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

• ClinicalTrials.gov Identifier: NCT05722886
• Recruitment Status: Recruiting
• First Posted: February 10, 2023
• Last Update Posted: March 20, 2024
• Sponsor: Cancer Research UK
• Collaborators: University of Manchester; University of Birmingham; Royal Marsden NHS Foundation Trust; Hoffmann-La Roche
• Information provided by (Responsible Party): Cancer Research UK

Tracking Information

• First Submitted Date: November 24, 2022
• First Posted Date: February 10, 2023
• Last Update Posted Date: March 20, 2024
• Actual Study Start Date: March 1, 2023
• Estimated Primary Completion Date: October 2029 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 31, 2023)

Number of patients who consent to each arm. [ Time Frame: Up to 5 years. ]

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.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Detailed 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.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Solid Tumor
• Haematological Malignancy

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.

  Other Name: Alecensa
• Drug: 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.

  Other Name: Tecentriq
• Drug: 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.

  Other Name: Rozlytrek
• Drug: 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.

  Other Name: Herceptin in combination with Perjeta
• Drug: 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.

  Other Name: Zelboraf in combination with Cotellic

Study Arms

• Experimental: Treatment Arm 1: Alectinib
  This alectinib treatment arm is for adult, teenage/young adults (TYA) and paediatric participants with ALK-positive cancers.
  Intervention: Drug: Alectinib
• Experimental: Treatment Arm 2: Atezolizumab
  This atezolizumab treatment arm is for adult, teenage/young adults (TYA) and paediatric participants with high tumour mutational burden (TMB) or microsatellite instability high (MSI-high) or proven (previously diagnosed) constitutional mismatch repair deficiency (CMMRD) only.
  Intervention: Drug: Atezolizumab
• Experimental: Treatment Arm 3: Entrectinib
  This entrectinib treatment arm is for adult, teenage/young adult (TYA) and paediatric participants with ROS1 gene fusion-positive malignancies only.
  Intervention: Drug: Entrectinib
• Experimental: Treatment Arm 4: Trastuzumab in combination with pertuzumab
  This trastuzumab and pertuzumab treatment arm is for adult, teenage/young adult (TYA) and paediatric participants with malignancies with HER2 amplification or activating mutations.
  Intervention: Drug: Trastuzumab in combination with pertuzumab
• Experimental: Treatment Arm 5: Vemurafenib in combination with cobimetinib
  This vemurafenib and cobimetinib appendix is for BRAF V600 mutation-positive malignancies occurring in adults only.
  Intervention: Drug: Vemurafenib in combination with cobimetinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 31, 2023): 825
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 2029
• Estimated Primary Completion Date: October 2029 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No

Contacts

Contact: Aida Sarmiento Castro; +442034695101; determine@cancer.org.uk

• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT05722886
• Other Study ID Numbers: CRUKD/21/004; IRAS ID: 1004057 ( Other Identifier: IRAS )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: 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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: All requests made within 5 years from last patient last visit for each of the treatment arms will be considered (refer to individual treatment arm records); requests made subsequently will be considered where possible.
• Access Criteria: When a request has been approved, Cancer Research UK will provide access to the de-identified individual patient-level data and appropriate supporting information. A signed Data Sharing Agreement must be in place before accessing requested information. Requests should be submitted to drugdev@cancer.org.uk

• Current Responsible Party: Cancer Research UK
• Original Responsible Party: Same as current
• Current Study Sponsor: Cancer Research UK
• Original Study Sponsor: Same as current

Collaborators

• University of Manchester
• University of Birmingham
• Royal Marsden NHS Foundation Trust
• Hoffmann-La Roche

Investigators

• Principal Investigator: Matthew Krebs, Prof; The Christie Hospital

• PRS Account: Cancer Research UK
• Verification Date: March 2024