Metastatic Castrate Resistant Prostate Cancer (mCRPC) and other advanced cancers with solid tumours.
Conditions
Interventions
Product Code: CCS1477
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: CCS1477
Current Sponsor code: CCS1477-M
Other descriptive name: Inhibitor of the bromodomain of p300 & CBP
Concentration u
Sponsors
CellCentric Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written informed consent; willing and and able to comply with study protocol procedures 3. = 18 years 4. ECOG performance status 0-1 with no deterioration over previous 2 weeks and minimum life expectancy of 12 weeks 5. Adequate organ functions: • AST/ALT =3 x ULN or AST/ALT =5 x ULN • Total bilirubin =1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin, patients with borderline elevation due to underlying liver involvement may be eligible). • Calculated creatinine clearance by Cockcroft-Gault formula =30 ml/min² • ANC =1.5 x 109/L • Platelets =100 x 109/L • Haemoglobin =9g/dL 6. For duration of the study and 1 week after the last study administration, sexually active male patients must be willing to use barrier contraception with all sexual partners. Where the sexual partner is a ‘woman of child-bearing potential’ who is not using effective contraception, men must use a condom and another form of contraception during the study and for 3 months after the last dose of study medication. 7. Females must agree to use highly effective contraceptive measures, must not be breast feeding and must have a negative serum pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential at screening per one of: • Post menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments • Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation • Amenorrhoeic for 12 months and serum FSH, LH and plasma oestradiol levels in the postmenopausal range for institution 8. Patients must have assessable disease (by CT, MRI, bone scan or X-ray) but are not required to have measurable disease Additional inclusion criteria for Parts A, B, C & D (mCRPC) 9. Patients must have previously received: • abiraterone and/or enzalutamide (or equivalent anti-androgen), and • a taxane (unless ineligible or refused) 10. Progressive disease documented by one or more of: • Biochemical progression defined as at least 2 stepwise increases in a series of any 3 PSA values collected while the patient has castrate levels of testosterone. The 3 PSA values selected do not need to be consecutive, and do not need to include the most recent PSA collected at, or prior to, study enrolment, but must meet the following criteria: a. PSA progression defined by minimum of 3 rising PSA levels with an interval of =1 week between each determination b. Each of the 3 PSA values must be collected while the patient is under medical castration or is surgically castrated c. Ideally all 3 should be done after anti-androgen withdrawal (if applicable), but they can be done during the withdrawal period • Progression as defined by RECIST v1.1 guideline for assessment of malignant soft tissue disease or modified RECIST v1.1 criteria as defined by PCWG-3 for progression of nodes • Progression defined as 2 or more new metastatic bone lesions confirmed on bone scan from a previous assessment 11. PSA at screening must be =2 µg/L (2 ng/mL) 12. Serum testosterone concentration =50 ng/dL sustained by medical or surgical castration 13. Serum albumin >2.5 g/dL Additional Part C inclusion criteria (CCS1477 plus abiraterone) 14. Patients must have previously progressed on abiraterone treatment 15. Patients whose last dose of abiraterone is >6 months prior to start
Exclusion criteria
Exclusion criteria: All Patients: 1. Intervention with any of the following • Any chemotherapy, investigational agents or other anti-cancer drugs within 14 days or 5 half-lives (whichever is longer of these two) of the first dose of study treatment (excludes treatment with immunotherapy agents which must be assessed on a case by case basis). This does not apply to prior treatment with abiraterone for patients in Part C1 or C2 or prior treatment with enzalutamide for patients in Part D1 (except patients in the DDI arm who must have a 4 week washout of enzalutamide prior to starting the study) and D2. • Radiotherapy with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks of the first dose of study treatment • Major surgical procedure or significant traumatic injury as judged by the investigator, within 4 weeks of the first dose of study treatment, or have an anticipated need for major surgery during the study • Strong inducers of CYP3A4 (See Appendix E) taken within 4 weeks of the first dose of study treatment or while on study treatment (excluding enzalutamide in Part D1 and D2 which does not require a 4 week wash-out prior to the first dose of study treatment, except for patients in the DDI arm). • Strong inhibitors of CYP3A4. CYP3A4 substrates with a narrow therapeutic range, CYP2C8 or CYP3A4 sensitive substrates (See Appendix E) taken within 2 weeks of the first dose of study treatment or while on study treatment. • Washout periods may be reduced for specific medications (eg. statins) following discussion with the medical monitor. • Herbal medications cannot be taken within 7 days of the first dose of study treatment (4 weeks for St John’s wort) or while on study treatment • Statins; patients should discontinue statins 5 half-lives prior to starting study treatment 2. Any unresolved