Study of Oral PQR309 in Patients With Advanced Solid Tumors
- Registration Number
- NCT02483858
- Lead Sponsor
- PIQUR Therapeutics AG
- Brief Summary
This is an open-label, multi-center, non-randomized, dose escalation Phase 1 study evaluating safety, tolerability, PK (pharmacokinetics) and efficacy of PQR309 in the treatment of selected patients with advanced solid tumors.
- Detailed Description
This is an open-label, multi-center, non-randomized, dose escalation Phase 1 study evaluating safety, tolerability, PK (pharmacokinetics)and efficacy of PQR309 in the treatment of selected patients with advanced solid tumors.
In the initial phase of the study, patients will be treated once daily until disease progression, unacceptable toxicity, patient's request for withdrawal, investigator judgment or death whichever comes first. Enrollment of an initial patient cohort of 3 or 6 patients will follow the traditional 3 + 3 dose escalation scheme to evaluate Dose Levels 1 - 5 with continuous q.d dosing schedule. Patients will be treated with PQR309 at starting Dose Level 1 enrolling exceptionally 6 patients (only applicable for continuous dosing schedule). Subsequent patient cohort(s) will be enrolled depending on the safety and tolerability of the initial cohort. If \< 33% patients treated at Dose Level 1 (80 mg) experience Dose Limiting Toxicities (DLT - see definition below) by the end of first treatment cycle (21 days), next cohort of 3 patients will be enrolled and treated at Dose Level 2 of the continuous dosing schedule, if 2 or more treatment-related DLTs are observed at Dose Level 1, patients will be accrued to Dose Level -1. If 2 or more patients experience a DLT during dose Level 2 (120 mg), the dose of 100 mg will be explored next.The MTD is defined as the maximum dose level at which ≤ 1/6 patients have DLTs. After the MTD has been established with the continuous dosing schedule, the study will be expanded to evaluate the MTD of intermittent dosing schedules. Initially 2 additional dosing schedules, intermittent schedule A and B, will be evaluated in parallel. Patients will be assigned to the two schedules in an alternating manner.
Patients will be treated only within dose and schedule cohort they have been enrolled in. No within-patient dose escalation or alteration of dosing schedule will be allowed.Both schedules A and B will evaluate intermittent dosing in 21 day cycles:
Intermittent schedule A:
Two days of once daily PQR309 administration followed by no treatment for 5 days.
Intermittent schedule B:
PQR309 administration on Monday and Thursday. Same dose escalation procedures will apply to intermittent schedule evaluation as for the continuous schedule. Based on the overall evaluation of safety and tolerability, the PK (pharmacokinetics) data of the intermittent dosing schedules and the continuous schedule as well as PQR309 non-clinical data, evaluation of additional dosing schedules may be considered and investigated if agreed between sponsor and study investigators.
After the MTD has been established with the intermittent dosing schedules, the study will be expanded to evaluate the MTD of one selected schedule in patients with:
* Solid tumors with PI3K/mTOR pathway activation
* HPV positive HNSCC patients containing activating PIK3CA mutations Evaluation of the data from these cohorts will allow for more complete evaluation of tolerability, pharmacokinetics, and correlative endpoints as well as the preliminary clinical efficacy of PQR309.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 70
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description PQR309 PQR 309 Different dose Evaluation (continous and intermittent) 20-160mg daily
- Primary Outcome Measures
Name Time Method To identify the Maximum Tolerated Dose (MTD) of PQR309 administered in different (continuous and intermittent) dosing schedules. To evaluate efficacy of PQR309 in selected patient population: • Solid tumors with PI3K/mTOR activation • Human Papilloma In average 1 year MTD based on the rate of dose-limiting toxicities. The MTD is defined as the maximum dose level at which ≤ 1/6 patients have dose limiting toxicities (DLTs).
