A Dose-Escalation Study of SPYK04 in Patients With Locally Advanced or Metastatic Solid Tumors (With Expansion).

Study Overview
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Brief Summary
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Phase I, open-label, multi-center study

Official Title
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A Phase I, Open-Label, Multicenter, Dose Escalation and Cohort Expansion Study of SPYK04 as Monotherapy in Patients With Locally Advanced or Metastatic Solid Tumors

Conditions
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Locally Advanced or Metastatic Solid Tumors

Intervention / Treatment
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* Drug: SPYK04


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (Both Part I and Part II) Age >= 18 years at time of signing informed consent form ECOG performance status of 0 or 1 Patients with a locally advanced, recurrent, or metastatic solid tumor for which standard therapy either does not exist or has proven ineffective or intolerable (Part I only) Patients with measurable and/or evaluable disease per RECIST v1.1 Patients with MAPK pathway alterations positive solid tumor (i.e., BRAF, K/N/H-RAS mutations) (Part II only) Patients with measurable disease per RECIST v1.1 Patients with KRAS mutated NSCLC (NSCLC cohort) Patients with KRAS mutated Ovarian Cancer (Ovarian Cancer cohort) Patients with RAS mutated solid tumor (Biopsy cohort) Exclusion Criteria: (Both Part I and Part II) Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), unstable angina, or myocardial infarction within the previous 6 months or unstable arrhythmias within the previous 3 months Patients with primary central nervous system (CNS) malignancy, untreated CNS metastases requiring any anti-tumor treatment, or active CNS metastases Patients with current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular disease, pulmonary disease, or renal disease, ongoing or active infection) Patients with a history or complication of interstitial lung disease (ILD)

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation cohort of SPYK04<br>Patients will receive SPYK04 at escalated dose. | Drug: SPYK04<br>* SPYK04 capsule<br>|
| Experimental: Expansion part in NSCLC, ovarian cancer and other solid tumors<br>Patients will receive SPYK04 at the recommended dose. | Drug: SPYK04<br>* SPYK04 capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of SPYK04 (Dose limiting toxicities) [Dose escalation] | Incidence and nature of DLTs | From first dose until the end of Cycle 1 (approximately 35 days) | 
| Safety and tolerability of SPYK04 (Adverse Events) [Dose escalation] | Incidence, nature, and severity of adverse events (AEs) as assessed by the NCI CTCAE v5.0 | From Cycle 0 Day 1 until 28 days after the last dose of study treatment, assessed up to 42 months (study completion) | 
| Safety and tolerability of SPYK04 (Electrocardiograms in triplicate) [Dose escalation] | Uncorrected QT interval, QTcF, PR duration, QRS interval and RR interval | From first dose until the end of Cycle 1 (approximately 35 days) | 
| Safety and tolerability of SPYK04 (Electrocardiograms in triplicate) [Dose escalation] | Heart Rate | From first dose until the end of Cycle 1 (approximately 35 days) | 
| Pharmacokinetics of SPYK04 [Dose escalation] | Plasma concentrations of SPYK04 | From Cycle 0 Day 1 until 28 days after the last dose of study treatment, assessed up to 42 months (study completion) | 
| Pharmacokinetics of SPYK04 [Dose escalation] | Maximum plasma concentration (Cmax) of SPYK04 | From Cycle 0 Day 1 until 28 days after the last dose of study treatment, assessed up to 42 months (study completion) | 
| Pharmacokinetics of SPYK04 [Dose escalation] | Time to reach maximum plasma drug concentration (Tmax) of SPYK04 | From Cycle 0 Day 1 until 28 days after the last dose of study treatment, assessed up to 42 months (study completion) | 
| Pharmacokinetics of SPYK04 [Dose escalation] | Area under the concentration versus time curve (AUC) of SPYK04 | From Cycle 0 Day 1 until 28 days after the last dose of study treatment, assessed up to 42 months (study completion) | 
| Preliminary anti-tumor activity of SPYK04 [Cohort expansion] | Objective Response Rate (ORR) is defined as proportion of patients who had a confirmed complete response (CR) or partial response (PR), as determined by the investigator with use of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) | From screening until disease progression, study discontinuation, withdrawal or death, whichever occurs first, assessed up to 42 months (study completion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary anti-tumor activity of SPYK04 [Dose escalation] | Objective Response | From screening until disease progression, study discontinuation, withdrawal or death, whichever occurs first, assessed up to 42 months (study completion) | 
| Safety and tolerability of SPYK04 (AEs) [Cohort expansion] | Incidence, nature, and severity of AEs assessed by the NCI CTCAE v5.0 | From Cycle 1 Day 1 until 28 days after the last dose of study treatment, assessed up to 42 months (study completion) | 
| Preliminary anti-tumor activity of SPYK04 [Cohort expansion] | Disease control rate (DCR) is defined as proportion of patients who had an objective response or stable disease (SD), as determined by the investigator with use of RECIST v1.1 | From screening until disease progression, study discontinuation, withdrawal or death, whichever occurs first, assessed up to 42 months (study completion) | 
| Preliminary anti-tumor activity of SPYK04 [Cohort expansion] | Progression-free survival (PFS) is defined as the time from the first study treatment to the first occurrence of progression as determined by the investigator using RECIST v1.1 or death from any cause, whichever occurs first | From screening until disease progression, study discontinuation, withdrawal or death, whichever occurs first, assessed up to 42 months (study completion) | 
| Preliminary anti-tumor activity of SPYK04 [Cohort expansion] | Duration of response (DoR) is defined for patients with a CR or PR at the time from the first documented CR or PR to documented disease progression as determined by the investigator with use of RECIST v1.1 or death from any cause, whichever occurs first | From screening until disease progression, study discontinuation, withdrawal or death, whichever occurs first, assessed up to 42 months (study completion) | 
| Pharmacokinetics of SPYK04 [Cohort expansion] | Plasma concentrations of SPYK04 | From Cycle 1 Day 1 until 28 days after the last dose of study treatment, assessed up to 42 months (study completion) | 
| Pharmacokinetics of SPYK04 [Cohort expansion] | Maximum plasma concentration (Cmax) of SPYK04 | From Cycle 1 Day 1 until 28 days after the last dose of study treatment, assessed up to 42 months (study completion) | 
| Pharmacokinetics of SPYK04 [Cohort expansion] | Time to reach maximum plasma drug concentration (Tmax) of SPYK04 | From Cycle 1 Day 1 until 28 days after the last dose of study treatment, assessed up to 42 months (study completion) | 
| Pharmacokinetics of SPYK04 [Cohort expansion] | Area under the concentration versus time curve (AUC) of SPYK04 | From Cycle 1 Day 1 until 28 days after the last dose of study treatment, assessed up to 42 months (study completion) | 
| Pharmacodynamics of SPYK04 [Cohort expansion] | Expression level of pMEK and pERK in solid tumor tissues (e.g., baseline archival or biopsy, and on treatment biopsy) | From screening until the time of partial response or stable disease lasting for more than 4 months, and the time of progressive disease, if possible, an average of 1 year |