Advanced or Metastatic Solid Tumors
Conditions
Keywords
PMC-309 and Anti-VISTA
Brief summary
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.
Detailed description
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.
Interventions
DRUGPMC-309 monotherapy
PMC-309 will be administered intravenously.
DRUGPMC-309 Dose Escalation in Combination with Pembrolizumab(KEYTRUDA®)
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.
DRUGPMC-309 Dose Expansion
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®)
Sponsors
Novotech (Australia) Pty Limited
Merck Sharp & Dohme LLC
PharmAbcine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
To be eligible for this study, a participant must meet ALL of the following inclusion criteria: 1. The participant voluntarily signs an informed consent form (ICF) indicating they understand the purpose and procedures required for the study and are willing to participate in the study. 2. Are at least 18 years of age. 3. Are diagnosed with advanced or metastatic solid tumors (non-lymphoma) by histology or pathology that is metastatic or unresectable and considered relapsed and/or refractory to prior therapy. Definition of anti-PD-1/L1 refractory participant: Participants must have progressed on treatment with an anti-PD1/L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria: 1. Has received at least 2 doses of an approved anti-PD-1/L1 mAb. 2. Has demonstrated disease progression (PD) after PD-1/L1 as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression. 3. PD has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb. i. PD is determined according to iRECIST v1.1. ii. This determination is made by the PI (or designee). Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression 4. Have measurable disease per RECIST v1.1 documented by computerized tomography scan (CT scan) and/or magnetic resonance imaging (MRI), measurable at Baseline. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 5. Have an ECOG performance status of 0 or 1. 6. Can satisfy the following criteria in hematologic, renal, and hepatic function tests performed within 7 days prior to screening: 1. Hematologic tests: * ANC more than and equal to 1.5 × 109 per L. * Platelets more than and equal to 100 × 109 per L. * Hemoglobin more than and equal to 9.0 g per dL or more than and equal to 5.6 mmol per L. Note: Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants can be on a stable dose of erythropoietin (more than equal to approximately 3 months). 2. Blood coagulation tests: * Prothrombin time less than and equal to 1.5 × upper limit of normal (ULN). * Activated partial thromboplastin time less than and equal to 1.5 × ULN. 3. Hepatic function tests: * Total bilirubin less than and equal to 1.5 × ULN or direct bilirubin less than and equal to ULN for participants with total bilirubin levels more than and equal to 1.5 × ULN. * Aspartate aminotransferase or alanine aminotransferase less than and equal to 2.5 × ULN (less than and equal to 5× ULN in case of liver metastasis). 4. Renal function test: * less than and equal to 1.5 × ULN or creatinine clearance more than and equal to 30 mL/min for participant with creatinine levels above 1.5 × institutional ULN. 7. Are willing and able to adhere to the prohibitions and restrictions as specified in the study protocol. 8. Eligible participants (male and female) of childbearing potential must agree to use reliable contraception (hormone, barrier method, or abstinence) from Screening (Day -1) until at least 120 days after administration of the last dose of the IP. 9. Women of childbearing potential (WOCBP) must have a negative urine pregnancy test at Screening (Day -1) and be willing to have additional pregnancy tests as required throughout the study. 10. Human immunodeficiency virus (HIV) infected participants must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined as: 1. Participants on ART must have a CD4+ T-cell count 350 cells/mm3 at time of Screening. 2. Participants on ART must have achieved and maintained virologic suppression defined as confirmed by HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of Screening and for at least 12 weeks prior to Screening. 3. Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1).
Exclusion criteria
A participant who meets ANY of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To determine the MTD and establish the preliminary RP2D of PMC-309 when administered in combination with pembrolizumab at 200 mg (Part B). | Upto 21 Days | MTD of PMC-309 by incidence of DLT at 21 days from the first dosing of PMC-309 in combination with pembrolizumab. |
| Number of participants with abnomal clinically significant results with physical examination in response to the treatment with PMC-309 | Phase 1a and 1b- Upto 35 Cycles (each cycle is 21 days) | 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. |
| Number of participants with abnormal clinically significant 12-lead electrocardiogram (ECG) parameters in response to treatment with PMC-309 | Phase 1a and 1b- Upto 35 Cycles (each cycle is 21 days) | The following ECG parameters will be recorded: heart rate, RR interval, HR interval, QTc interval, and QRS interval. |
| Number of participants with abnormal clinically significant laboratory results in response to treatment with PMC-309 | Phase 1a and 1b- Upto 35 Cycles (each cycle is 21 days) | Laboratory results will include biochemistry, Thyroid function test, hematology, coagulation and urinalysis |
| Number of participants with adverse events receiving treatment with PMC-309 | Phase 1a and 1b- Upto 35 Cycles (each cycle is 21 days) | Adverse events includes \[treatment-emergent AE, serious AEs, treatment-emergent AEs of special interest\] which will be coded using most current version of MedDRA. |
| Number of participants with abnormal changes in Eastern Cooperative Oncology Group (ECOG) performance status. | Phase 1a and 1b- Screening | — |
| To determine the maximum tolerated dose (MTD) of PMC-309 monotherapy (Part A) and establish the preliminary RP2D of PMC-309. | Upto 21 days | MTD of PMC-309 will be calculated by incidence of DLT at 21 days from the first dosing of PMC 309. |
| Number of participants with abnormal vital signs in response ot treatment with PMC- 309 | Phase 1a and 1b- Upto 35 Cycles (each cycle is 21 days) | Vital signs will be assessed by changes in systolic/diastolic blood pressure, respiratory rate, body temperature and heart rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The plasma pharmacokinetic endpoints of the study is assessed by peak serum concentration (Cmax) | Upto 35 Cycles (each cycle is 21 Days) | — |
| The plasma pharmacokinetic endpoints of the study is assessed by time to peak plasma concentration (Tmax) | Upto 35 Cycles (each cycle is 21 Days) | — |
| PK parameter assessed by serum concentration at specified timepoints for area under curve (AUC) | 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 | Upto 35 Cycles (each cycle is 21 Days) | This will be assessed by RECIST v1.1. |
| PK parameter assessed by serum concentration over time of PMC-309 at the RP2D as a monotherapy and in combination with pembrolizumab. | Upto 35 Cycles (each cycle is 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) | Upto 35 Cycles (each cycle is 21 days) | 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. |
Countries
Australia
Contacts
Primary ContactHyojin Koh, Dr
Outcome results
None listed