E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic, Previously-Treated, Microsatellite-Stable Colorectal Carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Colorectal cancer that has been previously treated and has spread to other parts of the body |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061451 |
E.1.2 | Term | Colorectal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010036 |
E.1.2 | Term | Colorectal carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The objective of the Phase Ib element of this study is to define a tolerable combination dose schedule of CXD101 and nivolumab. The primary objective of the Phase II element of this study is to estimate the efficacy MSS CRC tumours of CXD101 in combination with nivolumab by measuring: • Immune Disease Control Rate (iDCR); (ie, complete response [iCR], partial response [iPR], and stable disease [iSD] rate) after Seymour et al, 2017.”
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives are to determine: -Overall survival -immune Objective Response Rate (iCR + iPR) -20-week immune-related progression-free survival -Safety
The exploratory objectives of this study are to evaluate tumoural expression of a range of immunological biomarkers (e.g., MHC I & II, PD1, and HR23B expression; T reg cell infiltrates; TAP expression; IL-6) and molecular analyses (mutation/ chromosomal/ epigenetic signatures, and gene expression profiles) that may correlate with effects of study treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Written informed consent -Biopsy-confirmed MSS, Mismatch Repair proficient (MMR-P) CRC -Previous first and second line treatment/adjuvant therapy, including use of oxaliplatin and irinotecan unless documented intolerance of these -Measurable disease: longest diameter≥10mm (short axis ≥15mm for nodal lesions) -Age >= 18 years -Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 -Predicted life expectancy > 3 months -Adequate organ and bone marrow function: Hb> 10.0g/dL (may be transfused to this level), neutrophils> 1.5x10^9/L and platelets> 100x10^9/L -Female patients with reproductive potential must have a negative urine and serum pregnancy test prior to starting treatment. -Both women of reproductive potential and men must agree to use a medically acceptable method of contraception throughout the treatment period and for 5 months after discontinuation of treatment -All males with partners of childbearing potential or whose partners are pregnant must use barrier contraception for the duration of dosing and for 5 months post-dosing. |
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E.4 | Principal exclusion criteria |
-Pregnant or breast feeding -Pre-existing auto-immune conditions -Medical conditions requiring systemic immunosuppression -Previous treatment with an HDAC inhibitor or PD1/PDL1 inhibitor -Other chemotherapy, radiotherapy, or investigational therapy within 4 weeks prior to the Screening /Baseline Assessment -Unresolved clinically significant toxicity from a previous treatment -History of recent active chronic inflammatory bowel disease and/or bowel obstruction -Renal function: Serum creatinine >= 1.5 x ULN, or creatinine clearance < 60mL/min (Cockcroft-Gault formula) -Liver function: AST > 3.0; OR total bilirubin >1.5 x ULN. For subjects with involvement of metastatic liver disease: AST > 5.0 x ULN; OR total bilirubin > 3.0 x ULN -Clinically significant myocardial infarction, severe/unstable angina pectoris, congestive heart failure NYHA Class III or IV, or pulmonary disease within 6 months -Symptomatic brain metastasis, uncontrolled seizure disorder, spinal cord compression, or carcinomatous meningitis -Clinically significant active infection requiring antibiotic or antiretroviral therapy -History of malignancy other than MSS CRC, unless there is the expectation that the malignancy has been cured, and tumour specific treatment for the malignancy has not been administered within the previous 5 years -History of pneumonitis, immune hepatitis or myocarditis, or current uncontrolled thyroid disease -Current positive serology for Hepatitis B or C virus -History of any allergy to excipients of the Investigational Medicinal Products (sodium citrate dihydrate, sodium chloride, mannitol, pentetic acid, Polysorbate 80, sodium hydroxide, hydrochloric acid, hydroxypropyl methylcellulose) -Receipt of any live vaccine 30 days or fewer prior to administration of first dose IMP -Inability to comply with the study protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint • Phase Ib: the tolerable combination dosing schedule of CXD101 and nivolumab • Phase II: Immune Disease Control Rate (DCR (ie, complete response [iCR], partial response [iPR], and stable disease [SD] rate) after Seymour et al, 2017
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary endpoints (Phase Ib and Phase II) • 20-week progression free survival (PFS) • Immune Objective Response Rate (iCR + iPR) • Overall Survival (OS) • Type, incidence, severity, seriousness and relationship to study medications of adverse events (AE) and any laboratory abnormalities |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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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 | 6 |
E.8.9.1 | In the Member State concerned days | |