DETERMINE Trial Treatment Arm 01: Alectinib in Adult, Paediatric and Teenage/Young Adult Patients With ALK Positive Cancers
- Conditions
- Haematological MalignancyMalignant NeoplasmLymphoproliferative DisordersNeoplasms by Histologic TypeNeoplasms by SiteCancerAnaplastic Large Cell LymphomaLymphomaRenal Cell CarcinomaNeuroblastoma
- Interventions
- Registration Number
- NCT05770037
- Lead Sponsor
- Cancer Research UK
- Brief Summary
This clinical trial is looking at a drug called alectinib. Alectinib is approved as standard of care treatment for adult patients with certain types of lung cancer. This means it has gone through clinical trials and been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. Alectinib works in lung cancer patients with a particular mutation in their cancer known as ALK.
Investigators now wish to find out if it will be useful in treating patients with other cancer types which have the same mutation. 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.
- Detailed Description
DETERMINE Treatment Arm 01 (alectinib) aims to evaluate the efficacy of alectinib in ALK-positive rare\* adult, paediatric and teenage/young adult (TYA) cancers and in common cancers where an ALK 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 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 patient based on molecularly-defined cohorts (See information on Master Screening Protocol below).
Screening: Consenting patients undergo biopsy and collection of blood samples for research purposes.
Treatment: Patients will receive alectinib until disease progression without clinical benefit, unacceptable toxicity or withdrawal of consent. Patients will also undergo collection of blood samples at various intervals while receiving treatment and at 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 30
A. Confirmed diagnosis of an ALK-positive malignancy using an analytically validated method.
B. Women of childbearing potential are eligible, provided that they meet the following criteria:
- Have a negative serum or urine pregnancy test before enrolment and;
- Agree to use one form of highly effective birth control method such as:
I. combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation [oral, intravaginal or transdermal] II. progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable) III. intrauterine device (IUD) IV. intrauterine hormone-releasing system (IUS) V. bilateral tubal occlusion VI. vasectomised partner VII. sexual abstinence
Effective from the first administration of alectinib, throughout the trial and for three months after the last administration of alectinib.
C. Male patients with partners who are women of childbearing potential are eligible provided that they agree to the following, from first administration of alectinib, throughout the trial and for three months after the last administration of alectinib:
- Agree to take measures not to father children by using a barrier method of contraception (condom plus spermicide) or sexual abstinence.
- Non-vasectomised male patients with partners who are women of childbearing potential must also be willing to ensure that their partner uses a highly effective method of contraception, as in criterion B, above.
- Male patients with pregnant or lactating partners must be advised to use barrier method contraception (e.g. condom) to prevent drug exposure of the foetus or neonate.
All male patients must refrain from donating sperm for the same period.
D. Patients must be able and willing to undergo a fresh tissue biopsy.
E. Paediatric patients (patients aged <18 years) must have a body weight ≥40kg.
F. ADULT PATIENTS (≥18 years): Adequate organ function as per haematological and biochemical indices within the ranges shown below. These measurements should be performed to confirm the patient's eligibility.
Haemoglobin (Hb): ≥90 g/L (transfusion allowed)
Absolute neutrophil count (ANC): ≥1.5 × 10^9/L (no granulocyte colony-stimulating factor [GCSF] support in preceding 72 hours)
Platelet count: ≥100×10^9/L (unsupported for 72 hours)
Bilirubin: <1.5 × upper limit of normal (ULN) or ≤2.5 × ULN if raised due to metastases
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5 × ULN or ≤5 × ULN if raised due to metastases
Coagulation - prothrombin (PT) (or international normalized ratio [INR]) and activated partial thromboplastin clotting time (aPTT): ≤1.5 × lower limit of normal (LLN)/ULN (unless patient is on anticoagulants e.g. warfarin [INR should be stable and within indicated therapeutic range], or direct oral anticoagulants [DOAC])
Estimated glomerular filtration rate (eGFR): eGFR: ≥30 mL/min (uncorrected value)
G. PAEDIATRIC PATIENTS (<18 years): Adequate organ function as per haematological and biochemical indices within the ranges shown below. These measurements should be performed to confirm the patient's eligibility
Hb: ≥80 g/L (transfusion allowed)
ANC: ≥1.0×10^9/L (no GCSF support in preceding 72 hours)
Platelet count: ≥75×10^9/L (unsupported for 72 hrs)
Bilirubin: ≤1.5 × ULN for age or ≤2.5 × ULN if raised due to metastases
ALT and AST: ≤3.0 × ULN or ≤5 × ULN if raised due to metastases
Coagulation - PT or INR and aPTT: For patients not receiving therapeutic anticoagulation: INR and aPTT ≤1.5 × ULN for age. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen, e.g. warfarin (INR should be stable and within indicated therapeutic range) or DOAC.
