This is a Phase 1a/1b, first-in-human (FIH), open label study to evaluate the safety, tolerability, and pharmacokinetics (PK) of PMC-309, a mAb against the human VISTA ligand, in participants with advanced or metastatic solid tumors administered as a monotherapy and in combination with pembrolizumab.
Phase 1a is a 2-part dose escalation; both part will adopt the modified toxicity probability interval (mTPI) design with a dose limiting toxicity (DLT) rate of 30% for dose finding. * Part A is planned as a PMC-309 dose escalation. * Part B: is planned as a PMC-309 dose escalation in combination with pembrolizumab. Phase 1b is planned as a cohort expansion with PMC-309 administered as a monotherapy (Cohort A) at the preliminary recommended Phase 2 dose (RP2D) found at Phase 1a (Part A) and in combination with pembrolizumab (Cohort B) with PMC-309 at the maximum tolerated dose (MTD)/preliminary recommended Phase 2 dose (RP2D) found at Phase 1a (Part B). A minimum of 67 participants are to be enrolled to the study. Treatment Groups: Phase 1a Part A: PMC-309 Phase 1a Part B: PMC-309 + Pembrolizumab Phase 1b Cohort A: PMC-309 Phase 1b Cohort B: PMC-309 + Pembrolizumab Estimated overall study duration: approximately 2 to 6 years Dosing Cycle: the duration of a treatment cycle is 3 weeks/21 days.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
67
PMC-309 will be administered intravenously.
Both PMC-309 and pembrolizumab will be administered intravenously. At the time of the combination therapy (Week 1/Day 1 of each cycle), participants will be dosed with pembrolizumab(KEYTRUDA®) first, administered over 0.5 hours (± 10 minutes). Following an interval of 1 hour (± 15 minutes), participants will be dosed with PMC-309 administered over 1 hour (± 0.5 hours), after which participants will be observed for a period of 1.5 hours post administration.
Phase 1b will enroll participants with advanced or metastatic tumor types into 1 of 2 cohorts: * Cohort A: PMC-309 monotherapy therapy \- PMC-309 dosing will be at the preliminary RP2D, as identified in Phase 1a: Part A * Cohort B: PMC-309 plus pembrolizumab(KEYTRUDA®) combination therapy - PMC-309 dosing will be as identified in Phase 1a: Part B in combination with 200 mg pembrolizumab(KEYTRUDA®)
Australian Hospital Care (Pindara) PTY LTD. Trading as Pindara Private Hospital
Benowa, Queensland, Australia
RECRUITINGBallarat Regional Integrated Cancer Centre (Grampians Health)
Ballarat, Victoria, Australia
RECRUITINGCabrini Health Limited
Malvern, Victoria, Australia
Number of participants with abnormal vital signs in response ot treatment with PMC- 309
Vital signs will be assessed by changes in systolic/diastolic blood pressure, respiratory rate, body temperature and heart rate.
Time frame: Phase 1a and 1b- Upto 35 Cycles (each cycle is 21 days)
Number of participants with abnomal clinically significant results with physical examination in response to the treatment with PMC-309
A complete physical examinations of general appearance, head, ears, eyes, nose, throat, dentition, thyroid, chest (heart, lungs), abdomen, skin, neurological, extremities, back, neck, musculoskeletal, and lymph nodes.
Time frame: Phase 1a and 1b- Upto 35 Cycles (each cycle is 21 days)
Number of participants with abnormal clinically significant 12-lead electrocardiogram (ECG) parameters in response to treatment with PMC-309
The following ECG parameters will be recorded: heart rate, RR interval, HR interval, QTc interval, and QRS interval.
Time frame: Phase 1a and 1b- Upto 35 Cycles (each cycle is 21 days)
Number of participants with abnormal clinically significant laboratory results in response to treatment with PMC-309
Laboratory results will include biochemistry, Thyroid function test, hematology, coagulation and urinalysis
Time frame: Phase 1a and 1b- Upto 35 Cycles (each cycle is 21 days)
Number of participants with adverse events receiving treatment with PMC-309
Adverse events includes \[treatment-emergent AE, serious AEs, treatment-emergent AEs of special interest\] which will be coded using most current version of MedDRA.
Time frame: Phase 1a and 1b- Upto 35 Cycles (each cycle is 21 days)
Number of participants with abnormal changes in Eastern Cooperative Oncology Group (ECOG) performance status.
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Alfred Health
Melbourne, Victoria, Australia
RECRUITINGTime frame: Phase 1a and 1b- Screening
Number of participants with abnormal changes in Eastern Cooperative Oncology Group (ECOG) performance status.
Time frame: Day1 of every cycle (each cycle is 21 days)
To determine the maximum tolerated dose (MTD) of PMC-309 monotherapy (Part A) and establish the preliminary RP2D of PMC-309.
MTD of PMC-309 will be calculated by incidence of DLT at 21 days from the first dosing of PMC 309.
Time frame: Upto 21 days
To determine the MTD and establish the preliminary RP2D of PMC-309 when administered in combination with pembrolizumab at 200 mg (Part B).
MTD of PMC-309 by incidence of DLT at 21 days from the first dosing of PMC-309 in combination with pembrolizumab.
Time frame: Upto 21 Days
To assess the clinical efficacy of PMC-309 in the treatment of advanced or metastatic solid tumors by Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
RECIST consisting of overall response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) will be graded following CT/MRI of chest, abdomen and pelvis.
Time frame: Upto 35 Cycles (each cycle is 21 days)
The plasma pharmacokinetic endpoints of the study is assessed by peak serum concentration (Cmax)
Time frame: Upto 35 Cycles (each cycle is 21 Days)
The plasma pharmacokinetic endpoints of the study is assessed by time to peak plasma concentration (Tmax)
Time frame: Upto 35 Cycles (each cycle is 21 Days)
PK parameter assessed by serum concentration at specified timepoints for area under curve (AUC)
Time frame: Upto 35 Cycles (each cycle is 21 Days)
To assess the clinical efficacy of PMC-309 at the RP2D as a monotherapy and in combination with pembrolizumab
This will be assessed by RECIST v1.1.
Time frame: Upto 35 Cycles (each cycle is 21 Days)
PK parameter assessed by serum concentration over time of PMC-309 at the RP2D as a monotherapy and in combination with pembrolizumab.
Time frame: Upto 35 Cycles (each cycle is 21 Days)