DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial) - Master Screening Protocol

Solid Tumor Clinical Trial

— DETERMINE  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05722886
• Other study ID #: CRUKD/21/004
• Secondary ID: IRAS ID: 1004057
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: March 1, 2023
• Est. completion date: October 2029

Study information

• Verified date: March 2024
• Source: Cancer Research UK
• Contact: Aida Sarmiento Castro
• Phone: +442034695101
• Email: determine[@]cancer.org.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

DETERMINE is an open-label phase II/III trial. It will look at targeted treatments in rare cancers or common cancers with rare genetic change (mutation). Participants must have a cancer with an identified mutation. This could be found during routine testing or as part of another research programme. The DETERMINE trial will recruit adults, teenagers and children. If a drug is found to benefit a new patient group, the study team will work with the NHS and the Cancer Drugs Funds to see if these drugs can be available for patients in the future. This clinicaltrials.gov record refers to the Overall Trial Protocol (Master Screening Record), additional records will be added to clinicaltrials.gov for each treatment arm.

Description:

DETERMINE is an umbrella-basket platform trial to evaluate the efficacy of licensed targeted therapies in rare* adult, paediatric and teenage/young adult (TYA) cancers with actionable genomic alterations, including common cancers with rare actionable alterations. *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. The number of treatment arms opened will depend on the number of licensed medicines identified for inclusion. Each trial cohort 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 total number of patients recruited to the platform will depend on the number of treatment arms and sub-cohorts opened. This clinicaltrials.gov record refers to the Overall Trial Protocol (Master Screening Record), please refer to the references section for links to the individual treatment arm records. The main aims of the clinical trial arms are: - To evaluate the anti-cancer activity of licensed targeted drugs outside their license indication. - To assess the safety and adverse event (AE) profile of licensed, targeted anti-cancer drugs in the target population. - To understand biological mechanisms for response and resistance to targeted therapies. - This Master Screening Record will capture the number of patients with a cancer containing the appropriate genetic alteration that have been successfully allocated and consented to each arm. The trial results (according to the protocol defined outcome measures) will be reported per-arm for each treatment arm. The ultimate aim is to translate positive clinical findings to NHS England to provide new treatment options for rare adult, paediatric and TYA cancers.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 825
• Est. completion date: October 2029
• Est. primary completion date: October 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

THE PARTICIPANT MUST FULFIL THE ELIGIBILITY CRITERIA OUTLINED BELOW AND WITHIN THE SPECIFIC TREATMENT ARM APPENDIX TO WHICH THEY ARE ENROLLED. Core Inclusion Criteria

1. Any patient with histologically proven locally advanced or metastatic cancer (solid

tumour or haematological malignancy) who has:

1. exhausted (or declined) standard-of-care treatment options.

2. or for whom no effective standard treatment is available*. *In exceptional circumstances where upfront treatment on the CRUKD/21/004 DETERMINE trial is considered the best choice for the patient in the opinion of the Investigator, due to risk of considerable harm from standard treatment (e.g. where this involves mutilating surgery or is unacceptable due to patient age or genetic vulnerability such as CMMRD).

3. and whose disease has progressed, or is refractory.

2. Diagnosis of a rare cancer harbouring an actionable genomic alteration, or common cancer types with rare actionable genomic alterations, that have been identified using a validated sequencing technique and for which there is a relevant open treatment arm within the DETERMINE trial.

3. Life expectancy of at least three months.

4. Patients are able to provide written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up. For patients under 16 years of age, the parent or legal guardian will be asked to provide written informed consent and the patient will be asked to provide age-appropriate assent (written or verbal, commensurate with age and level of understanding).

5. Patients with objectively evaluable or measurable disease, according to an assessment method appropriate for their cancer type.

6. Patients must provide a fresh tissue biopsy at baseline and blood samples for translational research.

7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (ECOG performance status 2 may be considered on an individual basis) (= 16 years), Karnofsky score = 50% (12 years to 15 years) or Lansky Play scales = 50% (<12 years). Please see specific treatment arm appendices for any variations on this criterion. Note: Patients <16 years: patients with Central Nervous System (CNS) tumours and a neurological deficit may be eligible with a performance status below 50%, at the discretion of the Investigator. In such cases, the deficit must be stable for at least 7 days prior to trial enrolment, be due to tumour or due to a post-surgical adverse event that is deemed by the local Investigator.

8. 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 the birth control methods and duration of use of those methods, as specified in each treatment arm appendix.

9. Male patients with partners of childbearing potential are eligible provided that they agree to the birth control methods and duration of use of those methods, as specified in each treatment arm appendix.

Core exclusion criteria:

1. Ongoing AEs >Common Terminology Criteria of Adverse Events (CTCAE) Grade 2 attributable to previous anti-cancer treatments. Exceptions to this are any ongoing toxic manifestation, which in the opinion of the Investigator should not exclude the patient.

2. At high medical risk, in the opinion of the Investigator, because of non-malignant systemic disease (including active uncontrolled infection).

3. Female patients who are pregnant, breastfeeding or planning to become pregnant or male patients with a partner who is a woman of childbearing potential and is planning to become pregnant during the trial or following the last dose of IMP, as specified in each treatment arm appendix.

4. Is (or plans to be) a participant in another interventional clinical trial, whilst taking part in this trial. Participation in an observational trial which does not involve administration of an Investigational Medicinal Product (IMP) and which, in the opinion of the local Investigator, would not place an unacceptable burden on the patient would be acceptable e.g. sample collection* or Quality of Life (QoL) studies. *for paediatric patients participating in other studies involving tissue/circulating tumour (ct) DNA/other blood collection, consideration would need to be given to the total blood volumes collected (as per the European Medicines Agency blood volume limits for children).

