An open-label phase Ib time-to-event continual reassessment method of dose-escalation of tolinapant (ASTX660) in combination with standard radical chemotherapy and radiotherapy in patients with cervical cancer
| ISRCTN | ISRCTN18574865 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN18574865 |
| EudraCT/CTIS number | 2021-006555-34 |
| IRAS number | 1004372 |
| Secondary identifying numbers | RHMCAN1680, IRAS 1004372, CPMS 51584 |
- Submission date
- 25/06/2022
- Registration date
- 30/08/2022
- Last edited
- 11/04/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English summary of protocol
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-tolinapant-and-chemoradiotherapy-for-cervical-cancer-that-has-spread-crain
Background and study aims
Cervical cancer affects over 3,000 women a year in the UK. Half of these women are below the age of 45 years. With current treatment, 1 in 3 women will die within 5 years. Current treatment for advanced cervical cancer combines external radiotherapy and chemotherapy (chemoradiation) followed by internal radiotherapy (brachytherapy). The chemotherapy agent used is cisplatin. The drug to be tested, tolinapant, works by blocking the activity of certain proteins that help cancer cells to survive. These proteins can cause cancer cells to die (known as apoptosis). The purpose of this study is to find the best dose of tolinapant to use with radiotherapy. This trial will also look at the side effects of this drug and ensure that the combination is worthwhile.
Who can participate?
Women aged 16 or over, who are scheduled to receive chemoradiotherapy treatment for cervical cancer
What does the study involve?
Patients providing their informed consent for the trial will all receive tolinapant with chemoradiotherapy. Patients will receive chemoradiotherapy as a normal treatment for 5 weeks. On weeks 1, 3 and 5 they will receive tolinapant treatment taken as a tablet. This will be followed by 2 weeks of brachytherapy. The patients will then be followed up 6 weeks and 12 weeks after finishing brachytherapy treatment.
There is also a translational aspect to the study, patients will be asked to provide blood samples at each visit for the translational analysis. Patients will be asked for their consent to send their pre-treatment diagnostic biopsy and to provide an additional biopsy following tolinapant and chemoradiation treatment. Patients will also undergo MRI scans with specific sequences which will be shared for research purposes if they chose to consent to this aspect of the trial.
What are the possible benefits and risks of participating?
We cannot guarantee any specific treatment benefits when taking part in a clinical trial. However possible trial benefits are:
1. You will have access to a drug that would not be available to you outside of the study. Your condition may improve and you may benefit from more frequent medical supervision.
2. The outcome of this trial may find that the combination of tolinapant and CRT works better than the standard CRT alone. This could help change the standard treatment given to patients with the same type of cancer as you in the future.
The main risks are potential side effects from the drug combination, as outlined in the patient information sheet. Patients will be encouraged to discuss these with the research team and the patient will be monitored regularly to assess any side effects of the treatment. The reason for this initial study is to be sure that we have a safe and tolerable treatment before further testing.
During the study, additional blood will be collected from a vein, which may cause pain where the needle is inserted. There is a small risk of bruising or infection at the site of insertion. Some people may experience dizziness, an upset stomach or fainting when blood is taken, however, every effort will be made by hospital staff to minimise this.
Where is the study run from?
University of Southampton (UK)
When is the study starting and how long is it expected to run for?
June 2022 to January 2026
Who is funding the study?
Cancer Research UK
Who is the main contact?
