Clinical trial NCT05770037: DETERMINE Trial Treatment Arm 01: Alectinib in Adult, Paediatric and Teenage/Young Adult Patients With ALK Positive Cancers
Official title: 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 01: Alectinib in Adult, Paediatric and Teenage/Young Adult Patients With ALK Positive Cancers
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Haematological Malignancy
Malignant Neoplasm
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms by Site
Cancer
Anaplastic Large Cell Lymphoma
Lymphoma
Renal Cell Carcinoma
Neuroblastoma
Solid Tumour
Keywords: Adult
Alectinib
ALK Tyrosine Kinase Receptor
Antineoplastic Agents
Cancer
Child
Malignancy
Malignant Neoplasms
Molecular Targeted Therapy
Mutation
Neoplasms by Histologic Site
Neoplasms by Site
Paediatric
Precision Medicine
Protein Kinase Inhibitors
Rare
Tumour-agnostic
Young adult
Lead sponsor: Cancer Research UK
Sponsor class: OTHER
Collaborators: name: University of Manchester
name: University of Birmingham
name: Royal Marsden NHS Foundation Trust
name: Hoffmann-La Roche
First posted: 2023-03-15
Enrollment: 30
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: THE PATIENT MUST FULFIL THE ELIGIBILITY CRITERIA WITHIN THE DETERMINE MASTER PROTOCOL (NCT05722886) AND WITHIN THE TREATMENT ARM 01 (ALECTINIB) OUTLINED BELOW\*

\*When alectinib-specific inclusion/exclusion criteria or precautions below differ from those specified in the Master Protocol, the alectinib-specific criteria will take precedence.

Inclusion Criteria:

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

Exclusion Criteria:

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.

Primary outcomes:
measure: Objective Response (OR)
timeFrame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.
measure: Durable Clinical Benefit (DCB)
timeFrame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.
Secondary outcomes:
measure: Duration of response (DR)
timeFrame: 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.
measure: Best percentage change in sum of target lesion / index lesion diameters (PCSD)
timeFrame: 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.
measure: Time to treatment discontinuation (TTD)
timeFrame: From first dose of alectinib to discontinuation of trial treatment up to 5 years with an average calculated and presented with results entry.
measure: Progression-Free Survival time (PFS)
timeFrame: 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.
measure: Time to Progression (TTP)
timeFrame: 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.
measure: Growth Modulation Index (GMI)
timeFrame: 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.
measure: Overall Survival time (OS)
timeFrame: Time of death or up to 2 years after the EoT visit.
measure: Occurrence of at least one Suspected Unexpected Serious Adverse Reaction (SUSAR)
timeFrame: 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.
measure: Occurrence of at least one Grade 3, 4 or 5 alectinib related AE
timeFrame: 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.
measure: EQ-5D Standardised Area Under Index Value Curve (EQ5DSAUC) in adult patients
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).
measure: Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in paediatric patients.
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).
measure: Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in parents of paediatric patients
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).
Other outcomes:
measure: EORTC-QLQ-C30-Standardised Area Under Summary Score Curve (QLQSAUC) in adult patients.
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).
Locations:
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
city: Cardiff
country: United Kingdom
facility: Cardiff Children's Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: The Beatson Hospital
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children Glasgow
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Alder Hey Hospital
city: London Borough of Sutton
country: United Kingdom
facility: The Royal Marsden Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
city: Manchester
country: United Kingdom
facility: The Christie Hospital
city: Newcastle
country: United Kingdom
facility: Great North Children's Hospital
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield's Children's Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Wirral
country: United Kingdom
facility: Clatterbridge Cancer Centre
Study officials:
affiliation: The Christie Hospital
name: Matthew Krebs, Dr
role: PRINCIPAL_INVESTIGATOR
References: