Trial Details

Trial status:

In set-up (funded)

Recruitment start date:

Funder:

Cancer Research UK

Sponsor:

Chief Investigator:

Professor John Bridgewater

Recruitment target:

400 (screening phase), 78 (randomised phase)

EudraCT number:

Contact details:

ctc.safir-abc10@ucl.ac.uk

ABC-10 (SAFIR ABC-10 Precision Medicine)

SAFIR ABC-10 Precision Medicine - Molecular targeted maintenance therapy versus standard of care in advanced biliary cancer: an international, randomised, controlled, open- label, platform phase 3 trial

Description

Design:

This is a Phase 3, multicentre, randomised, open-label trial to evaluate whether the introduction of molecular targeted therapy (MTT) as maintenance after 4 cycles of standard-of-care first-line systemic therapy (1L SoC) is superior to continuation of 1L-SoC in the treatment of patients with ABC. The trial is composed of two phases: (i) An initial screening phase to identify a suitable patient population, and (ii) a randomised comparative trial.

The aim of the screening phase is to identify a medically suitable population, to obtain a molecular profile of the patient's tumour, to collect baseline data concerning patient demographics and disease characteristics and to obtain pre-treatment blood and tumour samples for further translational research.

A genetic profile will be obtained from tumour-derived DNA and RNA samples by next-generation sequencing and from circulating tumour DNA. The trial Molecular Tumour Board will determine whether each patient harbours a targetable molecular alteration for one or more of the trial MTTs.

Patients with disease control after 4 cycles of 1L-SoC, who did not experience limiting toxicity, and whose tumour harbours at least one targetable molecular alteration, will be invited to participate in the randomised phase of the trial in which 159 eligible patients will be randomised (2:1) to receive either maintenance therapy with a matched MTT or to continue 1L-SoC treatment.

Treatment:

During the screening phase, patients will receive 4 cycles of standard treatment consisting of cisplatin + gemcitabine:

Drug: Cisplatin

Dose: 25 mg/m2 IV on days 1 and 8 Q3W (CISGEM)

Drug: Gemcitabine

Dose: 1000 mg/m2 IV on days 1 and 8 Q3W (CISGEM)

For those that proceed on to the randomised phase of the trial, and are randomised to receive a molecular targeted therapy, they will receive one of the following drugs that corresponds to their particular targetable molecular alteration:

Drug: Futibatinib

Dose 20 mg once a day (QD)

Drug: Ivosidenib

Dose 500 mg QD

Other Name: Tibsovo

Drug: Zanidatamab

Dose: Patients

Drug: Trastuzumab

Loading dose 8 mg/kg, then 6 mg/kg Q3W (Combination with neratinib)

Other Name: Zercepac

Drug: Neratinib

Dose: 240 mg QD (combination with trastuzumab)

Other Name: Nerlynx

Drug: Encorafenib

Dose: 450 mg QD (Combination with binimetinib)

Other Name: Braftovi

Drug: Binimetinib

Dose: 45 mg twice a day (BID) (Combination with encorafenib)

Other Name: Mektovi

Drug: Niraparib

Dose: 200 mg QD or 300 mg QD

Other Name: Zejula

Key inclusion/exclusion criteria: For the screening phase, the key inclusion criteria are:

Histologically-proven intrahepatic, perihilar or distal cholangiocarcinoma, or gallbladder carcinoma (ampullary carcinoma excluded)
De novo or recurrent, locally advanced (non-resectable) or metastatic disease
Availability of a suitable archived sample of primary or metastatic tumour tissue (frozen, or FFPE) or able to undergo a biopsy to obtain a suitable malignant tissue sample
Aged ≥18 years
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Estimated life expectancy >3 months
Candidate for 1L-SoC therapy, or has initiated first cycle of 1L-SoC therapy

The key exclusion criteria are:

Patients who are candidates for locoregional therapy
Prior anticancer therapy in the palliative setting. Adjuvant capecitabine allowed if completed ≥183 days prior to study entry
Received more than 1 cycle of treatment with 1L-SoC
Prior treatment with any of the MTT under investigation in the SAFIR-ABC10 study
Current malignancies (other than ABC), with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for 5 years or more and are deemed at negligible risk for recurrence, are eligible for the trial

For the randomised phase, the key inclusion criteria are:

Molecular profile showing the tumour harbours at least one targetable molecular alteration with a MTT in the study portfolio (as determined by the trial MTB)
Disease control (stable or responsive) after 4 cycles of 1L-SoC, compared to a pre-treatment disease evaluation, as assessed by the investigator
ECOG performance status of 0 or 1
Presence of at least one evaluable lesion according to RECIST v1.1, or complete response to 12 weeks 1L-SoC
Adequate bone marrow, liver, renal and cardiac function
Adequate biliary drainage, with no evidence of ongoing infection

The key exclusion criteria are:

Disease progression occurring at any time prior randomisation, or toxicity that led to the discontinuation of the 1L-SoC before 4 full cycles have been delivered
Toxicities from 1L-SoC not resolved to Grade ≤2 (according to version 5.0 the National Cancer Institute - Common terminology criteria for adverse events [NCI-CTCAE v5.0]) before randomisation, with the exception of alopecia
Contraindication or known hypersensitivity to the MTT for the molecular alteration found in the patient, or any component in their formulation
Microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) cancers
Major surgery within 4 weeks of randomisation
Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks of start of study treatment. Stable, treated brain metastases are allowed (defined as subjects who are off steroids and anticonvulsants and are neurologically stable with no evidence of radiographic progression for at least 4 weeks at the time of screening).
Known leptomeningeal disease
Concurrent malignancy (other than ABC)
Known active hepatitis B virus or hepatitis C virus infection or human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
Women who are pregnant or breast-feeding
Participation in another therapeutic trial within the 30 days prior to entering the study. Participation in an observational trial would be acceptable

Duration of recruitment: 5 years.

Aim

The aim of this trial is to evaluate whether the introduction of a targeted therapy after 4 cycles of the current standard-of-care treatment for advanced biliary cancer is superior to continuing with the standard treatment.

Contact the trial team

View trial documents

Cancer Research UK & UCL Cancer Trials Centre
University College London
90 Tottenham Court Road
London
W1T 4TJ

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Email:
ctc.enquiries@ucl.ac.uk
Telephone:
+44 (0)20 7679 9898 (General CTC Enquiries)
Fax:
020 7679 9899

CTC staff

University College London, Gower Street, London, WC1E 6BT +44 (0)20 7679 2000