| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced or metastatic solid tumours and haematological malignancies |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced or metastatic (spread from a part of the body to another) solid tumours (abnormal malignant mass of tissue) and haematological malignancies (blood cancer) |
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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 | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066476 |
| E.1.2 | Term | Haematological malignancy |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I, Part A - Dose Escalation
• determine the MTD or RP2D of CB-103 as a single agent on 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 and anti-lymphoma activity of single agent CB-103 in the different expansion arms across the different indications |
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| E.2.2 | Secondary objectives of the trial |
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 and anti-lymphoma activity of single agent CB-103
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) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Disease
a.Patients with histologically or cytologically confirmed solid tumours that are surgically unresectable, locally advanced, or metastatic 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), sarcomas (osteosarcoma, liposarcoma, rhabdomyosarcoma, fibrosarcoma), desmoid tumours, adenoid cystic carcinoma, and malignant glomus tumour
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:
•Non-Hodgkin lymphomas (NHL): Follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma, nodal marginal zone lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma MCL), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL, ALK-positive and ALK-negative)
Specific criteria per type of lymphoma:
•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
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.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)
g.Patients in Part B: willing to provide a fresh pre-dose and, if feasible, on-treatment and an EOT tumour biopsy
h.Patients in Part A: must have sufficient archival tumour tissue samples preferably 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 ≤ 2.5xULN (if abnormalities are due to the underlying malignancy and known bone metastases, then ALP must be ≤ 5xULN)
f.AST/SGOT and ALT/SGPT ≤2.5xULN (if liver function abnormalities are due to the underlying malignancy and known hepatic metastases or bone metastases then AST and ALT must be ≤ 5xULN)
g.Serum creatinine ≤ 1.5xULN (if serum creatinine > 1.5xULN, then serum creatinine clearance (CrCl) ≥ 50 mL/min
h to k: Potassium, Total calcium (corrected for serum albumin), Magnesium and Phosphorus levels: within normal limits or correctable with supplements
l.Serum albumin concentration ≥ 30 g/L
m.Serum amylase and serum lipase ≤ ULN
n.PTT ≤ 1.5 x ULN and INR ≤ 1.3 (unless receiving therapeutic anticoagulants)
4.Contraceptive measures
a.Women of childbearing potential (serum pregnancy test performed within 7d before start of treatment, negative result must be documented)
b.Women of childbearing potential and men must agree to use at least two highly effective forms of contraception throughout the entire clinical trial period and for 90d post-treatment completion
c.Men whose partners could be of childbearing potential must routinely use a condom throughout the clinical trial period and for 90d post-treatment completion. The partner should also use a reliable form of contraception
d.Azoospermic males and females with sterilisation are exempt
e.Women who are continuously not heterosexually active are exempt (must still undergo pregnancy testing)
5.Informed consent
a.Ability to understand the patient information and ICF and comply with the protocol-related procedures
b.Signed and dated written informed consent obtained prior to performing any study-related procedure, including pre-screening (part B only) and screening
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| E.4 | Principal 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 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 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 atrial fibrillation
9.Clinically significant resting bradycardia (< 50 bpm)
10.Corrected QTcF > 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 < 50%. History of absolute decrease in LVEF of ≥ 15 absolute %, or ≥ 10 absolute % and crossing from > LLN to < LLN on prior anti-HER2 therapy, even if asymptomatic
14.Angina pectoris ≤ 6 months prior to starting CB-103
15.Acute myocardial infarction ≤ 6 months prior to starting CB-103
b.General conditions or other clinically significant diseases, including:
1.Haemorrhagic, embolic, or thrombotic stroke within 6 months prior to the first planned CB-103 infusion
2.Prior allogeneic bone marrow/haematopoietic stem cell transplant
3.Autologous haematopoietic stem cell transplant ≤ 6 months prior to starting study drug
4.Known infection with HIV or hepatitis B or C requiring treatment
5.Any active infection requiring the use of parenteral anti-microbial agents or > 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 (including NOTCH signalling inhibitors and prior treatments with CB-103) within 4 weeks of scheduled CB-103 dosing d1
e.PPIs and/or H2-blockers within ≥2 weeks of the scheduled first dose of CB-103 on d1
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-103 dosing day 1, unless the radiation comprised a limited field to non-visceral structures
h.Immunotherapy (including interferons, interleukins, immune-conjugates, immune checkpoint inhibitors), biological therapies (including monoclonal antibodies, antibody drug conjugates or other engineered proteins), targeted small molecules (including but not limited to kinase inhibitors), hormonal therapies within 3 weeks of scheduled CB-103 dosing day 1
i.Unresolved toxicity CTCAE grade >1 from previous anti-cancer therapy or radiotherapy (excluding neurotoxicity, alopecia, ototoxicity, lymphopenia), or incomplete recovery from previous surgery, unless agreed by Sponsor and Principal Investigator and documented
4.Concomitant medications
a.Drugs which prolong QT interval, either with a known or a conditional/ possible risk to induce Torsades de pointes
b.Acid reducing agents
c.Patients receiving warfarin and phenytoin that cannot be discontinued at least one week prior to start of treatment with CB-103 and for duration of study
d.Anticoagulants: Patients receiving coumarin-type anticoagulants who cannot discontinue at least one week prior to start of treatment and for the duration of the study. Low molecular weight heparin and direct oral anticoagulants are permitted
5.Demography
a.Patients who are pregnant or breast feeding
6.Others
a.Patients unable or unwilling to comply with all study requirements
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| E.5 End points |
| E.5.1 | 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 1.1)
‒ For non-Hodgkin lymphomas: to assess best overall response rate (CR + PR), assessed by Lugano Lymphoma classification
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I, Part A
Cyc1 d1, 2, 3, 8, 9, 15 & 22
Phase IIA, Part B
baseline, Cyc2 d15, after cycle 2 every 8 weeks until EOT or disease progression/overall survival
|
|
| E.5.2 | 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-∞), 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 non-Hodgkin lymphomas: to assess best overall response rate (CR + PR), assessed by Lugano Lymphoma classification
• To assess clinical benefit rate
‒ For solid tumour indications: clinical benefit rate (CR + PR + SD), assessed by RECIST 1.1.
