antibodies), and a PD-1 blocking immune checkpoint inhibitors (pembrolizumab, nivolumab or other experimental anti-PD-1 antibodies). Patients with BRAF V600mutant melanoma must have failed treatment with a BRAF-(+/- MEK) inhibitor. Patients who are not able to undergo such treatment will be considered eligible if all other eligibility criteria are fulfilled. Progression of disease per RECIST, version 1.1 [4] or per immune related response criteria [6] must have been documented during this prior treatment.
5. Cohort-B: patients should be on treatment with BRAF-/MEK-inhibitors or have interrupted for less than 4 weeks before initiation of the study treatment.
6. Cohort-C: patients should be off BRAF-/MEK-inhibitors for at least 12 weeks before initiation of the study treatment.
7. The presence of at least one measurable lesion per RECIST, version 1.1 [4].
8. Interval between the date of the last administration of prior therapy for melanoma and the date of initiation of study treatment: a. ≥ 12 weeks following the date of the first administration and ≥ 3 weeks following the date of the last administration of an anti-CTLA-4-, PD-1- or PD-L1 blocking immune checkpoint inhibitor; b. ≥ 4 weeks following the date of the last administration of chemotherapy (≥ 6 weeks in case of a nitrosurea or mitomycin C containing regimen); c. Cohort-C: ≥ 12 weeks following the date of the last administration of BRAF-/MEK-inhibitors
9. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed on Table 1) and non-medical treatments (e.g. surgery and radiation therapy) must be ≤ Grade 1 severity according to the Common Terminology Criteria for Adverse Events version 5 (CTCAE version 5.0; National Cancer Institute (NCI) 2017) at the time of enrollment.
10. Patients should be able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
11. Women of childbearing potential must have a negative serum pregnancy test during screening and within 72 hours prior to first administration of study drug and agree to use effective contraception throughout the treatment period, and for 16 weeks after the last dose of study treatment.
12. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from 14 days prior to administration of the first dose of study treatment, throughout the treatment period, and for 16 weeks after the last dose of study treatment.
13. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Oken et al, Am J Clin Oncol 1982).
14. Adequate baseline organ function as defined in Table 1. Absolute neutrophil count ≥ 1.2 x 103 /mm3 Hemoglobin ≥ 9.0 g/dL Platelet count ≥ 75 x 103 /mm3 PT/INR and APTTa ≤ 1.5 x ULN Hepatic Albumin ≥ 2.5 g/dL Total bilirubin ≤ 1.5 x ULN AST and ALT ≤ 2.5 x ULN Renal Calculated creatinine clearanceb ≥ 50 mL/min Cardiac Left ventricular ejection fraction ≥ LLN by transthoracic echocardiogram
15. Persistent proteinuria of CTCAE v5.0 Grade 3. Urine dipstick result of 3+ or abnormal, based on type of urine test strip used, is allowed if protein excretion (estimated by urine protein/creatinine ratio on a random urine sample) is <3.5 g / 24 hours.

Exclusion criteria 16

1. Patients with uveal melanoma.
2. Cohort-B: patients treated with vemurafenib/cobimetinib.
3. Patients who are unable to initiate regorafenib within 4 weeks after interrupting BRAF-/MEK-inhibitor therapy (cohort B) or have not interrupted such therapy for at least 12 weeks (cohort C).Patients with active brain metastases who experience ongoing progressive neurological deterioration or requiring increasing doses of steroids for at least 14 days prior to first dose of study treatment.
4. Patients who experienced or are experiencing grade > 3 treatment related adverse events related to BRAF-/MEK-inhibitor therapy.
5. Intolerance or drug allergies to tafinlar, mekinist, encorafenib, or binimetinib.
6. Any contra-indication for evaluation by whole body 18F-FDG-PET/CT and MRI of the brain.
7. History of another malignancy. Exception: subjects who have been disease-free for 3 years, (i.e., subjects with second malignancies that are indolent or definitively treated at least 3 years ago) or subjects with a history of completely resected nonmelanoma skin cancer.
8. Current use of any prohibited medication.
9. Administration of an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to recruitment.
10. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures.
11. Known Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Exception: subjects with laboratory evidence of cleared HBV and HCV infection will be permitted.
12. Ongoing infection CTCAE v5.0 Grade > 2 requiring systemic therapy.
13. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to recruitment
14. A history or evidence of cardiovascular risk including any of the following: a. Current LVEF < LLN b. QT interval corrected for heart rate using the Bazett’s formula (QTcB) ≥ 480 msec; c. History or evidence of current clinically significant uncontrolled arrhythmias; exception: subjects with atrial fibrillation controlled for > 30 days prior to recruitment are eligible. d. History (within 6 months prior to recruitment) of acute coronary syndromes (including myocardial infarction or unstable angina), or coronary angioplasty; e. History of deep venous or arterial thrombosis, or CVA the last 6 months f. History or evidence of current ≥ Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; g. Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by antihypertensive therapy; h. Patients with intra-cardiac defibrillators or permanent pacemakers; i. Abnormal cardiac valve morphology (≥ grade 2; moderate valvular thickening) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study).
15. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients
16. Female patients who are nursing.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective response rate (ORR; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, [4])

Secondary endpoints 6

1. Disease control rate (DCR; defined as the percentage of subjects with a confirmed stable disease (SD), partial response (PR) or complete response (CR) at any time per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. [4])
2. Objective response rate (ORR; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, [4] and RANO-BM criteria [5]) determined separately for extra- and intracranial metastases, respectively.
3. Progression-free survival (PFS; defined as the time from the date of the first dose of regorafenib until the earliest date of documented disease progression [per RECIST v1.1] or death due to any cause) and overall survival (OS; defined as the time from the date of the first dose of regorafenib until the date of death due to any cause).
4. Safety as assessed by anamnesis, clinical examination, analysis of blood and urine, electrocardiograms, cardiac echocardiography, and any additional medical examination that is indicated. AE will be graded by the Common Terminology Criteria of Adverse events (CTCAE), version 5.0 (National Institutes of Health, National Cancer Institute).
5. Duration of response (DOR; defined as the time from the date of first documented response (SD, PR or CR) until the earliest date of documented disease progression.
6.  The generic health status of the patients will be assessed by means of the EuroQOL-5D-3L (EQ-5D-3L).  Health-related quality of life (HRQoL) will be assessed with the European Organization for Research and Treatment of Cancer quality of life questionnaire-C30 (EORTC-QLQ-C30).  Melanoma specific health-related quality of life will be evaluated with the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M)

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

UZ Brussel

Sponsor organisation

UZ Brussel

Address

Laarbeeklaan 101

City

Jette

Postcode

1090

Country

Belgium

Scientific contact point

Organisation

UZ Brussel

Contact name

Catherine De Greef

Public contact point

Organisation

UZ Brussel

Contact name

Marketing & Communicatie

Locations

1 EU/EEA country · 1 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 15 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