OMO-1 in Solid Malignancies

This is a modular, first time in patient, open-label, multicentre study of OMO-1, administered orally, alone and in combination with anti-cancer treatments, in patients with locally advanced, unresectable or metastatic solid malignancies.

The study will consist of a number of study modules. The initial Module 1 will evaluate OMO-1 as monotherapy to provide dose(s) and schedule(s) for further Modules of combination therapy.

Module 2 will evaluate OMO-1 in combination with small molecule EGFR-TKIs.

Study modules will consist of a Part A (dose finding) and an optional Part B (cohort expansion). The option to start Part B and add further modules will be the decision of the safety review committee, based on emerging preclinical anti-tumour data and, safety and tolerability information from the study as a whole.

For all modules, Part A cohorts may be expanded by up to 12 additional patients at doses (at or above the MBAD) that have been confirmed to be tolerated. These patients will have mandatory paired biopsies to assess the tumour for relevant PDc biomarkers, and to explore further the tolerability, safety and PK activity at these doses.

In all combination modules, the dose of each combination agent investigated will not exceed their current recommended dose. The starting dose of OMO-1 in combination modules will not exceed the one currently tolerated in Module 1 (monotherapy). For cohorts in which OMO-1 is dosed in combination with cytotoxic chemotherapy, dosing will not continue once the cycles of chemotherapy have been completed.

Eligibility Criteria:
Inclusion Criteria:

* 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.
* Ability to swallow and retain oral medication.
* Adequate organ functions.
* Females of child-bearing potential:

  * Must use a highly effective method contraceptive measures during the study and for 1 month after the last dose of OMO 1.
  * Must not be breast feeding.
  * Must have a negative pregnancy test prior to start of dosing.
* Sexually active male patients must be willing to use barrier contraception

Exclusion Criteria:

* Patients receiving other cancer therapy, or other investigational product apart from the combination agent(s) described in the relevant combination modules.
* Patients who have received radiotherapy for the primary tumour within 1 week from the screening visit.
* Patients receiving medications predominantly metabolized by CYP2B6.
* Patients receiving cannabinoid substances.
* Patients receiving St John's Wort.
* Patients receiving medications that are known to have potent aldehyde oxidase (AO) inhibitory activity.
* Patients with prior splenectomy.
* 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.
* Patients with current, or a history of uveitis.
* 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.
* 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.
* Patients with major and/or planned surgery within 12 weeks of the first dose of study treatment.
* Patients with any known severe allergies (e.g., anaphylaxis) to any active or inactive ingredients in OMO-1.
* Patients with nephrolithiasis.
* Patients with current, or a 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 paired biopsy cohorts of Part A must have:

* at least 1 lesion suitable for biopsy.
* tumours that are MET gene amplified and/or mutated.
* had no prior therapy with a selective MET inhibitor.

Patients recruited into Part B cohorts must have:

* tumours that are MET gene amplified and/or mutated.
* at least one lesion, not previously irradiated, that can be accurately measured at baseline.
* had no prior therapy with a selective MET inhibitor.
* no coinciding malignancy that would impact on survival.
* no metastasis limited to the bone only.

Module 2:

Patients recruited into Part A and Part B cohorts must have:

* tumours that are EGFR gene mutant that are currently progressing on treatment with a small molecule EGFR-TKI. 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 their current dose of EGFR-TKI for at least 12 weeks.
* tumours that are MET gene amplified.
* had no prior therapy with a selective MET inhibitor.
* had no prior EGFR-TKI treatment of \>2 lines.
* no past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
* no significant GI disorders with diarrhoea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE Grade \>1 diarrhoea of any aetiology at the enrolment.
* no contra-indications (as per the relevant medication package insert) for therapy with the EGFR-TKI routinely used by their oncology unit.

In addition, patients recruited into Module 2 Part B cohorts must have:

* at least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or MRI and which is suitable for accurate repeated assessment.
* no coinciding malignancy that would impact on survival.
* no metastasis limited to the bone only.