| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced, unresectable or metastatic solid malignancies |
|
| E.1.1.1 | Medical condition in easily understood language |
| Inoperable or metastatic cancer |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 OMO-1 when given orally to patients with locally advanced, unresectable or metastatic solid malignancies, alone or in combination with anti-cancer treatments, and define the doses and schedules for further clinical evaluation |
|
| E.2.2 | Secondary objectives of the trial |
• To characterise the PK and pharmacodynamics (PDc) of OMO 1, following a single dose and/or at steady state after multiple dosing, when given orally alone or in combination with anti-cancer treatments.
• To assess the preliminary efficacy of OMO-1 by Response Evaluation Criteria In Solid Tumours (RECIST) 1.1. locally.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Module 1:
Primary Objectives:
• Parts A and B: To assess the safety and tolerability of OMO-1 when given alone in patients with locally advanced, unresectable or metastatic solid malignancies.
• Part B: To assess the preliminary efficacy of OMO-1 given orally as a single agent in patients with selected locally advanced, unresectable or metastatic solid malignancies.
Secondary Objectives:
• Part A: To determine the recommended dose and schedule of OMO-1 to take forward into Part B of the study module.
• Part A: To determine the dose(s) and schedule(s) of OMO-1 with which to begin to explore dose escalation of OMO-1 in combination with anti-cancer agents in further study modules.
• Part B: To refine the choice of tumour indications for controlled Phase 2 trial(s).
Module 2
Primary Objectives:
• Parts A and B: To assess the safety and tolerability of OMO-1 when given in combination with a small molecule EGFR-TKI in patients who have MET amplified tumours and whose disease is progressing on current EGFR TKI treatment.
• Part B: To assess the preliminary evidence of efficacy activity of OMO-1 when given in combination with a small molecule EGFR-TKI in patients who have MET amplified tumours and whose disease is progressing on current EGFR TKI treatment.
Secondary Objective:
• Part A: To determine the recommended dose and schedule of OMO-1 to take forward into Part B of the study module.
|
|
| E.3 | Principal inclusion criteria |
Core:
• Aged at least 18 years.
• Provision of signed and dated, written informed consent.
• Histological or cytological confirmation of locally advanced,
unresectable or metastatic solid malignancy
• Performance status: Eastern Co-operative Oncology Group (ECOG) ≤1
and life expectancy ≥3 months.
• Patients must have recovered from toxicities of prior therapies (i.e.
CTCAE Grade ≤1).
• Ability to swallow and retain oral medication.
• Adequate organ functions.
• Not receiving other cancer therapy, or other investigational product,
apart from the combination agent(s) described in the relevant
combination module(s).
• No radiotherapy for the primary tumour within 1 week from
screening visit.
• Not receiving medications predominantly metabolized by CYP2B6.
Washout period for medications predominantly metabolized by CYP2B6,
apart for tamoxifen, is 7 days prior to the first dose of study treatment.
Washout period for tamoxifen is 2 months prior to the first dose of study
treatment
• Not receiving cannabinoid substances and St. John's Wort.
Washout period for cannabinoid substances and St. John's Wort is 5 and
7 days respectively prior to the first dose of study treatment.
• Not receiving medication that are known to have potent aldehyde
oxidase (AO) inhibitory activity.
Washout period for medications that are known to have potent AO
inhibitory activity is 7 days prior to the first dose of study treatment.
• No prior splenectomy.
• No current or history of uveitis.
• No known uncontrolled inter-current illness including ongoing or
active infections, symptomatic congestive heart failure, conditions that
could adversely be affected by hypertension or tachycardia, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements.
• No history or clinical evidence of neoplastic central nervous system
(CNS) involvement if not stable for 9 weeks prior to the first dose of
study treatment.
Note: Patients with glioblastomas are allowed if their symptoms are
stable.
• No current or history of, any seizure or seizure disorder. This includes
receiving, or having received, seizure threshold-raising medication for
the treatment of epilepsy.
In addition to the main core eligibility criteria, module specific eligibility
criteria include:
Module 1:
Patient recruited into the sequential biopsy cohorts of Part A:
• At least 1 lesion suitable for biopsy.
• Tumours that are MET gene amplified and/or mutated.
(MET gene amplified and/or mutated status defined in the laboratory
manual).
• No prior therapy with a selective MET inhibitor.
Patients recruited into Part B cohorts:
• Tumours that are MET gene amplified and/or mutated.
(MET gene amplified and/or mutated status defined in the laboratory
manual).
• At least one lesion, not previously irradiated, that can be accurately
measured at baseline.
