Study to Determine the Safety and Pharmacokinetics of DO-2 in Patients With Advanced or Refractory Solid Tumours

Study Overview
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Brief Summary
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This study is a first-in-human, open-label, 2-part, Phase 1 dose escalation study of DO-2, administered orally to patients with advanced or refractory solid tumours, with MET aberrations, and no available, approved therapeutic alternative.

Detailed Description
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In Part 1, a Simon Design 3 accelerated titration design will be followed. One patient will be enrolled per cohort, until grade 2 toxicity is observed. Three sequential patients per cohort will be enrolled thereafter, with a minimum of 1 week between first dose administration in the first patient and the subsequent ones, in those latter cohorts.

Official Title
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A Phase 1 Study to Determine the Safety, and Pharmacokinetics of the Selective MET Kinase Inhibitor, DO-2 in Patients With Advanced or Refractory Solid Tumours

Conditions
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Adult Solid Tumor, Refractory Tumor, Non-small Cell Lung Cancer, Advanced Solid Tumor, Non-small Cell Carcinoma, Lung Cancer, Hereditary Renal Papillary Cancer

Intervention / Treatment
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* Drug: DO-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older histologically or cytologically confirmed advanced or refractory solid tumour and no longer eligible for approved, available standard therapies. Tumour types must have: proven MET activating mutations, determined by previous next generation sequencing (NGS), whole exome sequencing (WES), whole transcriptome sequencing (WTS) or other genomic analysis methods, or proven amplification (≥ 10 copies) on archived tumour tissue. or Hereditary Renal Papillary Cancer Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 adequate bone marrow function, without the support of cytokines adequate liver function adequate renal function agree to follow the contraception requirements of the trial signed informed consent, indicating study patients understand the purpose of and procedures required for the study and are willing to participate in the study. Exclusion Criteria: major surgery within 3 weeks before enrollment chemotherapy (in the case of nitrosoureas and mitomycin C within 6 weeks), radiotherapy, immunotherapy, or any other study drug within 3 weeks before study drug administration antibody based cancer therapy within 4 weeks before administration of the first dose of DO-2 patients with brain metastases are excluded unless all of the following criteria are met: CNS lesions are asymptomatic and previously treated No ongoing requirement for corticosteroids as therapy for CNS metastases Imaging demonstrates stability of disease > 28 days from last treatment for CNS metastases leptomeningeal involvement (leptomeningeal carcinomatosis) history of uncontrolled heart disease including unstable angina, congestive heart failure, myocardial infarction within preceding 12 months, clinically significant rhythm or conduction abnormality, congenital long QT syndrome, obligate use of a cardiac pacemaker, QTc at screening greater than 450 milliseconds in males and greater than 470 milliseconds in females uncontrolled arterial hypertension despite appropriate therapy positive pregnancy test (urinary beta-hCG) at screening (applicable to women of child-bearing potential who are sexually active) mental status alteration or history of major psychiatric illness, which may potentially impair patient's compliance with study procedures signs and symptoms of active infection requiring systemic therapy other medical condition (e.g. pre-existing kidney dysfunction) that in the opinion of the investigator makes it undesirable for a patient to participate

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (starting dose)<br>Oral administration, once a day for 28 days, in a 4-week cycle | Drug: DO-2<br>* Deuterated MET kinase inhibitor<br>|
| Experimental: Cohort 2 (dose level 2)<br>Oral administration, once a day for 28 days, in a 4-week cycle | Drug: DO-2<br>* Deuterated MET kinase inhibitor<br>|
| Experimental: Cohort 3 (dose level 3)<br>Oral administration, once a day for 28 days, in a 4-week cycle | Drug: DO-2<br>* Deuterated MET kinase inhibitor<br>|
| Experimental: Cohort 4 (dose level 4)<br>Oral administration, once a day for 28 days, in a 4-week cycle | Drug: DO-2<br>* Deuterated MET kinase inhibitor<br>|
| Experimental: Cohort 5 (dose level 5)<br>Oral administration, once a day for 28 days, in a 4-week cycle | Drug: DO-2<br>* Deuterated MET kinase inhibitor<br>|
| Experimental: Cohort 6 (dose level 6)<br>Oral administration, once a day for 28 days, in a 4-week cycle | Drug: DO-2<br>* Deuterated MET kinase inhibitor<br>|
| Experimental: Cohort 7 (dose level 7)<br>Oral administration, once a day for 28 days, in a 4-week cycle | Drug: DO-2<br>* Deuterated MET kinase inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects who experience Dose Limiting Toxicities (DLTs) | Only toxicities that occur during Cycle 1 will be considered for the purposes of defining DLT and for dose escalation, but toxicities that occur in all cycles will be recorded and considered in decisions about the Maximum Tolerated Dose. DLTs are defined as toxicities that meet pre-defined severity criteria. Toxicity grading will be performed in accordance with NCI-CTC Version 5.0. | Baseline up to Week 4 | 
| Number of subjects who experience specific treatment-related adverse events (TRAEs) | Number of subjects with specific treatment-related adverse events for each dose group. AE refers to any untoward medical occurrence or deterioration of existing medical event after the subject signed the ICF, whether or not considered related to the study treatment. TRAEs are any event that occurs after the subject has received study treatment. AE grading will be performed in accordance with NCI-CTC Version 5.0. | Baseline up to Week 36 | 
| Determination of the Maximum Tolerated Dose (MTD) | The MTD in milligram is defined as the highest dose at which less than one third of the subjects in a dose level cohort experience DLT. | Baseline up to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration (Cmax) and Area under the curve (AUC) of DO-2 | Determine the Cmax and AUC of DO-2 and its main metabolites in plasma sampled at different timepoints during Cycle 1. | Baseline up to Day 23 | 
| Time over treshold (ToT) for DO-2 | Time by which the observed concentration of DO-2 in plasma is above the expected efficacy treshold. | Baseline up to Day 23 | 
| Objective responses seen in Part I and objective response rate (ORR) in Part II | ORR is defined as the proportion of subjects with confirmed CR or confirmed PR. Radiologic assessment will be repeated after every second cycle (or more frequently if clinically indicated) and using same methodology as at baseline. Response assessment (radiologic) will be determined in accordance with RECIST (version 1.1) and current disease specific solid tumour response criteria. | Baseline through study completion, an average of 36 weeks | 
| Duration of response (DoR) | DoR is defined as the duration from the first documentation of objective response to the first documented disease progression (based on RECIST Version 1.1) or death due to any cause, whichever occurs first. | Baseline through study completion, an average of 36 weeks | 
| Progression-free survival (PFS) | PFS is defined as the time from the start of treatment until the first documentation of disease progression or death due to any cause, whichever occurs first (based on RECIST Version 1.1). | Baseline through study completion, an average of 36 weeks | 
| Overall survival (OS) | OS defined as the time from the first dose to death from any cause. | Baseline through study completion, an average of 36 weeks |