reversible toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the exception of alopecia and neuropathy 3. Female patients who are pregnant or breast-feeding at study entry 4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator’s opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol, or active infection* including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). *Active viral infection is defined as requiring antiviral therapy. Screening for chronic conditions is not required 5. Patients with any known uncontrolled inter-current illness including ongoing or active clinically significant infections, symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements 6. Repeatable QTcF prolongation (>480 msec) 7. Prior malignancy that could affect compliance with the protocol or interpretation of results. Patients with a history of non-melanoma skin cancers or carcinoma in situ treated with curative intent, are generally eligible 8. Primary brain tumours or known or suspected brain metastases. Patients with brain metastases could be eligible if treated and stable within 28 days of the first dose of study treatment (after discussion and agreement with the CellCentric medical advisor). 9. Patients with any known severe allergies to any active or i
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate the safety and tolerability of CCS1477 given alone and in combination with abiraterone or enzalutamide. ;Secondary Objective: To investigate the efficacy of CCS1477 given alone and in combination with abiraterone or enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC). To understand how the body handles the study medication (pharmacokinetics) of CCS1477, following a single dose and after multiple dosing, when given on its own or in combination with abiraterone or enzalutamide. To understand the pharmacokinetics of abiraterone, enzalutamide and N-desmethyl enzalutamide when dosed in combination with CCS1477. To investigate the efficacy of CCS1477 in cancer patients with solid tumours with molecular markers which may indicate potential for response to p300/CBP inhibition. ;Primary end point(s): The primary outcome measure for the study is: Safety and tolerability of CCS1477 as monotherapy and in combination with abiraterone and enzalutamide. Safety and tolerability will be assessed in terms of AEs, laboratory data, vital signs and ECG changes. These will be collected for all patients. Appropriate summaries of these data will be presented. ;Timepoint(s) of evaluation of this end point: AEs will be discussed and recorded at every visit. Blood and urine samples for clinical chemistry, haematology, and urinalysis (dipstick) parameters will be taken at the following time-points: Screening, Cycle 1 – D1, D8, D15, D22, Cycle 2 onwards – Day 1 of every cycle, Treatment discontinuation and the 28 day follow up. Blood pressure, heart rate, respiration rate and temperature will be recorded at the following timepoints: Screening, Cycle 1 – Every visit (D1, D2, D8, D15, D22) – pre-dose, Cycle 2 onwards – Day 1 of every cycle and Treatment discontinuation. 12-lead ECGs will be performed at the following timepoints: Screening, Cycle 1 – D1 pre-dose and D8 pre-dose, Cycle 2 onwards – – Day 1 of every cycle, | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: PSA:Scr, C1 - D1, D8, D15 & D22, C2 + D1 of every Cycle & treatment discontinuation CTC:Scr, D1 C1; pre-dose, D1 C2; pre-dose, D1 C3; pre-dose, D1 C5; pre-dose & at progression or treatment discontinuation PK Blood-A, B, C, D & E C1 D1, 2 & 3 Pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10, 24 -D2 & 48hr -D3 pre-dose C1 D8 & 9 (A, B & E only) and C2 D1 & 2 (A, B, C, D & E) Pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 & 24hr - pre-dose DDI cohort C0 D1, C0 D29, C1 D1-2, C2 D3-4: Pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10, 24 hours PK Urine:0-6, 6-12 & 12-24 hrs after dosing on D8/9 of C1 - A, B & E CT/MRI & Bone Scan:BL, every 8 wks after D1 for 24 wks, then every 12 wks until progression OS until sufficient data collected;Secondary end point(s): Anti-tumour activity of CCS1477 as monotherapy or in combination with abiraterone or enzalutamide in patients with mCRPC. Anti-tumour activity defined by measurement of changes in: • circulating prostate-specific antigen (PSA). • circulating tumour cells (CTCs). • malignant soft tissue response rate (Response Evaluation Criteria in Solid Tumours [RECIST] v1.1). • metastatic bone disease status (Prostate Cancer Clinical Trial Working Group 3 [PCWG-3] bone scan criteria). To characterise the pharmacokinetics (PK) of CCS1477, following a single dose and at steady state after multiple dosing, when given as a single agent or in combination. To characterise the PK of abiraterone, enzalutamide and N-desmethyl enzalutamide when dosed in combination with CCS1477. Anti-tumour activity of CCS1477 in patients with p300 or CBP mutation positive tumours by measurement of changes in CTCs and response rate (RECIST v1.1 or appropriate tumour specific response criteria as appropriate). To obtain a preliminary assessment of the efficacy of CCS1477 as monotherapy and in combination with abiraterone or enzalutamide by evaluation of radiological progression free survival (rPFS) and overall survival (OS). | — |
Countries
France, Germany, Netherlands, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactClinical Trial Information
CellCentric Ltd
Outcome results
None listed