| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castrate Resistant Prostate Cancer (mCRPC) and other advanced cancers with solid tumours. |
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| E.1.1.1 | Medical condition in easily understood language |
Prostate cancer that has spread to other parts of the body beyond the prostate and continues to spread despite the use of hormone therapy.
Cancers which have solid tumours. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To investigate the safety and tolerability of CCS1477 given alone and in combination with abiraterone or enzalutamide.
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| E.2.2 | Secondary objectives of the trial |
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.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 of study treatment will receive a 4-week run-in treatment with abiraterone to confirm refractoriness to abiraterone treatment
Additional Part D inclusion criteria (CCS1477 plus enzalutamide)
16. Patients must have previously progressed on enzalutamide treatment
17. Patients whose last dose of enzalutamide is >6 months prior to start of study treatment will receive a 4-week run-in treatment with enzalutamide to confirm refractoriness to enzalutamide treatment. All patients in drug-drug interaction (DDI) arm will receive enzalutamide monotherapy during Cycle 0
Additional Part E inclusion criteria (non-prostate only)
18. Histological or cytological confirmation of malignancy that is advanced. Patients must be refractory to, or intolerant of, or refusing existing therapies known to provide clinical benefit for their condition
19. Identification of markers which may indicate potential for response to p300/CBP inhibition will be determined by local testing and will include, but not be limited to, loss of function mutations in either p300 or CBP and/or Myc amplification or over-expression, determined by next generation sequencing in tumour biopsies/cell free DNA extracted from a pre-treatment blood sample. IHC may also be used, as appropriate, to determine over expression of proteins such as myc or AR. Patients with certain cancers where molecular testing has not been performed may be eligible upon discussion with medical monitor. |
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| E.4 | Principal 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 inactive ingredients in the study medications
Additional exclusion criteria for patients in CCS1477 plus abiraterone combination arm (Part C)
10. Patients with clinically significant cardiac abnormalities as assessed by the treating physician that may include (but not be limited to) recent myocardial infarction (≤6 months) or unstable angina (≤3 months), New York Heart association (NYHA) class III or IV heart failure except if LVEF is ≥50%, clinically significant uncontrolled rhythm disturbances, and patients with uncontrolled hypertension
Additional exclusion criteria for patients in CCS1477 plus enzalutamide combination arm (Part D)
11. History of seizures or other predisposing factors including, but not limited to, underlying brain injury, stroke, primary brain tumours, brain metastases and leptomeningeal disease, or alcoholism
12. Use of substrates with a narrow therapeutic index metabolised by CYP2C9 or CYP2C19 within 2 weeks of the first dose of study treatment
13. Patients with clinically significant cardiac abnormalities as assessed by the treating physician that may include (but not be limited to) recent myocardial infarction (≤6 months) or unstable angina (≤3 months), New York Heart association (NYHA) class III or IV heart failure except if LVEF is ≥50%, clinically significant uncontrolled rhythm disturbances, and patients with uncontrolled hypertension |
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| E.5 End points |
| E.5.1 | 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.
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| E.5.1.1 | 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, Treatment discontinuation and the 28 day follow up. |
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| E.5.2 | 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). |
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| E.5.2.1 | 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 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| France |
| Germany |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study is defined as the later of the last patient completing study treatment and the 28-day follow-up visit or 9 months after the last patient has been enrolled. Overall survival will be collected for patients and collection of this data may continue after the last patient has completed study treatment. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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