Clinical trial NCT05770102: DETERMINE Trial Treatment Arm 02: Atezolizumab in Adult, Paediatric and Teenage/Young Adult Patients With Cancers With High Tumour Mutational Burden (TMB) or Microsatellite Instability-high (MSI-high) or Proven Constitutional Mismatch Repair Deficiency (CMMRD) Disposition
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 02: Atezolizumab in Adult, Paediatric and Teenage/Young Adult Patients With Cancers With High TMB or MSI-high or Proven CMMRD Disposition.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Malignancy
Malignant Neoplasm
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms by Site
Cancer
Colorectal Neoplasms
Endometrial Neoplasms
Melanoma
Solid Tumours
Keywords: Adult
Antineoplastic Agents
Atezolizumab
Cancer
Child
Malignancy
Malignant Neoplasms
Molecular Targeted Therapy
Neoplasms by Histologic Type
Neoplasms by Site
Paediatric
Precision Medicine
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 atezolizumab. Atezolizumab is approved as standard of care treatment for adult patients with urothelial cancer, non-small cell lung cancer, extensive-stage small cell lung cancer, hepatocellular carcinoma and triple negative breast cancer. This means it has gone through clinical trials and been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK.

Atezolizumab works in patients with these types of cancers which have certain changes in the cancer cells called high tumour mutational burden (TMB) or high microsatellite instability (MSI) or proven (previously diagnosed) constitutional mismatch repair deficiency (CMMRD).

Investigators now wish to find out if it will be useful in treating patients with other cancer types which are also TMB/MSH-high or show CMMRD. 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 02 (atezolizumab) aims to evaluate the efficacy of atezolizumab in adult, paediatric and teenage/young adult (TYA) patients with rare\* cancers with high TMB or high MSI or proven CMMRD disposition and in common cancers where high TMB/MSI or proven CMMRD 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 participant based on molecularly-defined cohorts.

Screening: Consenting patients undergo biopsy and collection of blood samples for research purposes.

Treatment: Patients will receive atezolizumab 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 02 (ATEZOLIZUMAB) OUTLINED BELOW\*

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

Inclusion Criteria:

A. Confirmed diagnosis of a malignancy that is high TMB (defined as ≥10 mut/Mb), MSI-high or of proven (previously diagnosed) CMMRD disposition using an analytically validated method.

B. Women of childbearing potential are eligible provide they meet the following criteria:

* Have a negative serum or urine pregnancy test before enrolment and;
* Agree to use one form of 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 or without 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,

VIII. male or female condom with or without spermicide;

IX. cap, diaphragm or sponge with spermicide.

Effective from the first administration of atezolizumab, throughout the trial and for five months after the last administration of atezolizumab.

C. Male patients with partners who are women of childbearing potential are eligible provided that they agree to the following, from the first administration of atezolizumab, throughout the trial until the last administration of atezolizumab:

* 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 an effective method of contraception.
* 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. 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)

Lymphocyte count: ≥0.5 × 10\^9/L

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

Bilirubin: \<1.5 × upper limit of normal (ULN). Patients with known Gilbert disease: total bilirubin ≤3 × ULN

Serum albumin: ≥25 g/L (2.5 g/dL)

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 × ULN (unless patient is on anticoagulants, e.g. warfarin \[INR should be stable and within indicated therapeutic range\] or direct oral anticoagulants \[DOAC\]).

Amylase: ≤1.5 × ULN

Estimated glomerular filtration rate (eGFR): ≥30 mL/min

F. 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)

Lymphocyte Count: ≥0.5 × 10\^9/L

ANC: ≥1.0 × 10\^9/L (no GCSF support in preceding 72 hours)

Platelet count: ≥75 × 10\^9/L (unsupported for 72 hours)

Bilirubin: ≤1.5 × ULN for age with the following exception: Patients with known Gilbert disease: total bilirubin ≤3 × ULN.

Serum albumin: ≥25 g/L (2.5 g/dL)

ALT and AST: ≤2.5 × ULN for age or ≤5 × ULN if raised due to metastases.

Coagulation - PT (or INR) and aPTT: ≤1.5 × ULN (unless patient is on anticoagulants, e.g. warfarin \[INR should be stable and within indicated therapeutic range\], or DOAC).

Amylase: ≤1.5 × ULN

eGFR: \>60 mL/min (uncorrected value)

G. Patients must have stable thyroid function tests. Patients on stable doses of thyroxine replacement are permitted

Exclusion Criteria:

A. Diagnosis of urothelial cancer, non-small cell lung cancer, extensive-stage small cell lung cancer, hepatocellular carcinoma or triple negative breast cancer.

B. Patients with rapidly progressing or symptomatically brain metastases and/or leptomeningeal disease. 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 14 days prior to the start of IMP administration. 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 the start of IMP administration. Primary brain or central nervous system (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.