5. Co-administration of anti-cancer therapies other than those administered in this trial.

6. Radiotherapy (except for palliative reasons) or chemotherapy, endocrine therapy, nitrosoureas, mitomycin-C, immunotherapy and molecularly targeted agents or other investigational medicinal products within 4 weeks or 5 half-lives (whichever is the shorter).

7. Rapidly progressing or symptomatically deteriorating brain metastases. Patients with previously treated brain metastases are eligible, provided the patient has not experienced a seizure or had a clinically significant change in neurological status within the two weeks prior to registration. Such patients must be non-dependent on steroids or on a stable or reducing dose of steroid treatment for at least 14 days (or 7 days for paediatric patients) prior to trial enrolment. Primary brain or CNS malignancies are allowed providing the patient is clinically stable (if requiring corticosteroids must be at stable or decreasing doses for at least 14 days for adults and 7 days for paediatric patients prior to the start of IMP administration). Patients who have received brain irradiation must have completed whole-brain radiotherapy and/or stereotactic radiosurgery at least 14 days prior to the start of IMP administration.

8. Any other condition which, in the opinion of the local Investigator, would not be in the best interests of the patient.

Related Conditions & MeSH terms

• Haematological Malignancy
• Hematologic Neoplasms
• Neoplasms
• Solid Tumor

Intervention

Drug:
• Alectinib
Adult participants will be administered alectinib orally at a dose of 600 mg (four 150 mg capsules) twice daily. Paediatric participants 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 participants may continue on treatment until disease progression, unacceptable toxicity or withdrawal of consent.
• Atezolizumab
Adult participants will receive 1200 mg of atezolizumab intravenously every 21 days. Paediatric participants will receive atezolizumab at a dose of 15 mg/kg (maximum 1200 mg) every 21 days. Participants may continue on treatment until disease progression, unacceptable toxicity or withdrawal of consent.
• Entrectinib
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 will receive a dose adjusted for BSA. Each cycle of treatment will consist of 28 days and participants may continue until disease progression, unacceptable toxicity or withdrawal of consent.
• Trastuzumab in combination with pertuzumab
The initial loading dose of trastuzumab is 8 mg/kg body weight administered intravenously every 21 days followed thereafter by a maintenance dose of 6 mg/kg body weight. The initial loading dose of pertuzumab is 840 mg administered intravenously every 21 days followed thereafter by a maintenance dose of 420 mg. Participants may continue until disease progression, unacceptable toxicity or withdrawal of consent.
• Vemurafenib in combination with cobimetinib
Participants will receive vemurafenib at a dose of 960 mg (4 tablets of 240 mg) orally on a twice daily schedule throughout a 28-day cycle. Participants will receive cobimetinib at a dose of 60 mg (3 tablets of 20 mg) to be taken orally, once daily for 21 consecutive days (days 1 to 21 in each 28-day cycle); followed by a 7-day break. Participants may continue on treatment until disease progression, unacceptable toxicity or withdrawal of consent.

Locations

Country	Name	City	State
United Kingdom	Belfast City Hospital	Belfast
United Kingdom	Birmingham Children's Hospital	Birmingham
United Kingdom	University Hospital Birmingham	Birmingham
United Kingdom	Bristol Haematology and Oncology Centre	Bristol
United Kingdom	Bristol Royal Hospital for Children	Bristol
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Velindre Cancer Centre	Cardiff
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Royal Hospital for Children Glasgow	Glasgow
United Kingdom	The Beatson Hospital	Glasgow
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Alder Hey Hospital	Liverpool
United Kingdom	Great Ormond Street Hospital	London
United Kingdom	Guy's Hospital	London
United Kingdom	University College London Hospital	London
United Kingdom	The Royal Marsden Hospital	London Borough of Sutton
United Kingdom	Royal Manchester Children's Hospital	Manchester
United Kingdom	The Christie Hospital	Manchester
United Kingdom	Freeman Hospital	Newcastle
United Kingdom	Great North Children's Hospital	Newcastle
United Kingdom	Churchill Hospital	Oxford
United Kingdom	John Radcliffe Hospital	Oxford
United Kingdom	Weston Park Hospital	Sheffield
United Kingdom	Southampton General Hospital	Southampton
United Kingdom	Clatterbridge Cancer Centre	Wirral

Sponsors (5)

Lead Sponsor	Collaborator
Cancer Research UK	Hoffmann-La Roche, Royal Marsden NHS Foundation Trust, University of Birmingham, University of Manchester

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of patients who consent to each arm.	This is a master screening entry with sub-study entries to capture the results of each arm. As such a primary outcome measure for this entry is not relevant, however this entry will be used to report the number of patients with a cancer containing the appropriate genetic alteration that have been successfully allocated and consented to each arm.	Up to 5 years.

External Links

•   ClinicalTrials.gov record for DETERMINE Trial Treatment Arm 01 (alectinib) (NCT05770037)
•   ClinicalTrials.gov record for DETERMINE Trial Treatment Arm 02 (atezolizumab) (NCT05770102)
•   ClinicalTrials.gov record for DETERMINE Trial Treatment Arm 03 (entrectinib) (NCT05770544)
•   ClinicalTrials.gov record for DETERMINE Trial Treatment Arm 04 (trastuzumab in combination with pertuzumab) (NCT05786716)
•   ClinicalTrials.gov record for DETERMINE Trial Treatment Arm 05 (vemurafenib in combination with cobimetinib) (NCT05768178)
•   Overview of the DETERMINE trial.