OMX-0407 Phase I Study

Prior treatment

• Untreated CNS metastases. Patients with CNS metastases that have completed treatment at least two weeks previously and have either an unchanging or no neurological deficit whilst not receiving corticosteroid therapy are eligible. Patients with known CNS metastases must have received CNS directed therapy and not systemic therapy alone to be eligible for the study.
• Additional Exclusion Criteria for Cohort Expansion Phase: ccRCC, sqNSCLC and UC > More than 3 previous lines of therapy in an unresectable or metastatic setting.
• Chronic anticoagulant therapy that cannot be discontinued for tumour biopsy if necessary.
• Treatment within 5 terminal half-lives (if known) or within the last 30 days prior to Day 1 of Cycle 1, whatever is shorter, with anti-cancer or investigational drugs.

Other illness

• History of ventricular arrhythmia within the last five years. Known untreated aberrant preexcitation pathways such as Wolf-Parkinson-White syndrome. Ongoing atrial fibrillation unless the ventricular rate is controlled by medical therapy.
• Unstable hypertension requiring changes in antihypertensive medication within the preceding three months, Myocardial Infarction or Cerebrovascular accident within the preceding three months. Cardiac failure New York Heart Association (NYHA) Grade III or IV.
• Additional Exclusion Criteria for Cohort Expansion Phase: ccRCC > Uncontrolled hypertension defined as persistent blood pressure (BP) greater than diastolic 90 mm Hg and systolic 150 mm Hg
• Allergy to OMX-0407 or any of its excipients.
• Persistent fever or other signs of uncontrolled infection.

Lab values

• Creatinine clearance by Cockcroft-Gault formula or local equivalent < 45 ml/min.
• History of long QT syndrome.
• Left ventricular ejection fraction (LVEF) < 50%
• Either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 upper limit of normal (ULN) unless in the presence of hepatic metastases when AST or ALT as high as 5 ULN is acceptable. Serum bilirubin > 1.5 ULN unless in the presence of hepatic metastases when serum bilirubin as high as 3 x ULN is acceptable. Patients with isolated increases in alkaline phosphatase (ALP) are eligible for the study.
• Prothrombin Time or equivalent such as international normalized ratio (INR) or the Quick test > 1.5 ULN.
• Activated partial thromboplastin time (PTT) > 1.5 ULN.

Other

• QTcF of greater than 450 ms (men) or 460 ms (women) (mean of three readings performed two to five minutes apart).
• Live vaccinations in the preceding four weeks of Day 1 of Cycle 1.

• General Inclusion Criteria for both Dose Escalation and Cohort Expansion Phases : Age ≥18 years (≥16 years for the AS expansion cohort) and willing to provide informed consent for the study.
• Additional Inclusion Criteria For Cohort Expansion Phase: ccRCC > Prior histological confirmation of ccRCC. In the case of mixed histology in order to be eligible at least 70% of reviewed tumour should be of clear cell histology.
• Patients with known renal vascular involvement should be on stable anticoagulation at the start of treatment with OMX-0407. (Note: Tumour/skin biopsies should be performed prior to the onset of anticoagulation, if possible).
• Previous treatment must include PD-1 blockade and VEGFR inhibition (unless contraindicated or not reimbursed).
• Additional Inclusion Criteria for Cohort Expansion Phase: sqNSCLC > Prior histological confirmation of sqNSCLC. Patients with mixed histology tumours must have predominantly squamous histology (unless contraindicated or not reimbursed).
• Previous treatment must include PD-1 blockade and platinum chemotherapy.
• Patients with known oncogenic drivers including EGFR mutations ALK genomic rearrangements must have received prior directed therapy (unless contraindicated or not reimbursed)..
• Additional Inclusion Criteria for Cohort Expansion Phase: UC > Prior histological confirmation of UC.
• Previous treatment must include platinum-based chemotherapy PD-1 blockade and a Nectin A4 targeting agent (unless contraindicated or not reimbursed).
• Additional Inclusion Criteria for Cohort Expansion Phase: AS > Clinical and histopathological confirmation of advanced/metastatic or unresectable visceral AS, cutaneous AS secondary to radiotherapy or other cutaneous AS.
• Patients should have progressive disease (PD) according to the discretion of the investigator.
• Cytological or pathological confirmation of advanced cancer.
• Patient has received at least one prior line of systemic therapy for metastatic or unresectable disease which must have included a taxane or an anthracycline (unless contraindicated or not reimbursed).
• Willingness to undergo serial tumour biopsies before and during study treatment. Patient will still be eligible if the investigator deems the biopsy procedure to be an unacceptable health risk to the patient.
• Patients treated in three patient cohorts onwards will be required to provide either archival tumour material or be willing to undergo a core biopsy to provide tumour material during screening.
• Patients should have completed or be unsuitable for licensed therapies for their primary cancer unless such therapies are not available according to local practice – for example not reimbursed or included in treatment guidelines. All patients must have received at least one previous line of systemic therapy for the tumour type under investigation. Patients who according to their treating physician are unsuitable for an existing licensed therapy are eligible for the study.
• ECOG performance status 0, 1 or 2 for the dose escalation phase. Patients treated in the cohort expansion phase of the study should have an ECOG Performance status of 0 or 1.
• Able to swallow oral medication with no existing evidence of underlying gastrointestinal malabsorption or abnormal gastrointestinal transit.
• For female patients and male partners of childbearing potential, willingness and able to use two forms of highly effective contraception methods (e.g., oral contraceptive and condom, intra-uterine device, and condom) while on study and for 30 days after the last study treatment. For male patients and female partners of childbearing potential, willingness and able to use two forms of highly effective contraception methods (e.g., oral contraceptive and condom, intra-uterine device, and condom) while on study and for 3 months after the last study treatment. Women who last experienced menses more than one year previously or who have undergone bilateral ovariectomy, hysterectomy or tubal ligation which is documented in their medical notes do not require to use contraception during or after treatment with OMX-0407. Male patients who have previously undergone vasectomy are not required to use contraception.
• All toxicity from previous anti-cancer therapy including radiotherapy must have recovered to either Grade 1 or stable (at least 3 weeks) Grade 2 (CTCAE v5.0).
• Patients should have at least evaluable tumour by iRECIST criteria. Patients treated in the Cohort Expansion phases of the study must have measurable disease.