Mrs Marina Lee (UK)
crain@soton.ac.uk
Contact information
Public
MP131
Southampton General Hospital
Southampton
SO16 6YD
United Kingdom
| Phone | +44 (0)2381 205154 |
|---|---|
| crain@soton.ac.uk |
Principal Investigator
Faculty of Biology
Medicine and Health
The University of Manchester
Withington
Manchester
M20 4BX
United Kingdom
 ORCID ID |
0000-0001-8323-9567 |
|---|---|
| Phone | +44 (0)1614 468279 |
| peterhoskin@nhs.net |
Scientific
Faculty of Biology
Medicine and Health
The University of Manchester
Withington
Manchester
M20 4BX
United Kingdom
| Phone | +44 (0)1614 468279 |
|---|---|
| peterhoskin@nhs.net |
Study information
| Study design | Open-label dose-escalation phase Ib |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A phase Ib TiTE-CRM dose-escalation clinical trial of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer |
| Study acronym | CRAIN |
| Study objectives | 1. To establish the maximum tolerated safe dose of tolinapant in combination with cisplatin and radiotherapy (CRT) to aid dose selection for a phase II trial 2. To determine the safety and tolerability of tolinapant in combination with CRT 3. To assess how the tumour responds to tolinapant in combination with CRT 4. To ensure the addition of tolinapant does not interfere with planned delivery of CRT |
| Ethics approval(s) | Approved 12/08/2022, North West - Haydock Research Ethics Committee (3rd Floor - Barlow House, 4 Minshull Street, Manchester, M1 3DZ, UK; +44 (0)2071048248; haydock.rec@hra.nhs.uk), ref: 22/NW/0235 |
| Health condition(s) or problem(s) studied | Adenocarcinoma or squamous cell carcinoma of the cervix |
| Intervention | Cisplatin and radiotherapy (CRT) will be given using a standard dose of 45 Gy in 25 daily fractions over 5 weeks with once weekly cisplatin of 40 mg/m2. This is followed by brachytherapy for which common schedules will be a further 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed-dose capsules of 30 mg or 90 mg taken orally daily for seven consecutive days as an outpatient (followed by seven consecutive days off) prior to radiotherapy on alternate weeks (weeks 1, 3, 5) during chemoradiation. Patients will be followed up 6 and 12 weeks after radiotherapy treatment. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | Tolinapant (ASTX660), cisplatin |
| Primary outcome measure | 1. The rate of dose-limiting toxicities (DLTs), identified using CTCAE v5 as defined as per the protocol, at each dose level measured using a TiTE-CRM Bayesian model and assessed continually for 12 weeks from the start of treatment. Any of the following events occurring after the first dose of tolinapant will constitute a DLT if, in the opinion of the investigator, the event is defined as definitely or probably related to tolinapant: 1.1. Grade 4 neutropenia ≥7 days duration 1.2. Grade 3 or 4 febrile neutropenia (neutrophils <1000/mm3 with a single temperature of >38.3°C or a sustained temperature of ≥38°C for more than one hour AND/OR life-threatening consequences with urgent intervention indicated) 1.3. Grade 3 or 4 neutropenia associated with a separate event of bacteriologically proven sepsis happening at the same time 1.4. Grade 3 or 4 thrombocytopenia 1.5. Death 1.6. Any other grade 3 or 4 adverse event will constitute a DLT if, in the opinion of the investigator, the event is defined as definitely or probably related to tolinapant |
| Secondary outcome measures | 1. Drug-related adverse events (AEs) and serious AEs (SAEs), graded using CTCAE v5, assessed 3 months from completion of chemoradiation treatment 2. Response rate measured using MRI categorised using RECIST version 1.1 criteria at baseline, treatment week 5 and follow-up 2 3. Relative dose intensity of planned courses of CRT will be calculated and total chemotherapy delays will be assessed 3 months after the completion of chemoradiation treatment |
| Overall study start date | 23/06/2022 |
| Completion date | 31/01/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 16 Years |
| Sex | Female |
| Target number of participants | 42 |
| Total final enrolment | 11 |
| Key inclusion criteria | 1. Histologically confirmed adenocarcinoma or squamous cell carcinoma of the cervix stage IB2/IIB/IIIB 2. Suitable for radical treatment with radiotherapy and cisplatin (using a standard dose of 45Gy in 25 daily fractions over 5 weeks with weekly cisplatin 40 mg/m2) 3. Adequate haematological parameters: 3.1. Haemoglobin ≥ 90 g/l 3.2. Neutrophil count ≥ 1.5 x 109/l 3.3. Platelets ≥ 100 x 109/l 4. Adequate biochemical parameters: 4.1. Bilirubin ≤ 1.5 x ULN 4.2. AST and ALT ≤2.0 x ULN 4.3. ALP ≤ 2.5 x ULN 5. Lipase and Amylase ≤1.2 x ULN 6. GFR Calculated (by Cockcroft-Gault formula or other accepted formula) or measured directly as ≥ 50 mL/min 7. Aged 16 years and over 8. ECOG Performance Status of 0-1 9. Willing and able to give written informed consent |