• No prior therapy with a selective MET inhibitor.
• No co-incident malignancy that would impact on survival.
• No metastasis limited to the bone only.
Module 2:
Patient recruited into both Part A and Part B:
• Tumours that are EGFR gene mutant that are currently progressing on
treatment with a small molecule EGFR-TKI (gefitinib, erlotinib, afatinib
or osimertinib administered as per the relevant medication package
insert, or recognised dose reduction in the case of afatinib). Enrolment
must be restricted to patients that are resistant to all relevant EGFR TKI
therapy according to their tumour mutated status.
• Received the EGFR-TKI as monotherapy for at least 12 weeks.
• Tolerated current dose of EGFR-TKI for at least 12 weeks.
• Tumours that are MET gene amplified
(MET gene amplified status defined in the laboratory manual).
• No prior therapy with a selective MET inhibitor.
• No prior EGFR-TKI treatment of >2 lines.
• No past medical history of interstitial lung disease (ILD), druginduced
ILD, radiation pneumonitis which required steroid treatment, or
any evidence of clinically active ILD.
• No significant gastrointestinal disorders with diarrhoea as a major
symptom, mal-absorption, or Common Terminology Criteria for Adverse
Events (CTCAE) Grade >2 diarrhoea of any aetiology.
In addition to the above inclusion criteria, additional criteria for patients
recruited into Part B:
• At least one lesion, not previously irradiated, that can be accurately
measured at baseline.
• No co-incident malignancy that would impact on survival.
• No metastasis limited to the bone only. |
|
| E.4 | Principal exclusion criteria |
1. Patients receiving other cancer therapy, or other investigational
product, apart from the combination agent(s) described in the relevant
combination module(s).
Note:
Bisphosphonates and granulocyte-colony stimulating factor (GCSF) are
acceptable.
Immunotherapy's such as mAbs, interferons and cytokines should not be
taken other than the combination therapy agent. Immunosuppressant's
such as cyclosporine, rapamycin, tacrolimus, rituximab, alemtuzumab,
natalizumab etc, should not be taken other than the combination therapy
agent.
Hormone replacement therapy (HRT) and stable treatment of >6 months
with luteinizing hormone releasing hormone (LHRH) analogues are
acceptable.
During the study period, patients using HRT and bisphosphonates should
maintain a constant dose and should not change existing regimen.
However, if a change in HRT is indicated, e.g. due to intolerable adverse
effects, the regimen may be modified but change should be minimized
thereafter.
Washout period for cytotoxic drugs and other mAbs is 21 days prior to
the first dose of study treatment. Washout period for approved
molecular targeted non-cytotoxic drugs is 5 half-lives prior to the first
dose of study treatment.
2. Patients who have received radiotherapy for the primary tumour
within 1 week from screening visit.
3. Patients receiving medications predominantly metabolized by
CYP2B6 (refer to Section 12.1 for more information).
Washout period for medications predominantly metabolized by CYP2B6,
apart for tamoxifen, is 7 days prior to the first dose of study treatment.
Washout period for tamoxifen is 2 months prior to the first dose of study
treatment.
4. Patients receiving cannabinoid substances.
Washout period for cannabinoid substances is 5 days prior to the first
dose of study treatment.
5. Patients receiving St. John's Wort.
Washout period for St. John's Wort is 7 days prior to the first dose of
study treatment.
6. Patients receiving medications that are known to have potent AO
inhibitory activity (refer to Section 12.1 for more information).
Washout period for medications that are known to have potent AO
inhibitory activity is 7 days prior to the first dose of study treatment.
7. Patients with prior splenectomy.
8. Patients testing positive for human immunodeficiency virus (HIV)
infection, hepatitis B based on findings of persistent hepatitis B virus
surface antigen (HBsAg) or other serology test, hepatitis C virus (HCV)
or Epstein-Barr Virus (EBV) infection.
9. Patients with current, or a history of, uveitis.
10. Patients with any known uncontrolled inter-current illness including
ongoing or active infections, symptomatic congestive heart failure,
conditions that could adversely be affected by hypertension or
tachycardia, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study
requirements.
11. Patients with a history or clinical evidence of neoplastic central
nervous system (CNS) involvement if not stable for 9 weeks prior to the
first dose of study treatment.
Note: Patients with glioblastomas are allowed if their symptoms are
stable.
12. Patients with major and/or planned surgery within 12 weeks of the
first dose of study treatment.
13. Patients with any known severe allergies (e.g., anaphylaxis) to any
active or inactive ingredients in OMO 1.