Objective response rate (ORR) according to the response evaluation• Solid tumors with PI3K/mTOR activation • Human Papilloma Virus (HPV) positive Head and neck squamous cell carcinoma (HNSCC) containing activating PIK3CA mutations in average 2 years Expansion part criteria in solid tumors (RECIST), version 1.1
- Secondary Outcome Measures
Name Time Method Number of patients with adverse Events and serious adverse events Assessment on Day 1 after basline, Cycle1 on Day 8,15, Cycle 2 and subsequent cycles on Day 1, End of the treatment up to 3 days and as follow up 30 days after last dosing "Monday/ Thursday"
Physical examination according to ECOG (Eastern Cooperative Oncology Group) Performance Status Assessment on Day1,2, Cycle 1 on Day 4,8,9,15 Intermittent Dosing "Monday/ Thursday"
Change in ECG After Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication Intermittent Dosing "2days on/5days off" and "Monday/ Thursday"
Depression test (PHQ-9) Cycle 1 on Day 8,15, Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication Intermittent Dosing "2days on/5days off" and "Monday/ Thursday"
Generalized anxiety disorder mood scale score (GAD7) Cycle 1 on Day 8,15, Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication Continous Dosing and Intermittent Dosing "2days on/5days off" and "Monday/ Thursday"
Changes in routine blood chemistry Assessment on Day 1 after baseline, Cycle 1 on Day 8,15, Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication Intermittent Dosing "Monday/ Thursday"
Changes of hematology Assessment on Day 1 after baseline, Cycle 1 on Day 8,15, Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication Intermittent Dosing "Monday/ Thursday"
Changes of insulin/Glucose/ C-peptide Assessment on Day 1,2 after baseline, Cycle1 on Day 4, 8,9,15 " Intermittent Dosing "Monday/ Thursday"
Changes of haemostasis Assessment on Day 1 after baseline, Cycle 1 on Day 1,15 Cycle 2 and subsequent cycles on Day1, end of treatment up to 3 days after last medication Intermittent Dosing "Monday/ Thursday"
Determination of Cmax Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15 Intermittent Dosing "Monday/ Thursday"
Determination of AUC 0-24 Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15 Intermittent Dosing "Monday/ Thursday"
Determination of tmax Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15 Intermittent Dosing "Monday/ Thursday"
Determination of AUClast (area under the curve) Assessment on Day 3,2,1 after baseline, Cycle 1 on Day 8,15, Cycle 2 on Day1 Continous Dosing
Determination of AUClast Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15 Intermittent Dosing "Monday/ Thursday"
Change in Pulse Rate Assessment on Day1,2,Cycle 1 on Day 4,8,9,15 Intermittent Dosing "Monday/ Thursday"
Change in Temperature Assessment on Day1,2,Cycle 1 on Day 4,8,9,15 Intermittent Dosing " Assessment on Day1,2,Cycle 1 on Day 4,8,9,15
Change in Respiratory Rate Assessment on Day1,2,Cycle 1 on Day 4,8,9,15 Intermittent Dosing " Monday/ Thursday"
Change in Blood Pressure Assessment on Day1,2,Cycle 1 on Day 4,8,9,15 Intermittent Dosing "Monday/ Thursday"
Change in Blood Body Weight Assessment on Day1,2,Cycle 1 on Day 4,8,9,15 Intermittent Dosing "Monday/ Thursday"
Determination of AUC0-∞ Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15 Intermittent Dosing "Monday/ Thursday"
Determination of t 1/2 Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15 Intermittent Dosing "Monday/ Thursday"
Determination of RAC (Accumulation Ratio) Assessment on Day 1,2 after baseline, Cycle 1 on Day 4,8,9,15 Intermittent Dosing "Monday/ Thursday"
Determine Time to Response (TTR) up to 2 years Efficacy
Determine Duration of Response (DOR) baseline and on Day 1 of every subsequential cycle which can be up to 24 months Defined as the time from the date of the first confirmed response to the first documentation of relapse or progressive disease, whichever occurs first
Time to Treatment Failure (TTF) Tumor Measurement preferably with a ruler and/or MRI scans e.g. and incorporated clinical signs will be assesses at baseline and on Day 1 of every subsequential cycle which can be up to 24 months Defined as the time from study entry to any treatment failure including disease progression or discontinuation of treatment for any reason (e.g., disease progression, AE, patient preference, initiation of new treatment without documented progression, death)
Determine Progression Free Survival (PFS) baseline and on Day 1 of every subsequential cycle which can be up to 24 months Defined as the time from study entry to progression or death due to any cause
1- year Survival Rate baseline and on Day 1 of every subsequential cycle which can be up to 36 months Defined as the time from study entry to death as a result of any cause at 1-year cutoff date
Trial Locations
- Locations (1)
M.D. Anderson Cancer Center
🇺🇸Houston, Texas, United States