Adenocarcinoma or squamous cell carcinoma of the cervix Cancer
Conditions
Interventions
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 com
Sponsors
University of Southampton
Eligibility
Sex/Gender
Female
Age
16 Years to 100 Years
Inclusion criteria
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 45 Gy 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
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 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
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
England, Scotland, United Kingdom, Wales
Contacts
Public ContactMarina Lee
Outcome results
None listed