A Phase 1a/1b, First-in-Human, Open Label Study to Assess the Safety, Tolerability, and Pharmacokinetics of PMC-309 (Anti-VISTA), as Monotherapy and Combined With Pembrolizumab, in Patients With Advanced or Metastatic Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- PMC-309 monotherapy
- Conditions
- Advanced or Metastatic Solid Tumors
- Sponsor
- PharmAbcine
- Enrollment
- 67
- Locations
- 4
- Primary Endpoint
- Number of participants with abnormal vital signs in response ot treatment with PMC- 309
- Status
- Recruiting
- Last Updated
- 4 months ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •To be eligible for this study, a participant must meet ALL of the following inclusion criteria:
- •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.
- •Are at least 18 years of age.
- •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:
- •Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
- •Has demonstrated disease progression (PD) after PD-1/L1 as defined by RECIST v1.
- •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.
- •PD has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb.
Exclusion Criteria
- •A participant who meets ANY of the following exclusion criteria must be excluded from the study:
- •Has received treatment with a VISTA targeting agent.
- •Has a history of positive testing for hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-hepatitis C virus) or other clinically active liver disease, or positive testing at Screening for HBsAg or anti- hepatitis C virus.
- •HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
- •Has a medical condition which, in the opinion of the PI (or designee), places the participant at an unacceptably high risk for toxicity.
- •Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
- •Is currently participating in or has participated in a study of an investigational agent or have received anticancer immunotherapy within 4 weeks prior to the first dose of IP.
- •Has an active autoimmune disease with a history of flares requiring immunosuppressant medications within the past 6 months or that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
- •History of known or suspected seizure disorder.
- •Has oxygen-dependent chronic disease.
Arms & Interventions
Phase 1 a: Part A: PMC-309 Monotherapy Dose Escalation
Phase 1a will enroll participants with advanced or metastatic solid tumors to assess safety, tolerability, PK and clinical efficacy in response to treatment with PMC-309 as a monotherapy Dosage form and Route of administration: The duration of a treatment cycle is 3 weeks/21 days. Participants will be administered a weekly dose of PMC-309 per cycle as follows: * Cycle Week 1/Day 1 * Cycle Week 2/Day 8 ± 2 days * Cycle Week 3/Day 15 ± 2 days PMC-309 will be administered intravenously over 1 hour (± 0.5 hours), after which participants will be observed for a period of 1.5 hours post administration.
Intervention: PMC-309 monotherapy
Phase 1a: Part B: PMC-309 Dose Escalation in Combination with Pembrolizumab
Part B will establish the MTD/preliminary RP2D of PMC-309 when administered in combination with 200 mg pembrolizumab. Part B will be conducted after completion of Part A (PMC-309 monotherapy dose escalation) and before the commencement of Phase 1b. Dosage form and Route of administration: The duration of a treatment cycle is 3 weeks/21 days. Participants will be administered a weekly dose of PMC-309 plus one dose of pembrolizumab at 200 mg per cycle as follows: * Cycle Week 1/Day 1: pembrolizumab (administered first), followed by administration of PMC-309. * Cycle Week 2/Day 8 ± 2 days: PMC-309 only * Cycle Week 3/Day 15 ± 2 days: PMC-309 only. Both PMC-309 and pembrolizumab will be administered intravenously.
Intervention: PMC-309 Dose Escalation in Combination with Pembrolizumab(KEYTRUDA®)
Phase 1b: Dose Expansion
Phase 1b will enroll participants after completion of DLT assessments for Phase 1a. Phase 1b will enroll participants with advanced or metastatic tumor types into 1 of 2 cohorts to assess response of monotherapy of PMC-309 and response of PMC-309 in combination with pembrolizumab. * 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 combination therapy - PMC-309 dosing will be as identified in Phase 1a: Part B in combination with 200 mg pembrolizumab Participants will be randomly assigned to Cohort A or Cohort B until 20 participants are enrolled in each cohort.
Intervention: PMC-309 Dose Expansion
Outcomes
Primary Outcomes
Number of participants with abnormal vital signs in response ot treatment with PMC- 309
Time Frame: 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.
Number of participants with adverse events receiving treatment with PMC-309
Time Frame: 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 clinically significant 12-lead electrocardiogram (ECG) parameters in response to treatment with PMC-309
Time Frame: 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 abnomal clinically significant results with physical examination in response to the treatment with PMC-309
Time Frame: 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.
To determine the MTD and establish the preliminary RP2D of PMC-309 when administered in combination with pembrolizumab at 200 mg (Part B).
Time Frame: 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 abnormal clinically significant laboratory results in response to treatment with PMC-309
Time Frame: 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 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.
Time Frame: Upto 21 days
MTD of PMC-309 will be calculated by incidence of DLT at 21 days from the first dosing of PMC 309.
Secondary Outcomes
- 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))
- 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))
- 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))