Cancer, Colorectal Neoplasms, Endometrial Neoplasms, Lymphoproliferative Disorders, Malignancy, Malignant Neoplasm, Melanoma, Neoplasms by Histologic Type, Neoplasms by Site, Solid Tumours
Conditions
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
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 (MTB) 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 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.
Interventions
DRUGAtezolizumab
Adult patients will receive 1200 mg of atezolizumab intravenously every 21 days. Paediatric patients will receive atezolizumab at a dose of 15 mg/kg (maximum 1200 mg) every 21 days. Patients may continue on treatment until disease progression without clinical benefit, unacceptable AEs or withdrawal of consent.
Sponsors
University of Manchester
University of Birmingham
Royal Marsden NHS Foundation Trust
Hoffmann-La Roche
Cancer Research UK
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion 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 next-generation sequencing method. Patient cases with TMB between 10-15 mut/Mb may be discussed in an MTB meeting. TMB ≥19 mut/Mb will be fast-tracked for an MTB recommendation, unless there are any patient-specific individualities (such as multiple gene amplifications) that require MTB discussion. 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 at baseline and blood samples for translational research. 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. 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. F. PAEDIATRIC 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. Patients must have stable thyroid function tests. Patients on stable doses of thyroxine replacement are permitted.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response (OR) | Disease assessments to be performed up to 24 weeks from the start of trial treatment. | An OR is defined as the confirmed occurrence of either a Complete Response (CR) or Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 criteria (or immune related \[ir\]-RECIST or standard imaging criteria for specific disease e.g. Response Evaluation in Neuro Oncology criteria \[RANO\]). In patients with leukaemia, OR will be defined as the occurrence of CR, CRi (CR incomplete neutrophil recovery) or CRp (CR with incomplete platelet recovery). The trial will report the proportion of patients with an OR and 95% credible interval. |
| Durable Clinical Benefit (DCB) | Disease assessments to be performed up to 24 weeks from the start of trial treatment. | DCB is defined as the absence of disease progression for at least 24 weeks from the start of trial treatment according to RECIST Version 1.1 criteria (or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria) and, where relevant (e.g. for haematological malignancies), by standard bone marrow response assessment criteria. Alternative definitions of DCB based on different time points may be pre-specified for particular sub-cohorts if 24 weeks is not clinically relevant. The trial will report the proportion of patients with a DCB and 95% credible interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best percentage change in sum of target lesion / index lesion diameters (PCSD) | 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. | PCSD is defined as the greatest decrease or least increase in the sum of target lesion diameters (RECIST) or index lesion diameters (irRECIST) as a percentage compared to the baseline measurement. The trial will report the mean PCSD and 95% credible interval. |
| Time to treatment discontinuation (TTD) | From first dose of atezolizumab to discontinuation of trial treatment up to 5 years. | TTD is defined as the time from date of starting trial treatment to date of discontinuing trial treatment, in days estimated by the median of the posterior inverse gamma probability distribution. The trial will report the median TTD and 95% credible interval. |
| Progression-Free Survival time (PFS) | 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. | PFS is defined as the time from date of starting trial treatment to date of progression or date of death without a previous progression recorded estimated by the median of the posterior inverse gamma probability distribution. |
| Time to Progression (TTP) | 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. | TTP is defined as the time from date of starting trial treatment to date of progression or date of death without recorded progression censored rather than events. The trial will report the median TTP and 95% credible interval. |
| Growth Modulation Index (GMI) | 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. | GMI is defined as the ratio of TTP with the trial protocol treatment to TTP on the most recent prior line of therapy. The trial will report the mean GMI and 95% credible interval. |
| Occurrence of at least one Grade 3, 4 or 5 atezolizumab related AE | 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. | Number of patients who experience at least one atezolizumab related Grade 3, 4 or 5 AE according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0. |
| Occurrence of at least one Suspected Unexpected Serious Adverse Reaction (SUSAR) | 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. | The trial will report the number of patients who experience at least one SUSAR to atezolizumab. |
| EORTC-QLQ-C30 Standardised Area Under Summary Score Curve (QLQSAUC) in adult patients | QoL surveys performed prior to inclusion, every cycle (each cycle is 21 days) and at EoT visit (up to 5 years). | For adult populations, multiple measures of Quality of Life (QoL) will be generated from patient completion of the European Organisation for Research and Treatment of Cancer QLQ-C30 (EORTC-QLQ-C30) questionnaire (15 measures). For each patient the Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean QLQSAUC and 95% credible interval. |
| EQ-5D Standardised Area Under Index Value Curve (EQ5DSAUC) in adult patients. | QoL surveys performed prior to inclusion, every cycle (each cycle is 21 days) and at EoT visit (up to 5 years). | For adult populations, two measures of QoL will be generated from patient completion of the EQ-5D-5L questionnaire. For each measure, scores based on responses from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean EQ5DSAUC and 95% credible interval. |
| Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in paediatric patients. | QoL surveys performed prior to inclusion, every cycle (each cycle is 21 days) and at EoT visit (up to 5 years). | For paediatric populations multiple measures of QoL will be generated from patient completion of the PedsQL 4.0 (4 measures). The Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean PedsSAUC and 95% credible interval. |
| Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in parents of paediatric patients. | QoL surveys performed prior to inclusion, every cycle (each cycle is 21 days) and at EoT visit (up to 5 years). | For paediatric populations multiple measures of QoL will be generated from patient's parent completion of the PedsQL 4.0 (4 measures). The Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean PedsSAUC and 95% credible interval. |
| Overall Survival time (OS) | Time of death or up to 2 years after the EoT visit. | OS is defined as the time from date of starting trial treatment to date of death from any cause estimated by the median of the posterior normal probability distribution. |
| Duration of response (DR) | 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. | DR is defined as the time from the date of the first confirmed CR or PR according to RECIST 1.1 or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria to the date of disease progression. The trial will report the median DR and 95% credible interval. |
Countries
United Kingdom
Contacts
Primary ContactAida Sarmiento Castro
Outcome results
None listed