CAcTUS - Circulating Tumour DNA Guided Switch

NCT03808441 | Unknown Phase 2

• 1 other identifier: CFTSp129
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

The stay aims to determine whether switching from targeted therapy to immunotherapy based on a decrease in levels of circulating tumour DNA in the blood, will improve the outcome in melanoma patients.

Conditions

Melanoma

Keywords

Circulating tumour DNA; targeted therapy; immune therapy; dabrafenib; trametinib; ipilimumab; nivolumab

Outcome Measures

Primary Outcomes (2)

• CtDNA result critical (red) blood samples returned within 7 working days of samples being received in the laboratory

  Feasibility of returning samples to hospitals from the laboratory to inform clinical decisions

  12 months from last patient starting trial treatment

• Decrease in ctDNA level of mutant BRAF≥80%

  To assess whether a decrease in ctDNA levels of mutant BRAF by ≥80% on targeted therapy is an appropriate cut off for switching to immune therapy

  Through study completion, an average of 1 year

Secondary Outcomes (5)

• Screen failure due to ctDNA levels of mutant BRAF VAF <1.5% Efficacy

  Through study completion, an average of 1 year

• First progression free survival (PFS) at 12 months

  Through study completion, an average of 1 year

• First progression free survival

  When all patients finished follow up, 4 years after last patient starting treatment

• Second progression free survival

  When all patients finished follow up, 4 years after last patient starting treatment

• Overall survival

  When all patients finished follow up, 4 years after last patient starting treatment

Other Outcomes (11)

• Time to ctDNA first progression

  Through study completion, an average of 1 year

• Time to ctDNA second progression

  Through study completion, an average of 1 year

• Increase in ctDNA levels of BRAF VAF during washout period from targeted to immune therapy switch in arm B

  When all patients finished treatment, an average of 1 year after last patient starting treatment

Study Arms (2)

Standard Arm

NO INTERVENTION

Dabrafenib + Trametinib Switch to N+I at first progression

ctDNA Guided Switch

ACTIVE COMPARATOR

Dabrafenib + Trametinib Switch to N+I when ctDNA levels in the blood have dropped by ≥80%.

Other: ctDNA analysis

Interventions

ctDNA analysis OTHER

Regular ctDNA analysis, which upon a decrease in mutant BRAF VAF (variant allele frequency) level of ≥80% the switch to N+I is triggered.

ctDNA Guided Switch

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient capable of giving written informed consent
• Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.
• Histological confirmation of cutaneous melanoma
• ≥ 16 years
• Stage III un-resectable/ IV disease
• BRAF p.V600E/K/R mutation confirmed (exact point mutation must be provided to the investigators)
• At least one target lesion measurable by CT or MRI as per RECIST 1.1
• Baseline ctDNA (as defined by the mutant BRAF VAF in plasma) ≥1.5%
• Adequate organ function
• ECOG performance status 0/1
• Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drug
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
• WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus 5 half-lives of the drugs they are taking at treatment completion (5 times the half-life = 125 days \[nivolumab\]; 5 times the half-life = 90 days \[ipilimumab\]; 5 times the half life = 40 hours \[dabrafenib\]; 5 times the half life = 50 days \[trametinib\]) plus 30 days (duration of ovulatory cycle).
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 5 half-lives of the study drug as above plus 90 days (duration of sperm turnover).
• Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements

You may not qualify if:

• Prior systemic anti-cancer treatment (immune therapy, targeted therapy, vaccine therapy, or investigational treatment) for unresectable Stage III or Stage IV melanoma.
• Prior adjuvant therapy with BRAF +/- MEK inhibitor or adjuvant therapy with combination PD-1 inhibitor plus CTLA-4 inhibitor. Prior adjuvant therapy with PD-1 inhibitor is allowed so long as relapse occurred \> 6 months from discontinuation of treatment and treatment not stopped due to grade 3 or 4 toxicity.
• Current use of a prohibited medication
• History of another malignancy. Exception: patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago) or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study.
• Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patients safety, obtaining informed consent, or compliance with study procedures.
• Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (patients with laboratory evidence of cleared or chronic (not active) HBV and HCV infection will be permitted).
• A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
• Patients with active, known or suspected autoimmune disease. Patients with type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger will be permitted to enrol.
• Patients with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
• Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
• Brain metastases and leptomeningeal metastases are excluded unless:
• Asymptomatic and untreated at presentation, OR
• Symptomatic lesions have been definitively treated with surgery or stereotactic surgery (whole-brain radiation may be given as adjuvant treatment), and do not require steroids for control of symptoms
• Symptomatic metastases, treated or untreated, or metastases requiring steroids to control symptoms, are excluded
• No enzyme inducing anticonvulsants for ≥ 4 weeks prior to randomisation

Sponsors & Collaborators

• The Christie NHS Foundation Trust: lead
• Bristol-Myers Squibb: collaborator
• University of Manchester: collaborator
• Manchester Academic Health Science Centre: collaborator

Study Sites (1)

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

MeSH Terms

Conditions

Melanoma

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Paul Lorigan

  The Christie National Health Service (NHS) Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 7, 2018
• First Posted: January 17, 2019
• Study Start: May 2, 2019
• Primary Completion: April 26, 2023
• Study Completion: May 2, 2024
• Last Updated: August 25, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)