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Entrectinib

Protein Kinase Inhibitors

Enzyme Inhibitors

This entrectinib treatment arm is for adult, teenage/young adult (TYA) and paediatric participants with ROS1 gene fusion-positive malignancies.

Adult and paediatric participants with body surface area (BSA) ≥1.51 m\^2 will receive entrectinib orally at a dose of 600 mg daily dose (three 200 mg capsules per day).

Paediatric participants with BSA \<1.51 m\^2 will receive entrectinib at a dose of 100 mg (BSA=0.43-0.50 m\^2) or 200 mg (BSA=0.51-0.80m\^2) or 300 mg (BSA=0.81-1.10 m\^2) or 400 mg (BSA=1.11-1.50 m\^2).

Each cycle of treatment will consist of 28 days and participants may continue until disease progression, unacceptable toxicity or withdrawal of consent.

Aida Sarmiento Castro

Vicky Coyle, Prof

Gary Middleton, Prof

Susanne Gatz, Dr

Antony Ng, Dr

Bristi Basu, Dr

Robert Jones, Dr

Stefan Symeonides, Dr

Patricia Roxburgh, Dr

Milind Ronghe, Dr

Martin Elliott, Dr

Anne Thomas, Dr

Lisa Howell, Dr

Lynley Marshall, Dr

Martin Foster, Prof

James Spicer, Dr

Darren Hargrave, Dr

Guy Makin, Dr

Matthew Krebs, Prof

Alastair Greystoke, Dr

Sarah Pratap, Dr

Sarah Danson, Dr

Juliet Gray, Prof

Dan Palmer, Dr

This clinical trial is looking at a drug called entrectinib. Entrectinib is approved as standard of care treatment for adult patients with non-small cell lung cancer (NSCLC) which have a particular molecular alteration called ROS1-positive, and patients 12 years of age or older with solid tumours which have another type of change in the cancer cells. This means it has gone through clinical trials and been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK.

Investigators now wish to find out if it will be useful in treating patients with other cancer types which have the same molecular alteration (ROS1-positive). If the results are positive, the study team will work with the NHS and the Cancer Drugs Fund to see if these drugs can be routinely accessed for patients in the future.

This trial is part of a trial programme called DETERMINE. The programme will also look at other anti-cancer drugs in the same way, through matching the drug to rare cancer types or ones with specific mutations.

DETERMINE Treatment Arm 03 (entrectinib) aims to evaluate the efficacy of entrectinib in ROS1 gene fusion-positive rare\* adult, paediatric and teenage/young adult (TYA) cancers and in common cancers where a ROS1 mutation or amplification is considered to be infrequent.

\*Rare is defined generally as incidence less than 6 cases in 100,000 patients (includes paediatric and teenagers/young adult cancers) or common cancers with rare alterations.

This treatment arm has a target sample size of 30 evaluable patients. Sub-cohorts may be defined and further expanded where promising activity is identified to a target of 30 evaluable patients each.

The ultimate aim is to translate positive clinical findings to the NHS (Cancer Drugs Fund) to provide new treatment options for rare adult, paediatric and TYA cancers.

OUTLINE:

Pre-screening: The Molecular Tumour Board makes a treatment recommendation for the participant based on molecularly-defined cohorts.

Screening: Consenting participants undergo biopsy and collection of blood samples for research purposes.

Treatment: Participants will receive entrectinib until disease progression, unacceptable toxicity or withdrawal of consent. Participants will also undergo collection of blood samples at various intervals while receiving treatment and at the end of trial visit (EoT).

After completion of study treatment, patients are followed up every 3 months for 2 years

THE DETERMINE TRIAL MASTER (SCREENING) PROTOCOL:

Please see DETERMINE Trial Master (Screening) Protocol record (NCT05722886) for information on the DETERMINE Trial Master Protocol and applicable documents.

DETERMINE Trial Treatment Arm 03: Entrectinib in Adult, Teenage/Young Adults and Paediatric Patients With ROS1 Gene Fusion-positive Cancers.

DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations. Treatment Arm 03: Entrectinib in Adult, Teenage/Young Adults and Paediatric Patients With ROS1 Gene Fusion-positive Cancers.

Individual de-identified patient data will be shared with researchers whose proposed use of the data is approved by a review committee of the Sponsor.

An OR is defined as the confirmed occurrence of either a Complete Response (CR) or Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 criteria (or immune related (ir)-RECIST or standard imaging criteria for specific disease e.g. Response Evaluation in Neuro Oncology criteria (RANO)). In patients with leukaemia, OR will be defined as the occurrence of CR , CRi (CR incomplete neutrophil recovery) or CRp (CR with incomplete platelet recovery). The trial will report the proportion of patients with an OR and 95% credible interval.

DCB is defined as the absence of disease progression for at least 24 weeks from the start of trial treatment according to RECIST Version 1.1 criteria (or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria). Alternative definitions of DCB based on different time points may be pre-specified for particular sub-cohorts if 24 weeks is not clinically relevant. The trial will report the proportion of patients with a DCB and 95% credible interval.

Duration of response, is defined as the time from the date of the first confirmed CR or PR according to RECIST 1.1 or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria to the date of disease progression. The trial will report the median DR and 95% credible interval.

PCSD is defined as the greatest decrease or least increase in the sum of target lesion diameters (RECIST) or index lesion diameters (irRECIST) as a percentage compared to the baseline measurement. The trial will report the mean PCSD and 95% credible interval.

TTD is defined as the time from date of starting trial treatment to date of discontinuing trial treatment, in days estimated by the median of the posterior inverse gamma probability distribution. The trial will report the median TTD and 95% credible interval.

PFS is defined as the time from date of starting trial treatment to date of progression or date of death without a previous progression recorded estimated by the median of the posterior inverse gamma probability distribution.

TTP is defined as the time from date of starting trial treatment to date of progression or date of death without recorded progression censored rather than events. The trial will report the median TTP and 95% credible interval.

GMI is defined as the ratio of TTP with the trial protocol treatment to TTP on the most recent prior line of therapy. The trial will report the mean GMI and 95% credible interval.

OS is defined as the time from date of starting trial treatment to date of death from any cause estimated by the median of the posterior normal probability distribution.

The trial will report the number of patients who experience at least one SUSAR to entrectinib.

Number of patients who experience at least one entrectinib related Grade 3, 4 or 5 AE according to NCI CTCAE Version 5.0.

For adult populations, multiple measures of QoL will be generated from patient completion of the European Organisation for Research and Treatment of Cancer QLQC30 (EORTC-QLQC30) questionnaire (30 measures). For each patient the Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean QLQSAUC and 95% credible interval.

For adult populations, two measures of QoL will be generated from patient completion of the EQ-5D-5L questionnaire. For each measure, scores based on responses from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean EQ5DSAUC and 95% credible interval.

For paediatric populations multiple measures of QoL will be generated from patient completion of the PedsQL 4.0 (4 measures). The Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean PedsSAUC and 95% credible interval.

For paediatric populations multiple measures of QoL will be generated from patient's parent completion of the PedsQL 4.0 (4 measures). The Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean PedsSAUC and 95% credible interval.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
DETERMINE Trial Treatment Arm 03: Entrectinib in Adult, Teenage/Young Adults and Paediatric Patients With ROS1 Gene Fusion-positive Cancers.	NCT05770544	Solid Tumor Haematological ... Malignancy Malignant Neopl... Lymphoprolifera... Neoplasms by Hi... Neoplasms by Si... Cancer Brain Neoplasms Melanoma Glioma	Entrectinib	-	Cancer Research UK
DETERMINE Trial Treatment Arm 03: Entrectinib in Adult, Teenage/Young Adults and Paediatric Patients With ROS1 Gene Fusion-positive Cancers.	NCT05770544	Solid Tumor Haematological ... Malignancy Malignant Neopl... Lymphoprolifera... Neoplasms by Hi... Neoplasms by Si... Cancer Brain Neoplasms Melanoma Glioma	Entrectinib	-	Cancer Research UK

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