• Paediatric patients with either primary brain tumours or extracranial solid tumours with intracranial metastases with one or more intracranial lesions should only be considered for inclusion if largest intracranial lesion is ≤6 cm in longest axis. Consideration should also be given to the intracranial location of the tumour and potential risk should swelling occur. This is because of the class risk of immune checkpoint inhibitors such as atezolizumab causing immune-mediated inflammatory response and 'tumour flare' which may result in acute neurological deterioration.

C. Female patients who are pregnant, breastfeeding or planning to become pregnant during the trial or within five months following their last dose of atezolizumab.

D. History or clinical evidence of current inflammatory lung disease:

* History of idiopathic pulmonary fibrosis, organising pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis.
* Evidence of active pneumonitis on screening chest computed tomography (CT) scan.

E. Active autoimmune disease that requires the use of systemic immunomodulatory therapy (i.e. with disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy for hypothyroidism and adrenal or pituitary insufficiency is acceptable.

F. Ongoing lung pathologies which, in the opinion of the Investigator present a compromise to safety (e.g. active tuberculosis).

G. Systemic immunomodulatory agents within 14 days prior to trial entry (immunostimulatory agents within four weeks). Exceptions to this are:

* Patients who received acute, low dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g. 48 hours of corticosteroids for a contrast allergy) are eligible for the trial.
* Patients who received corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma equivalent to ≤10 mg prednisolone a day or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the trial.
* Patients with primary CNS disease can be receiving concurrent treatment with corticosteroids. Patients must be receiving a stable or decreasing dose for ≥14 days for adults and ≥7 days for paediatric patients prior to the screening magnetic resonance imaging (MRI) scan and at the time of drug initiation.
* Patients who receive physiological doses of steroid replacement (e.g. hydrocortisone) are permitted.

H. Known to be serologically positive (as detected by polymerase chain reaction) for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).

I. History of severe allergic anaphylactic reactions to chimeric, human or humanised antibodies, or fusion proteins including other immune checkpoint inhibitors.

J. Known hypersensitivity to Chinese hamster ovary cell products.

K. Known hypersensitivity to atezolizumab or any of the excipients.

L. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment, or anticipation of need for such a vaccine during atezolizumab treatment or within six months after the final dose of atezolizumab.

M. Patients with clinically significant pre-existing cardiac conditions, including uncontrolled or symptomatic angina, uncontrolled atrial or ventricular arrhythmias, or NYHA class III or IV congestive heart failure.

Patients with a cerebrovascular event (including stroke or transient ischaemic attacks \[TIA\]) or cardiovascular event (including acute myocardial infarction \[MI\]) within three months before the first dose of atezolizumab.

• Patients with primary CNS tumours may be considered unless intra-tumoural bleeding has occurred within 2 weeks of the first dose of atezolizumab, and patients with punctate CNS haemorrhages \<3 mm may be considered.

Patients with a prior history of pericardial disorders, including pericarditis, pericardial effusion and cardiac tamponade.

N. Prior allogeneic stem cell or solid organ transplantation on immunosuppression.

O. Prior treatment with the same class of drug unless genetic profile demonstrates a mechanism of resistance known to be potentially sensitive to atezolizumab.

P. Uncontrolled diabetes.

Q. 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.

R. Severe infection within four weeks prior to the first IMP administration or the administration of antibiotics within two weeks prior to the first IMP administration, with the exemption of patients requiring prophylaxis.

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 every 2 cycles of atezolizumab (each cycle is 21 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 atezolizumab for up to 2 years.
measure: Best percentage change in sum of target lesion / index lesion diameters (PCSD)
timeFrame: Disease assessment every 2 cycles of atezolizumab (each cycle is 21 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 atezolizumab for up to 2 years.
measure: Time to treatment discontinuation (TTD)
timeFrame: From first dose of atezolizumab to discontinuation of trial treatment up to 5 years.
measure: Progression-Free Survival time (PFS)
timeFrame: Disease assessment every 2 cycles of atezolizumab (each cycle is 21 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 atezolizumab for up to 2 years.
measure: Time to Progression (TTP)
timeFrame: Disease assessment every 2 cycles of atezolizumab (each cycle is 21 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 atezolizumab for up to 2 years.
measure: Growth Modulation Index (GMI)
timeFrame: Disease assessment every 2 cycles of atezolizumab (each cycle is 21 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 atezolizumab 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 90 days after last dose of atezolizumab (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 atezolizumab related AE
timeFrame: From the time of consent until 90 days after last dose of atezolizumab (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: 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 21 days) and at EoT visit (up to 5 years).
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 21 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 21 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 21 days) and at EoT visit (up to 5 years).
Other outcomes:
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: