advanced or metastatic solid tumours and haematological malignancies MedDRA version: 20.0 Level: LLT Classification code 10049280 Term: Solid tumour System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10066476 Term: Haematological malignancy System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Code: CB-103
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: not applicable
CAS Number: 218457-67-1
Current Sponsor code: CB-103
Concentration unit: mg milligram(s)
Concentration type:
Sponsors
Cellestia Biotech AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Disease a.Patients with histologically or cytologically confirmed solid tumours that are surgically unresectable, locally advanced, or metastatic and whose disease has progressed on at least one line of systemic therapy and for whom no standard curative therapy exists b.The following solid tumour indications are allowed to be enrolled into Part A: •Breast cancer (TNBC, ER+/-, HER2+/-), gastrointestinal (GI) cancers (colorectal cancer, CCC, gastric cancer), ovarian cancer, cervical cancer, prostate cancer, NSCLC (lung adenocarcinoma), melanoma, sarcomas (osteosarcoma, liposarcoma, rhabdomyosarcoma, fibrosarcoma), desmoid tumours, adenoid cystic carcinoma, and glioblastoma multiforme (GBM) c.Patients with histologically or cytologically confirmed, advanced haematological malignancies whose disease has relapsed or progressed upon standard therapy and for whom at that point no standard therapy exists: •Hodgkin lymphoma (HL) •Non-Hodgkin lymphomas (NHL): Follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma, marginal zone B-cell lymphoma (MZCL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma MCL), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), CNS lymphoma •Multiple myeloma (MM) Specific criteria per type of lymphoma: •HL: relapsed/refractory to at least two lines of treatment, among which includes brentuximab vedotin •B-cell NHL: relapsed/refractory upon at least one line of chemo-immunotherapy, no standard therapy available •T-cell NHL: relapsed/refractory upon at least one line of chemotherapy, no standard curative therapy available Specific criteria for multiple myeloma: •Relapsed/refractory to at least two lines of therapy, including both a proteasome inhibitor and an immunomodulatory agent (IMiD), and no standard alternative therapy available d.Solid tumours: =1 measurable lesion according to RECIST v1.1 guideline for solid tumours e.Lymphomas: =1 measurable lesion according to The Lugano Classification f.Multiple myeloma: must have measurable disease (serum M-protein = 10 g/L or urine M-protein = 200 mg/24 hours or abnormal free light chain (FLC) ratio with involved FLC > 100 mg/L) or proven plasmacytoma by biopsy) g.Patients in Part B: must have tumours characterised by activation of the NOTCH signalling pathway. All patients should have sufficient archival biopsy tissue not older than 6 months prior to pre-screening (or if not available-a fresh tumour biopsy must be taken) h.Patients in Part B: willing to provide a fresh pre-dose and, if feasible, on-treatment and an EOT tumour biopsy i.Patients in Part A: must have sufficient archival tumour tissue samples not older than 6 months prior to screening (or if not available a fresh pre-dose tumour biopsy) 2.Demography a.Men and women = 18 years old on the day of signing informed consent b.ECOG performance status 0 or 1 c.Patients able and willing to swallow capsules 3.Organ function and laboratory results Patients must have the following laboratory values (obtained within 14d of enrolment): a.ANC = 1.5x10^9/L (solid tumour indications) or = 1.0x10^9/L (haematological malignancies) b.Haemoglobin (Hgb) = 10 g/dL (= 100 g/L) c.Platelet count = 75 x 109/L (no platelet transfusion or growth factor support in the preceding 7d) d.Total serum bilirubin = 1.5xULN e.ALP, AST/SGOT and ALT/SGPT = 2.5xULN (if abnormalities are due to the underlying malignancy and known hepatic metastases, AST and ALT must be = 5xULN) f.Serum
Exclusion criteria
Exclusion criteria: 1.Medical History a.Patients with symptomatic CNS metastases (neurologically unstable or requiring increasing doses of steroids to control their CNS disease) b.Hypersensitivity to any of the excipients of CB-103 c.Patients with unresolved nausea, vomiting, or diarrhoea of CTCAE grade > 1 d.Impairment of GI function or presence of GI disease that may significantly alter the absorption of CB-103 e.History of second or other primary cancer with the exception of •Curatively treated non-melanomatous skin cancer •Curatively treated cervical cancer or breast carcinoma in situ •Other primary solid tumour treated with curative intent and no known active disease present and no treatment administered during the last 2 years 2.Exclusionary concurrent medical conditions a.Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: 1.Clinically significant cardiac disease including congestive heart failure (NYHA class III or IV), arrhythmia or conduction abnormality requiring medication, or cardiomyopathy 2.Clinically uncontrolled hypertension (blood pressure > 160/110 mmHg) 3.Complete left bundle branch block 4.Right bundle branch block + left anterior hemiblock 5.Mandatory use of a cardiac pacemaker 6.Congenital long QT syndrome 7.History or presence of sustained or symptomatic ventricular tachyarrhythmia 8.Presence of unstable atrial fibrillation (ventricular response > 110 bpm) 9.Clinically significant resting bradycardia ( 450 ms for males and > 470 ms for females at the screening ECG 11.QRS = 110 ms 12.History of symptomatic congestive heart failure 13.LVEF LLN to Grade 2 6.Non-malignant interstitial lung disease or pneumonitis 7.Dyspnoea of any cause requiring supplemental oxygen therapy and dyspnoea at rest due to complications of advanced malignancy and co-morbidities 8.Significant traumatic injury or major surgery within 14d of scheduled dosing day 1 9.Other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol 3.Prior Therapy a.Cytotoxic chemotherapy within 3 weeks (6 weeks for nitrosoureas and mitomycin C) of scheduled first dose of CB-103 on day 1 b.Prior cumulative doxorubicin exposure of = 450 mg/m2 c.Prior cumulative epirubicin exposure of = 900 mg/m2 d.Any investigational treatment within 4 weeks of scheduled CB-103 dosing day 1. e.Prior treatment with any NOTCH signalling inhibitor compound f.Concurrent enrolment in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo g.Radiation therapy within 2 weeks of scheduled CB-1
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I, Part A - Dose Escalation • determine the MTD or RP2D of CB-103 as a single agent when administered orally and with repeat dosing to adult patients with advanced or metastatic solid tumours and haematological malignancies, who have progressed despite curative therapy or for whom no curative therapy exists Phase IIA, Part B - Expansion • assess preliminary anti-tumour, anti-lymphoma and anti-myeloma activity of single agent CB-103 when administered orally and with repeat dosing in the different expansion arms across the different indications;Secondary Objective: Secondary objectives - part A&B • characterise the PK characteristics of CB-103 in patients after single and repeated administration at various dose levels Secondary objectives - Part A only • characterise safety and tolerability of the MTD/RP2D of CB-103 in patients with selected solid tumours and haematological malignancies • assess preliminary anti-tumour, anti-lymphoma and anti-myeloma activity of single agent CB-103 when administered orally and with repeat dosing Secondary objectives - part B only • characterise safety and tolerability of the MTD/RP2D of CB-103 in patients with selected solid tumours and haematological malignancies, stratified into separate expansion arms for the respective indications and with tumours characterised by genetic alterations and activation of the NOTCH pathway Exloratory objectives • explore potential correlations of PK, biomarkers, PD (genes/proteins) with safety and efficacy parameters in tissue samples (tumour, blood, hair follicles);Primary end point(s): Phase I, Part A • The number of patients experiencing dose-limiting toxicity (DLT) during the first 28 day cycle of CB-103 treatment Phase IIA, Part B • To assess tumour response rates in each expansion arm: ? For solid tumour indications: to assess best overall response rate (complete response [CR] + partial response [PR]), assessed by Response Evaluation Criteria in Solid Tumours (RECIST | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints - part A and B: • The incidence rate, severity and relationship to CB-103 of adverse drug reactions and serious drug reactions according to common terminology criteria for adverse events (CTCAE) V4.03, safety laboratory, vital signs, ECG and ECHO/MUGA assessments in each dose group and expansion arm. • CB-103 plasma concentrations, PK parameters: Cmax, tmax, area under the curve (AUC) during 8 and 24 hours (AUC0 8, AUC0 24), AUC from time 0 extrapolated to infinite time (AUC0-8), apparent volume of distribution (Vd/F), apparent volume of distribution at steady (Vss/F), apparent clearance after oral administration (CL/F), t1/2 and AR. Secondary endpoints - part A: • to assess tumour response rates ? For solid tumour indications: to assess best overall response rate (CR + PR), assessed by RECIST 1.1. ? For Hodgkin and non-Hodgkin lymphomas: to assess best overall response rate (CR + PR), assessed by Lugano Lymphoma classification ? For multiple myeloma: to assess best overall response rate (sCR + CR + VGPR + PR), assessed by IMWG uniform response criteria • To assess clinical benefit rate ? For solid tumour indications: clinical benefit rate (CR + PR + SD), assessed by RECIST 1.1. ? For Hodgkin and non-Hodgkin lymphomas: clinical benefit rate (CR + PR + SD), assessed by Lugano Lymphoma classification ? For multiple myeloma: clinical benefit rate (sCR + CR + VGPR + PR + SD), assessed by IMWG uniform response criteria • Duration of response (DOR), time to response, progression-free survival (PFS), OS. Exploratory endpoints: • To assess plasma levels and PK parameters (Cmax, tmax, AUC0-8, AUC0-24, AUC0–8, t1/2 and AR) of metabolite(s) when feasible • To evaluate the relationship between CB-103 plasma concentrations and/or PK parameters (eg, Cmax and AUC0-24) and safety, efficacy and PD parameters • To assess changes in the expression of NOTCH and NOTCH target genes (NOTCH1 4 receptors, NOTCH ligands, NICD1-4 and NOTC | — |
Countries
Germany, Netherlands, Spain, Switzerland
Contacts
Public ContactProject manager
Chiltern International
Outcome results
None listed