| Key exclusion criteria | 1. Previous pelvic radiotherapy 2. Liver cirrhosis, or chronic liver disease Child-Pugh Class B or C 3. Pregnancy or breastfeeding (Women of child bearing potential (WOCBP) must have a negative serum pregnancy test at screening) 4. Patients of child-bearing potential who are not able to use a highly effective method of contraception 5. Any investigational medicinal product (IMP) within 30 days prior to consent 6. Major surgery within 30 days prior to enrolment 7. Hypersensitivity to tolinapant, excipients of the drug product, or other components of the study treatment regimen 8. Patients with known HIV infection 9. Patients with known active hepatitis B virus (HBV; chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test) or hepatitis C. Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody and the absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA 10. Coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable arrhythmias, unstable angina, left bundle branch block, third-degree heart block, pacemakers or congestive cardiac failure (New York Heart Association ≥ grade 2) within 6 months prior to enrolment 11. Any patient who has received a live vaccine within 4 weeks of initiation of their treatment (COVID-19 vaccination is allowed) 12. Conditions requiring systemic treatment with either corticosteroid (≥ 20 mg daily prednisolone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. 13. Prior anticancer treatments or therapies within the indicated time window prior to the first dose of study treatment (tolinapant), as follows: 13.1.Cytotoxic chemotherapy or radiotherapy within 3 weeks prior and any encountered treatment-related toxicities (excepting alopecia) not resolved to Grade 1 or less. 13.2. Skin-directed treatments, including topicals and radiation within 2 weeks prior 13.3. Monoclonal antibodies within 4 weeks prior and any encountered treatment-related toxicities not resolved to Grade 1 or less 13.4. Small molecules or biologics (investigational or approved) within the longer of 2 weeks or 5 half-lives prior to study treatment and any encountered treatment-related toxicities not resolved to Grade 1 or less 13.5. At least 6 weeks must have elapsed since CAR-T infusion and subjects must have experienced disease progression, and not have residual circulating CAR-T cells in peripheral blood (based on a local assessment). Any encountered treatment-related toxicities must have resolved to Grade ≤1. 14. Patients taking a QT-prolonging agent 15. Use of a concomitant medication which is a strong CYP3A4 inhibitor 16. Abnormal left ventricular ejection fraction (LVEF) of <50% on echocardiogram (ECHO) 17. History of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy 18. Screening 12-lead electrocardiogram (ECG) with measurable QTc interval of ≥470 msec (according to either Fridericia’s or Bazett’s correction) 19. Any other active malignancy |
| Date of first enrolment | 30/09/2022 |
| Date of final enrolment | 31/01/2025 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Withington
Manchester
M20 4BX
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
Harehills
Leeds
LS9 7TF
United Kingdom
Broomhall
Sheffield
S10 2SJ
United Kingdom
London
NW1 2BU
United Kingdom
Northwood
HA6 2RN
United Kingdom
Sponsor information
University/education
MP131
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
England
United Kingdom
| Phone | +44 (0)2381205154 |
|---|---|
| crain@soton.ac.uk | |
| Website | http://www.southampton.ac.uk/ |
"ROR" |
https://ror.org/01ryk1543 |
Funders
Funder type
Charity
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- CR_UK, Cancer Research UK - London, CRUK
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/01/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | 1. Peer-reviewed scientific journals 2. Conference presentation 3. Publication on website 4. Submission to regulatory authorities 5. Pseudonymised participant data within the clinical trial dataset will be available for sharing via controlled access by authorised SCTU staff. The request for data access will need to detail the specific requirements and the proposed research, statistical analysis, publication plan and evidence of research group qualifications. Data access requests will be reviewed against specific eligibility criteria by the SCTU data custodian and key members of the trial team. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be available upon request from Southampton Clinical Trials Unit (ctu@soton.ac.uk). As a minimum, anonymous data will be available for request from three months after the publication of an article, to researchers who provide a completed Data Sharing request form that describes a methodologically sound proposal, for the purpose of the approved proposal and if appropriate a signed Data Sharing Agreement. Data will be shared once all parties have signed relevant data-sharing documentation. Researchers interested in the trial data are asked to complete the Request for Data Sharing form [template located on the SCTU website, www.southampton.ac.uk/ctu] to provide a brief research proposal on how they wish to use the data. It will include; the objectives, what data are requested, timelines for use, intellectual property and publication rights, data release definition in the contract and participant informed consent etc. If considered necessary, a Data Sharing Agreement from Sponsor may be required. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol article | 07/06/2024 | 11/06/2024 | Yes | No |
Editorial Notes
11/04/2025: Total final enrolment added. The study participating centres were updated to add University College Hospital and Mount Vernon Cancer Centre and remove Velindre Hospital and Beatson West of Scotland Cancer Centre.
25/10/2024: The following changes were made to the study record:
1. The recruitment end date was changed from 15/09/2024 to 31/01/2025.
2. The overall study end date was changed from 13/10/2025 to 31/01/2026.
3. The intention to publish date was changed from 01/09/2026 to 31/01/2027.
11/06/2024: Publication reference added.
11/12/2023: The study website was added.
24/11/2023: Cancer Research UK plain English summary link added.
14/09/2022: Ethics approval details added. The recruitment start date was changed from 15/09/2022 to 30/09/2022.
05/09/2022: Internal review.
27/06/2022: Trial's existence confirmed by the HRA.
