PTC596 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1, open-label, first-in-human, safety and pharmacokinetic study of PTC596 in patients with advanced cancer.

Detailed Description
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This is a Phase 1, open-label, first-in-human, safety and pharmacokinetic (PK) study of PTC596 in patients with advanced cancer. A variation of the traditional 3+3 dose escalation design will be employed. PTC596 will be administered orally on a twice a week (biw) schedule. Each 4-week period of drug administration will be considered one cycle. The objective of the study will be to determine the recommended Phase 2 dose (RP2D) and to determine preliminary proof of mechanism of action. Collectively, data from the Good Laboratory Practice (GLP) and non-GLP studies indicate that 40 mg/kg biw is approximately the severely toxic dose in 10% of animals (STD 10). Therefore, the starting dose in this study will be calculated as one-tenth of the human equivalent dose (HED) of 40 mg/kg biw in rats, which is 0.65 mg/kg biw. In this study, escalating dose levels will be evaluated to determine the RP2D. Three patients will be enrolled at the starting dose level (0.65 mg/kg biw); if 1 of the 3 patients experiences a dose-limiting toxicity (DLT), an additional 3 patients will be enrolled at the same dose level. Thus, 3 to 6 patients will receive the starting dose level of 0.65 mg/kg. Dose escalation will continue until the occurrence of DLT in ≥2/6 patients at a given dose level. Dose escalation will occur in approximately 100% increments until Grade ≥2, first-cycle toxicity is seen in at least 2 patients across all dose levels, after which dose escalation will occur in smaller (50% or 33%) increments.

Official Title
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A Phase 1 Study of PTC596 in Patients With Advanced Solid Tumors

Conditions
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Cancer

Intervention / Treatment
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* Drug: PTC596


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed solid malignancy that is metastatic or unresectable, for which standard curative measures do not exist, that has progressed on at least one line of standard therapy or for which no standard therapies exists Discontinuation of all other therapies (including other investigational drugs, radiotherapy, or chemotherapy) for the treatment of cancer ≥4 weeks (≥6 weeks if nitrosoureas, ≥12 weeks if radiotherapy) before initiation of study treatment Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Life expectancy of at least 3 months A measured or estimated creatinine clearance (CrCl) ≥60 mL/min/1.73 m2 Exclusion Criteria: Prior bone marrow/hematopoietic stem cell transplantation History of solid organ, bone marrow, or progenitor cell transplantation History of major surgical procedure within 28 days prior to start of study treatment Evidence of ongoing systemic bacterial, fungal, or viral infection. Known human immunodeficiency virus (HIV) infection or acquired-immunodeficiency syndrome (AIDS)-related illness Any of the following in the past 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV), cerebrovascular accident, transient ischemic attack, other arterial thromboembolic event, or pulmonary embolism

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
Interventional Model Description: Open-label, first-in-human, safety and pharmacokinetic (PK)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>PTC 596 administered twice daily- Dose level 0.65mg/kg | Drug: PTC596<br>* PTC 596 will be administered orally twice a day until unmanageable toxicity, disease progression, or withdrawal of consent is noted<br>|
| Experimental: Cohort 2<br>PTC 596 administered twice daily-Dose level 1.3mg/kg | Drug: PTC596<br>* PTC 596 will be administered orally twice a day until unmanageable toxicity, disease progression, or withdrawal of consent is noted<br>|
| Experimental: Cohort 3<br>PTC 596 administered twice daily-2.6mg/kg | Drug: PTC596<br>* PTC 596 will be administered orally twice a day until unmanageable toxicity, disease progression, or withdrawal of consent is noted<br>|
| Experimental: Cohort 4<br>PTC 596 administered twice daily-Dose level 5.2mg/kg | Drug: PTC596<br>* PTC 596 will be administered orally twice a day until unmanageable toxicity, disease progression, or withdrawal of consent is noted<br>|
| Experimental: Cohort 5<br>PTC 596 administered twice daily-Dose level 10mg/kg | Drug: PTC596<br>* PTC 596 will be administered orally twice a day until unmanageable toxicity, disease progression, or withdrawal of consent is noted<br>|
| Experimental: Cohort 6<br>PTC 596 administered twice daily-Dose level 7mg/kg | Drug: PTC596<br>* PTC 596 will be administered orally twice a day until unmanageable toxicity, disease progression, or withdrawal of consent is noted<br>|
| Experimental: Cohort 7 (Bio Marker cohort)<br>PTC 596 administered twice daily-Dose level 5.2mg/kg | Drug: PTC596<br>* PTC 596 will be administered orally twice a day until unmanageable toxicity, disease progression, or withdrawal of consent is noted<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities | Determine the RP2D based on occurrence of DLTs and/or biological efficacy as determined by biomarker changes. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse effects | Define and describe the adverse effects of PTC596 in humans when orally administered on a biw schedule. | 28days | 
| Time to Maximum Plasma Concentration (T max) | Evaluate the Time to Maximum Plasma Concentration (T max) of PTC596 in humans. | 28days | 
| Antitumor activity | Describe any preliminary evidence of antitumor activity of PTC596. | 28days | 
| Maximum Plasma Concentration (C max) | Evaluate the Maximum Plasma Concentration (C max) of PTC596 in humans | 28 days | 
| Plasma Concentration at 24 hours | Evaluate the Plasma Concentration at 24 hours of PTC596 in humans | 28days | 
| Area under the plasma concentration-time curve (AUC) | Evaluate the area under the plasma concentration-time curve (AUC) of PTC 596 in humans. | 28 days | 
| Terminal half-life (t1/2). | Evaluate the terminal half-life (t1/2) of PTC 596 in humans. | 28 days. |