eGFR: ≥60 mL/min/1.73m^2
A. Diagnosis of ALK-positive non-small cell lung cancer.
B. Female patients who are pregnant, breastfeeding or planning to become pregnant during the trial or for three months following their last dose of alectinib.
C. Prior treatment with the same class of drug unless genetic profile demonstrates a mechanism of resistance known to be potentially sensitive to alectinib.
D. History of or radiological evidence of interstitial lung disease and/or pneumonitis. Prior localised radiotherapy related pneumonitis is permitted if resolved and off steroids and asymptomatic for >6 months.
E. Patients at risk of gastrointestinal (GI) perforation e.g. history of diverticulitis, concomitant use of medicinal product with a recognized risk of gastrointestinal perforation (unless patient has also been co-prescribed gastric protection).
• Patients who present with a GI primary tumour or metastases to the GI tract may be considered.
F. Patient unable to swallow or tolerate oral medication or any GI disorder that may affect absorption of oral medications, such as malabsorption syndrome or following major bowel resection. Paediatric patients will be excluded if they are unable to swallow the capsules, as per the dosing schedule (150 mg dose strength).
G. Patients with clinically significant pre-existing cardiac conditions, including uncontrolled or symptomatic angina, uncontrolled atrial or ventricular arrhythmias (within three months), or New York Heart Association (NYHA) class III or IV congestive heart failure.
Patients with a cerebrovascular event (including stroke or transient ischaemic attack [TIA]), or cardiovascular event (including acute myocardial infarction [MI]), within three months before the first dose of alectinib.
• Patients with primary CNS tumours may be considered unless intra-tumoural bleeding has occurred within 2 weeks of the first dose of alectinib, and patients with punctate CNS haemorrhages <3 mm may be considered.
H. History of organ transplantation.
I. Symptomatic bradycardia for age.
J. Known hypersensitivity to alectinib or any of the excipients. See the current alectinib (Alecensa® 150 mg hard capsules) SmPC relevant to the site (e.g. Great Britain or Northern Ireland [NI]) for the full list.
K. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment, or anticipation of need for such a vaccine during alectinib treatment or within six months after the final dose of alectinib.
L. Active hepatitis B or C virus or known human immunodeficiency virus (HIV) positivity or acquired immune deficiency syndrome (AIDS) related illness. Patients with history of testing positive for HIV infection are eligible provided the each of the following conditions are met:
- CD4 count ≥350/μL;
- undetectable viral load;
- receiving antiretroviral therapy (ART) that does not interact with IMP (patients should be on established ART for at least four weeks); and
- no HIV/AIDS-associated opportunistic infection in the last 12 months.
M. Familial or personal history of congenital bone disorders, bone metabolism alterations or known osteopenia in the patient.
N. Any clinically significant concomitant disease or condition (or it's treatment) that could interfere with, the conduct of the trial or absorption of oral medications that would, in the opinion of the Investigator, pose an unacceptable risk to the patient in this trial.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment Arm 01: Alectinib Alectinib This alectinib treatment arm is for adult, paediatric and teenage/young adult (TYA) patients with ALK-positive cancers.
- Primary Outcome Measures
Name Time Method Objective Response (OR) Disease assessments to be performed up to 24 weeks from the start of trial treatment. 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.
Durable Clinical Benefit (DCB) Disease assessments to be performed up to 24 weeks from the start of trial treatment. 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) and, where relevant (e.g. for haematological malignancies), by standard bone marrow response assessment 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.
