A phase 1b TiTE-CRM dose escalation clinical trial of ASTX660 in combination with standard radical chemoradiotherapy in cervical cancer

Study ID: 51584
Short Title: CRAIN
Trust Name: UHS
Recruitment Site: Southampton General Hospital
Disease Area: Gynaecological cancers
Phase: I
Expected End Date: 01/09/2024
Postcode: SO16 6YD
Contact Name: Amanda Pattie
Contact Email: studysupport1and3.crnwessex@nihr.ac.uk
Active: Yes

Inclusion criteria, exclusion criteria and study summary

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 40mg/m2 ). 3. Adequate haematological parameters: • Haemoglobin ≥ 90 g/L • Neutrophil count ≥ 1.5 x 109/L • Platelets ≥ 100 x 109/L 4. Adequate biochemical parameters: • Bilirubin ≤ 1.5 x ULN • AST and ALT ≤2.0 x ULN • ALP ≤ 2.5 x ULN • Lipase and Amylase ≤1.2 x ULN • GFR Calculated (by Cockcroft-Gault formula or other accepted formula) or measured directly as ≥50 mL/min 5. Age 16 years or over. 6. ECOG Performance Status of 0-1. 7. Willing and able to give written informed consent.

1. Previous pelvic radiotherapy 2. Liver cirrhosis,or chronic liver disease Child-Pugh Class B or C 3. Women who are pregnant or breast feeding (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 (as detailed in section 4.6) 5. Any investigational medicinal product 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 corticosteroids (≥ 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 first dose of study treatment (tolinapant),as follows: a. Cytotoxic chemotherapy or radiotherapy within 3 weeks prior and any encountered treatment-related toxicities (excepting alopecia) not resolved to Grade 1 or less. b. Skin directed treatments,including topicals and radiation within 2 weeks prior. c. Monoclonal antibodies within 4 weeks prior and any encountered treatment-related toxicities not resolved to Grade 1 or less. d. 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. e. 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 local assessment). Any encountered treatment-related toxicities must have resolved to Grade ≤1. 14. Patients taking a QT prolonging agent (see appendix for example list). 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.

The primary objective of this phase 1b trial is to establish the maximum tolerated safe dose of tolinapant (ASTX660) in combination with Cisplatin and Radiotherapy (CRT) to aid dose selection for a phase II trial in women with histologically proven adenocarcinoma or squamous cell carcinoma of the cervix stage IB2/IIB/IIIB suitable for radical treatment with CRT. In addition to standard of care chemoradiotherapy participants will receive tolinapant for 7 consecutive days on weeks 1,3 and 5 of CRT treatment.

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