| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic solid tumours and relapsed or refractory T-cell acute lymphoblastic leukaemia or T-cell lymphoblastic lymphoma that show Notch pathway activation. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Locally advanced or metastatic (spread from a part of the body to another) solid tumours (abnormal malignant mass of tissue) or cancers of the blood where Notch (a molecular pathway) is activated. |
|
| 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 | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066105 |
| E.1.2 | Term | T-cell lymphoblastic leukaemia acute |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025236 |
| E.1.2 | Term | Lymphoblastic lymphoma (Precursor B-lymphoblastic lymphoma/leukaemia) |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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:
• To determine the maximum tolerated dose (MTD) or recommended
phase 2 dose (RP2D) of CB-103 as a single agent in adult patients.
Phase I, Part A – Confirmatory Cohort:
• To confirm safety of the RP2D of CB-103 as a single agent in adult
patients.
Phase IIA, Part B - Expansion:
• To assess preliminary anti-tumour activity of single agent CB-103 in
the different expansion arms across the different indications. |
|
| 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 activity of single agent CB-103
Secondary objectives - part B only
• further characterise safety and tolerability of the MTD/RP2D of CB-103
in patients with selected solid tumours and haematological
malignancies, stratified by disease into separate expansion arms
Exploratory objectives
To characterise PK characteristics of CB-103 in subgroups of patients
(e.g., by indication or ethnicity) after single and repeated administration at various dose levels.
For the rest of exploratory objectives, please, refer to protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Disease
a. Histologically or cytologically confirmed solid tumours that are
surgically unresectable, locally advanced, or metastatic, which have
progressed on at least one line of systemic therapy (with the exception
of ACC patients who are allowed to be systemic treatment-naïve) and for
which no established therapeutic alternatives exist.
Or
b. Relapsed or refractory (r/r) T-ALL or T-LBL. Refractory patients are
defined as T-ALL/T-LBL patients with ≥ 5% bone marrow blasts, and/or concomitant extramedullary involvement, who have not
achieved a CR after standard induction/consolidation therapy attempt.
Relapsed patients are defined as T-ALL/T-LBL patients who have
recurrent disease, i.e. ≥ 5% bone marrow blasts and/or
concomitant extramedullary relapse, after having achieved a prior CR.
[For all other disease related inclusion criteria refer to protocol]
2. Demography
a. Men and women ≥ 18 years old on the day of signing informed
consent.
b. Eastern Cooperative Oncology Group (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 14
days of enrolment):
a. Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN)
b. Alkaline phosphatase (ALP) ≤ 2.5 x ULN; if liver function
abnormalities are due to the underlying malignancy and known bone
metastases, then ALP must be ≤ 5 x ULN
c. Serum aspartate aminotransferase (AST/SGOT) and alanine
aminotransferase (ALT/SGPT) ≤ 2.5 x ULN; if liver function
abnormalities are due to the underlying malignancy and known hepatic
metastases, then AST and ALT must be ≤ 5 x ULN
d. Serum creatinine ≤ 1.5 x ULN; or if serum creatinine > 1.5 x ULN, then
serum creatinine clearance (CrCl) ≥ 50 mL/min (estimated by Cockcroft-
Gault formula)
e. Potassium levels within normal limits or correctable with supplements
f. Total calcium levels (corrected for serum albumin) within normal limits
or correctable with supplements
g. Magnesium levels within normal limits or correctable with
supplements
h. Phosphorus levels within normal limits or correctable with
supplements
i. Serum albumin concentration ≥ 30 g/L
j. Patients with solid tumours must have:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Haemoglobin (Hgb) ≥ 10 g/dL (≥ 100 g/L)
• Platelet count ≥ 75 x 109/L (without platelet transfusion or growth
factor support in the preceding 7 days)
• Partial thromboplastin time (PTT) ≤ 1.5 x ULN and international
normalised ratio (INR) ≤ 1.3 (unless the patient is receiving therapeutic
anticoagulants)
4. Contraceptive measures
a. Women of childbearing potential must have a serum pregnancy test
performed within a maximum of 7 days before start of study treatment,
and a negative result must be documented before start of study
treatment.
b. Women of childbearing potential and men must agree to use at least
two highly effective forms of contraception (i.e., two of the following –
oral contraception, injectable contraceptives, mechanical contraception
including a condom for the partner, or an intrauterine coil) and must
continue using them throughout the entire clinical trial period and for 90
days post-treatment completion (duration of 3 ovulatory cycles).
Contraception must start from the day of 1st administration of CB-103.
c. Men whose partners could be of childbearing potential must routinely
use a condom throughout the entire clinical trial period and for 90 days
post-treatment completion (duration of sperm turnover). The partner
should also use a reliable form of contraception such as the oral
contraceptive pill or an intrauterine device.
d. Azoospermic males and females with sterilisation (e.g. tubal ligation)
are exempt from contraceptive requirements.
e. Women capable of becoming pregnant who are continuously not
heterosexually active are exempt from contraceptive requirements.
However, they must still undergo pregnancy testing as described in
inclusion criterion "4a".
5. Informed consent
a. Ability to understand the patient information and informed consent
form (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 A
- MTD/RP2D confirmatory cohort - and part B) and screening. |
|
| 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 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 (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 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-cancer therapy (e.g anti-HER therapy, anthracyclines),even if asymptomatic
14.Angina pectoris≤6 months prior to starting CB-103
15.Acute myocardial infarction≤6 months prior to startingCB-103
b.General conditions or other clinically significant diseases, including any one of the following:
1.Haemorrhagic, embolic, or thrombotic stroke within 6 months prior to the first planned CB-103 treatment
2.For patients with solid tumours: prior bone marrow/haematopoietic stem cell transplant
3.Known infection with HIV or hepatitis B or C requiring treatment
4.Any active infection requiring the use of parenteral anti-microbial agents or>Grade2
5.Non-malignant interstitial lung disease or pneumonitis
6.Dyspnoea of any cause requiring supplemental oxygen therapy and dyspnoea at rest due to complications of advanced malignancy and comorbidities
7.Significant traumatic injury or major surgery within 14d of scheduled dosing day 1
8.Other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol
3.Prior Therapy
a. In patients with solid tumours, cytotoxic chemotherapy within 3 weeks (6 weeks for nitrosoureas and mitomycin C) of the scheduled first dose of CB-103 on day 1.
b.In T-ALL/T-LBL patients, prior anti-cancer therapy less than 2 weeks prior to starting therapy or 5 half-lives (whichever is longer) with the following exceptions:
1. Up to 5 days of glucocorticoids (10 mg/m2 dexamethasone or equivalent/day) in combination with up to 3 doses of cyclophosphamide (200 mg/m2/day) are allowed as standard prephase treatment up to 1 day before start of study treatment
2. Mercaptopurine may be dosed up to 5 days prior to first dose of CB103
3. Vinca alkaloids may be dosed up to 5 days prior to first dose of CB103
4. Prophylactic IT chemotherapy may be dosed up to 3 days prior to first dose of CB103.
[Refer to protocol for further prior therapy exclusions]
4.Concomitant medications
a. Drugs which prolong QT interval, either with a known or a conditional/possible risk to induce Torsades de Pointes (a list of drugs is given in Appendix 4 of the protocol). However, in case of a life-threatening infection, in the best interest of the patient, concomitant treatment with the study drug and the relevant anti-infectious drug, though this may be included in the list given in Appendix 4, can be continued with closer monitoring.
b.Patients receiving warfarin and phenytoin that cannot be discontinued at least one week prior to start of treatment with CB-103 and for the duration of the study
c.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 who are unable or unwilling to comply with all study requirements for clinical visits, examinations, tests, and procedures |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I, Part A (dose excalation)
• The number of patients experiencing dose-limiting toxicity (DLT)
during the first 28 day cycle of CB-103 treatment
Phase I, Part A (confirmatory) of this study is as follows:
• 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
Phase IIA, Part B
• To assess tumour response rates in each expansion arm as best overall
response rate (in solid tumours complete response [CR] + partial
response [PR]) assessed by Response Evaluation Criteria in Solid
Tumours (RECIST 1.1); in T-ALL/T-LBL patients, confirmed CR and
Complete Remission with Incomplete Hematologic Recovery (CRi)
assessed by the criteria according to NCCN Guidelines on Adult Acute
Lymphoblastic Leukaemia (Version 1.2020). |
|
| 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 and after cycle 6 every 12 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 haematologic malignancies: to assess the best overall response rate (CR or CRi) per NCCN guidelines
• To assess clinical benefit rate
‒ For solid tumour indications: clinical benefit rate (CR + PR + SD), assessed by RECIST 1.1.
• 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 NOTCH, NOTCH-related genes and NOTCH target genes expression changes in pre- and post-treatment tumour
tissue samples, whole blood / plasma samples and hair follicles in solid tumours and in T-lymphocytes from blood and/or bone marrow samples, whole blood and plasma in T-ALL/T-LBL, and assess their relation to clinical activity of CB-103.
• To assess the cerebrospinal fluid (CSF) exposure of CB-103 in
haematological malignancies, in patients in whom IT prophylaxis is planned by the treating physician.
• To assess certain genotypes (e.g. cytochrome P450 enzymes or NAT) and assess relation to PK outcome data
• To assess NOTCH1-4 NICD expression assessed by IHC staining or by Western Blot in pre- and post-treatment in solid tumour tissue samples and to assess their relation to clinical activity of CB-103
• To assess NOTCH mutations by genomic mutation analysis in tumour tissue samples in solid tumours and in T-lymphocytes from blood and/or bone marrow samples, whole blood and plasma in T-ALL/T-LBL, and to assess their relation to clinical activity of CB-103 treatment.
• To assess the changes in the percentage of mutated alleles in liquid biopsies pre- and post CB-103 dosing and their relation to the effect of CB-103 treatment.
• To evaluate the intra-tumoral quantification of CB-103 in solid tumour tissue samples.
• To profile tumour tissue samples in solid tumours and T-lymphocytes from blood and/or bone marrow samples in T-ALL/T-LBL by single cell RNA-seq and/or other gene expression and genetic profiling techniques.
• To explore and assess changes in the immune system in pre- and post-CB-103 dosing whole blood and plasma (e.g., measure expression of cytokines/chemokines by RNA expression analysis, quantify proinflammatory and anti-inflammatory cytokines and chemokines, phenotype different types of immune cells (T cells, B cells, dendritic cells and macrophages, etc.) using flow cytometry).
• To assess change from baseline cardiac intervals versus increasing plasma CB-103 concentrations.
• To assess the metabolic profile of CB-103 in biological matrices such as urine and/or stool samples based on metabolic expressions of CB-103 in urine and/or stool samples |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Refer to schedule of assessments in protocol |
|
| 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 | 5 |
| 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 |
| China |
| Korea, Republic of |
| Taiwan |
| United States |
| Switzerland |
| Germany |
| 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 overall is reached when the last patient in Part B has
been on study treatment for up to 12 cycles (or after completion of the
treatment period in T-ALL/T-LBL patients as defined above) plus the
safety follow-up period of 28 days. 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. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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