‒ For non-Hodgkin lymphomas: clinical benefit rate (CR + PR + SD), assessed by Lugano Lymphoma classification
• Duration of response (DOR), time to response, progression-free survival (PFS), OS.
Exploratory endpoints:
• To assess plasma levels and PK parameters (Cmax, tmax, Cmin, Clast, tlast, AUC0-8, AUC0-24, AUC0–∞, 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 NOTCH target genes) assessed by Nanostring expression analysis from pre- to post- CB-103 treatment in tumour tissue samples, whole blood, plasma and hair follicles to determine on-target effects of CB-103.
• To assess NOTCH and NOTCH target genes expression (NOTCH1-4 receptors, NOTCH ligands, NICD1-4 and NOTCH target genes) assessed by Nanostring expression analysis in pre- and post-treatment tumour tissue samples, whole blood / plasma samples and hair follicles and assess relation to clinical activity of CB-103.
• To assess certain genotypes (e.g. cytochrome P450 enzymes or NAT) and assess relation to PK outcome data
• To assess NOTCH genetic aberrations in pre- and post-treatment tumour tissue samples, whole blood and hair follicles and assess relation to clinical activity of CB 103
• To assess NOTCH1-4 NICD expression assessed by IHC staining or by Western Blot in pre- and post-treatment tumour tissue samples and to assess relation to clinical activity of CB-103
• To assess genetic aberrations on DNA derived from blood samples (liquid biopsy with circulating tumour DNA and/or blood cell-derived DNA) and to assess relation to results from corresponding tumour tissue samples.
• To assess NOTCH mutations by genomic mutation analysis in tumour tissue samples and to assess relation to clinical activity of CB-103 treatment
• To assess change from baseline cardiac intervals versus increasing plasma CB 103 concentrations
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary
safety assess. incl. AE/SAEs: Scr., Base, Cyc1 d1, 2, 3, 8, 9, 15 & 22, Cyc2-6 d1 & 15, Cyc7+ d1, EoT, safety FU, unsched. V
ECOG perf and physic exam.: Scr., Base, Cyc1 d2, 3, 8, 15 & 22 (d2,3 part A only), Cyc2-6 d1 & 15, Cyc7+ d1, EoT, safety FU (only ECOG) and unsched. V
ECG: Scr., Cyc1 d1, 8, 15 & 22, Cyc2 d1 & 15 (d15 part A only), Cyc3+ d1, EoT and unsched. V
ECHO/MUGA: Base, Cyc1 d8, Cyc3 d1, EoT, unsched. V
plasma, pk: Cycle 1 days 1, 2, 3, 8, 9, 15 & 22, Cyc2-6 d1 & 15
tumour assess.: Base, Cyc2 d15, after cycle 2, every 8 weeks until EOT or disease progress./OS
pfs: EoT
Exploratory
Whole blood, plasma &: base, Cyc2-6 d1
Hair follicles: base, Cyc1-6 d1
Tumour biopsy: same as tumor assess.
Liquid biopsy: same as tumor assesment up to Cyc6, EoT, unsched. V |
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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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Switzerland |
| Netherlands |
| Spain |
|
| 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
|
| The end-of-study is reached when the last patient in Part B of the study has been on study treatment for up to 12 cycles plus the safety follow-up period of 28 days after the first dose of CB-103. In case the study is stopped before any patient was treated for 12 months, the end-of-study is reached 28 days after the last patient in Part B of the study has received his/her last dose of CB-103 |
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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 | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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