- Secondary Outcome Measures
Name Time Method Duration of response (DR) Disease assessment performed every 2 cycles of alectinib (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose of alectinib for up to 2 years. DR 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.
Best percentage change in sum of target lesion / index lesion diameters (PCSD) Disease assessment performed every 2 cycles of alectinib (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose of alectinib for up to 2 years. 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.
Time to treatment discontinuation (TTD) From first dose of alectinib to discontinuation of trial treatment up to 5 years with an average calculated and presented with results entry. 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.
Progression-Free Survival time (PFS) Disease assessment performed every 2 cycles of alectinib (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose of alectinib for up to 2 years. 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.
Time to Progression (TTP) Disease assessment performed every 2 cycles of alectinib (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose of alectinib for up to 2 years. 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.
Growth Modulation Index (GMI) Disease assessment performed every 2 cycles of alectinib (each cycle is 28 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose of alectinib for up to 2 years. 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.
Overall Survival time (OS) Time of death or up to 2 years after the EoT visit. 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.
Occurrence of at least one Suspected Unexpected Serious Adverse Reaction (SUSAR) From the time of consent until 28 days after last dose of alectinib (up to 5 years) or until patient starts another anti-cancer therapy, whichever came first. An average time frame will be presented with results entry. The trial will report the number of patients who experience at least one SUSAR to alectinib.
Occurrence of at least one Grade 3, 4 or 5 alectinib related AE From the time of consent until 28 days after last dose of alectinib (up to 5 years) or until patient starts another anti-cancer therapy, whichever came first. An average time frame will be presented with results entry. Number of patients who experience at least one alectinib related Grade 3, 4 or 5 AE according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0
EQ-5D Standardised Area Under Index Value Curve (EQ5DSAUC) in adult patients QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years). For adult populations, two measures of Quality of Life (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.
Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in paediatric patients. QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years). 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.
Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in parents of paediatric patients QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years). 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.
Trial Locations
- Locations (27)
Belfast City Hospital
🇬🇧Belfast, United Kingdom
University Hospital Birmingham
🇬🇧Birmingham, United Kingdom
Birmingham Children's Hospital
🇬🇧Birmingham, United Kingdom
Bristol Royal Hospital for Children
🇬🇧Bristol, United Kingdom
Bristol Haematology and Oncology Centre
🇬🇧Bristol, United Kingdom
Addenbrooke's Hospital
🇬🇧Cambridge, United Kingdom
Velindre Cancer Centre
🇬🇧Cardiff, United Kingdom
Cardiff Children's Hospital
🇬🇧Cardiff, United Kingdom
Western General Hospital
🇬🇧Edinburgh, United Kingdom
The Beatson Hospital
🇬🇧Glasgow, United Kingdom
Royal Hospital for Children Glasgow
🇬🇧Glasgow, United Kingdom
Leicester Royal Infirmary
🇬🇧Leicester, United Kingdom
Alder Hey Hospital
🇬🇧Liverpool, United Kingdom
The Royal Marsden Hospital
🇬🇧London Borough of Sutton, United Kingdom
University College London Hospital
🇬🇧London, United Kingdom
Guy's Hospital
🇬🇧London, United Kingdom
Great Ormond Street Hospital
🇬🇧London, United Kingdom
Royal Manchester Children's Hospital
🇬🇧Manchester, United Kingdom
The Christie Hospital
🇬🇧Manchester, United Kingdom
Great North Children's Hospital
🇬🇧Newcastle, United Kingdom
Freeman Hospital
🇬🇧Newcastle, United Kingdom
Churchill Hospital
🇬🇧Oxford, United Kingdom
John Radcliffe Hospital
🇬🇧Oxford, United Kingdom
Weston Park Hospital
🇬🇧Sheffield, United Kingdom
Sheffield's Children's Hospital
🇬🇧Sheffield, United Kingdom
Southampton General Hospital
🇬🇧Southampton, United Kingdom
Clatterbridge Cancer Centre
🇬🇧Wirral, United Kingdom