DETERMINE Trial Treatment Arm 01: Alectinib in Adult, Paediatric and Teenage/Young Adult Patients With ALK Positive Cancers

Официальное название

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

Обзор

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.

Подробное описание

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 adverse events (AEs) 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.

Вмешательства

• Препарат Alectinib
  Adult patients will be administered alectinib orally at a dose of 600 mg (four 150 mg capsules) twice daily. Paediatric patients with a body weight ≥40 kg and who are able to swallow the capsules, will be administered alectinib orally at a dose of 600 mg (four 150 mg capsules) twice daily. Each cycle of treatment will consist of 28 days and patients may continue on treatment until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.

Первичные конечные точки

• Objective Response (OR) [Срок оценки: Disease assessments to be performed up to 24 weeks from the start of trial treatment.]
• Durable Clinical Benefit (DCB) [Срок оценки: Disease assessments to be performed up to 24 weeks from the start of trial treatment.]

Вторичные конечные точки (12)

• Duration of response (DR) [Срок оценки: 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.]
• Best percentage change in sum of target lesion / index lesion diameters (PCSD) [Срок оценки: 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.]
• Time to treatment discontinuation (TTD) [Срок оценки: From first dose of alectinib to discontinuation of trial treatment up to 5 years with an average calculated and presented with results entry.]
• Progression-Free Survival time (PFS) [Срок оценки: 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.]
• Time to Progression (TTP) [Срок оценки: 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.]
• Growth Modulation Index (GMI) [Срок оценки: 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.]
• Overall Survival time (OS) [Срок оценки: Time of death or up to 2 years after the EoT visit.]
• Occurrence of at least one Suspected Unexpected Serious Adverse Reaction (SUSAR) [Срок оценки: 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.]
• Occurrence of at least one Grade 3, 4 or 5 alectinib related AE [Срок оценки: 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.]
• EQ-5D Standardised Area Under Index Value Curve (EQ5DSAUC) in adult patients [Срок оценки: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).]
• Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in paediatric patients. [Срок оценки: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).]
• Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in parents of paediatric patients [Срок оценки: QoL surveys performed prior to inclusion, every cycle (each cycle is 28 days) and at EoT visit (up to 5 years).]

Критерии участия

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.

Критерии включения

A. Confirmed diagnosis of an ALK-positive malignancy using an analytically validated next-generation sequencing 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. Note that for patients with haematological malignancies or neuroblastomas, blood, bone marrow aspiration and/or trephine or lymph node biopsy samples may be taken.

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 defined in the protocol. These measurements should be performed to confirm the patient's eligibility.

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.

Критерии исключения

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. Patients who have previously received crizotinib (Xalkori\^\[®\]) and did not respond, or who responded inadequately or responded adequately and subsequently progressed, are allowed into the trial.

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 GI 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 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 its treatment) that could interfere with the conduct of the trial or absorption of oral medications or that would, in the opinion of the Investigator, pose an unacceptable risk to the patient in this trial.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Великобритания · 27 центров

• Belfast City Hospital — Belfast
• University Hospital Birmingham — Birmingham
• Birmingham Children's Hospital — Birmingham
• Bristol Royal Hospital for Children — Bristol
• Bristol Haematology and Oncology Centre — Bristol
• Addenbrooke's Hospital — Cambridge
• Velindre Cancer Centre — Cardiff
• Cardiff Children's Hospital — Cardiff
• … и ещё 19 центров

Идентификаторы

NCT: NCT05770037 · CRUKD/21/004 - Treatment Arm 1 · IRAS ID: 1004057

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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