14. Patients with nephrolithiasis;
15. Patients with current, or a history of any seizure or seizure
disorder. This includes receiving, or having received, seizure thresholdraising
medication for the treatment of epilepsy.
In addition, the following are criteria for exclusion from the optional
exploratory genetic research:
16. Patients with previous allogenic bone marrow transplant.
17. Patients with non-leukocyte depleted whole bloodtransfusion
within 120 days of the date of the genetic sample collection. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Module 1:
Safety Endpoints
The following safety parameters will be assessed:
•Physical examination and ophthalmological examination, vital signs, and ECOG performance status
•12-lead ECG
•Laboratory parameters: Haematology, coagulation, clinical chemistry, serum renal markers, urinalysis, urine renal markers, and tumour markers (patients with relevant tumour types)
•Number of DLTs
•Adverse events (AEs) (graded by CTCAE) (including pregnancy)
•Number of withdrawals, discontinuations and dose reductions
Module 2
Safety Endpoints
The following safety parameters will be assessed:
• Physical examination and ophthalmological examination, vital signs, and ECOG performance status
• 12-lead ECG
• Laboratory parameters: Haematology, coagulation, clinical chemistry, serum renal markers, urinalysis, urine renal markers, and tumour markers (patients with relevant tumour types)
• Number of DLTs
• AEs (graded by CTCAE) (including pregnancy)
• Number of withdrawals, discontinuations and dose reductions
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The investigator will assess the safety end points at each visit. |
|
| E.5.2 | Secondary end point(s) |
Module 1:
Efficacy Endpoints
Key efficacy endpoints for Part A and Part B:
•Tumour response defined as:
oPartial CR using standard RECIST 1.1 criteria, providing ORR and DRR (refer to Section 22.8)
•Time to progression (TTP)
Pharmacokinetic Endpoints
•MBAD (as defined in Section 22.4.6.3.3)
•Dose linearity of PK parameters for doses up to and beyond MBAD
Pharmacodynamic Endpoints
•Tumour tissue PoM
oPaired tumour biopsies:
Reduction in % and intensity of phospho MET positive tumour cells (immunohistochemistry [IHC])
•Surrogate tissue PoP
oSerum:
Increase in serum creatinine (OCT 2 inhibition)
oPlasma:
Reduction in kynurenine/tryptophan ratio
Increased ratios between effector (CD8+) T cells and Tregs and between effector (CD8+) T cells CD4+ T cells
Decreased neutrophil- to- lymphocyte ratio (NLR) and other markers of inflammation (platelet-to-lymphocyte ratio [PLR]/systemic immune inflammation [SIII])
Modulation of ShedMET levels
Modulation of HGF levels
•Tumour tissue PoP
oPaired tumour biopsies (n=6 evaluable biopsy pairs):
Reduction in phenotypic biomarker (e.g. Ki67) in tumour cells
Increase in apoptosis biomarker (e.g. cleaved caspase) in tumour cells
Reduction in pERK in tumour cells
Reduction in pAKT in tumour cells
Reduction in pGAB2 in tumour cells
Reduction in TILs
Significant modulation of immune oncology biomarker panel (e.g. Nanostring immune-oncology profile)
Reduction of MET amp/mut cftDNA in patient positive for this at baseline
Module 2
Efficacy Endpoints
Key efficacy endpoints:
• Tumour response defined as:
o Partial or CR (RECIST 1.1), providing ORR and DRR (refer to Section 23.8)
• TTP
Pharmacokinetic Endpoints
• Dose linearity of PK parameters for doses for all doses of OMO 1
• Trough levels of the EGFR TKIs
Pharmacodynamic Endpoints
• Tumour tissue PoM
o Paired tumour biopsies:
Reduction in % and intensity of phospho MET positive tumour cells (IHC)
• Surrogate tissue PoP
o Plasma:
Decreased NLR
• Tumour tissue PoP
o Paired tumour biopsies (n=6 evaluable biopsy pairs):
Reduction in phenotypic biomarker (e.g. Ki67) in tumour cells
Increase in apoptosis biomarker (e.g. cleaved caspase) in tumour cells
Reduction in TILs
Significant modulation of immune oncology biomarker panel (e.g. Nanostring immune-oncology profile)
Reduction of MET amp cftDNA in patient positive for this at baseline
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The investigator will assess the efficacy, PDc and PK end points at varying visits as according to protocol version 22.8, 22.9, 22.10 (for module 1) and 23.8, 23.9, 23.10 (for module 2) |
|
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Belgium |
| France |
| Netherlands |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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 | 0 |
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