One of the following solid tumors which has progressed on or following at least one systemic therapy regimen administered for advanced or metastatic disease or for which no approved therapy exists: • NTRK-fusion-positive, locally advanced (i.e., not amenable to surgical resection) or metastatic solid tumor • NTRK-gene amplified, locally advanced or metastatic solid tumor (Phase 1 only) • EWSR1-WT1-positive DSRCTs (Phase 1 only) MedDRA version: 20.0 Level: SOC Classification code 10029104 Term:
Conditions
Interventions
Product Name: PBI-200
Product Code: PBI-200
Pharmaceutical Form: Tablet
INN or Proposed INN: (R)-5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl) pyrazolo[1,5-a] pyri
Sponsors
Pyramid Biosciences
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subject has one of the following solid tumors which has progressed on or following at least one systemic therapy regimen administered for advanced or metastatic disease or for which no approved therapy exists (subjects who have received a prior TRK inhibitor may be eligible after progression or intolerance of therapy): • NTRK-fusion-positive, locally advanced (i.e., not amenable to surgical resection) or metastatic solid tumor • NTRK-gene amplified, locally advanced or metastatic solid tumor (Phase 1 only) • EWSR1-WT1-positive DSRCTs (Phase 1 only) Note: Subjects with any grade of glioma previously treated with systemic therapy and documented NTRK gene fusion or amplification are eligible. For phases 1 and 2, subject's prior treatment should include all approved regimens that have demonstrated a survival advantage for the subject's disease, stage, and line of therapy. 2. Phase 1 • Subjects with NTRK-fusion-positive solid tumors other than primary brain tumors (non-brain primary tumors) must have previously received treatment with a TRK inhibitor, unless the subject does not have access to TRK-inhibitor therapy (e.g., no TRK inhibitor is marketed and available to the subject in the subject's country) or unless the subject is ineligible for marketed TRK-inhibitor therapy (e.g., subject has a resistance mutation). • Subjects with NTRK-gene-amplified solid tumors, primary brain tumors or EWSR1-WT1- positive DSRCTs may have received prior treatment with a TRK inhibitor but this is not required. 3. Phase 2 • Has measurable disease by RECIST v1.1 for subjects with non-brain primary tumors or RANO criteria for subjects with primary brain tumors. • Subjects with non-brain primary tumors must have previously received treatment with a TRK inhibitor and must have a documented on-target resistance mutation(s) (e.g., solvent front, gatekeeper or xDFG mutation) as the mechanism of resistance to their prior TRK-inhibitor treatment based on a tumor biopsy obtained following their most recent systemic therapy. Archival tissue from a prior biopsy taken after the subject completed TRK-inhibitor treatment but prior to additional systemic therapy may be used to meet this eligibility criterion. • Subjects with primary brain tumors may have received prior treatment with a TRK inhibitor but this is not required. For these subjects, a tumor biopsy any time following TRK-inhibitor treatment is encouraged, and if analyzed for resistance mechanisms, must demonstrate an on-target resistance mutation (e.g. solvent front, gatekeeper or xDFG mutation) as the mechanism of resistance to their prior TRK-inhibitor treatment. However, biopsies of brain tumors are not required for eligibility. • Note: Subjects with NTRK-gene amplified tumors or EWSR1-WT1- positive DSRCTs are not eligible in Phase 2. 4. Subjects with brain tumors and brain metastasis must be neurologically stable. Subjects with asymptomatic brain metastases are eligible. 5. Age = 18 years at the time of signing the ICF. 6. Has provided written informed consent. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1. 8. Acceptable liver, renal, hematologic, and coagulation function • Bilirubin = 1.5x ULN • AST, ALT = 3.0x ULN • Estimated creatinine clearance of = 45 ml/min based on the Cockcroft-Gault formula • Absolute neutrophil count = 1000/mm3 • Platelet count = 75,000/mm3 • Hemoglobin = 8 g/dL • INR = 1.5 ULN and aPTT = 1.5 ULN. Study subjects on therapeutic doses of anti
Exclusion criteria
Exclusion criteria: 1. Cytotoxic chemotherapy, biologic agent, or radiation therapy = 3 weeks prior to the first dose of study treatment (6 weeks for nitrosoureas). The interval may be reduced to 2 weeks for bone-onlyradiation therapy or investigational agents not expected to be associated with AEs after 2 weeks of last administration. • Subjects with either primary brain tumors or brain metastasis who require radiation must have completed brain radiation therapy at least 12 weeks prior to the brain MRI obtained within 4 weeks of the first dose of study treatment. The Medical Monitor should be consulted if there is an interval of less than 12 weeks if there is reasonable certainty of radiographic disease progression (e.g., new disease outside the radiation therapy field following completion of the radiation therapy) or histopathologic documentation of unequivocal disease progression. Subjects with asymptomatic brain metastases are not required to have received radiation therapy. 2. Small-molecule kinase inhibitors or hormonal agents = 14 days or within 5 half-lives prior to the first dose of study treatment, whichever is shorter. 3. For subjects enrolled in Phase 2: Treatment with more than one prior TRK inhibitor. Note: Subjects enrolled in the Phase 1 part of the study may have received more than one TRK inhibitor. 4. Clinically significant AEs that have not returned to baseline or = Grade 1 based on NCI CTCAE v5.0. 5. Major surgery = 6 weeks or minor surgery = 14 days prior to the first dose of study treatment 6. Clinically significant intercurrent disease including but not limited to: • New York Heart Association Class III or IV heart failure • Myocardial infarction or stroke = 26 weeks prior to the first dose of study treatment • Unstable angina within = 13 weeks prior to the first dose of study treatment unless the underlying disease has been corrected by procedural intervention e.g., stent, bypass • Severe aortic stenosis • Uncontrolled arrhythmia. • Congenital long QT syndrome. • QTc > 470 milliseconds by Fredericia criteria (QTcF) based on the average of 3 ECGs taken approximately 1 minute apart and all within 10 minutes of each other. The subject should be reclining for 5 minutes prior to ECGs. Local readings may be used for this inclusion criterion. • Clinically significant active infection requiring systemic antibiotic, antiviral or antifungal medication. Subjects must be medically stable, afebrile, no documented evidence of ongoing infection and not taking antimicrobial treatment for = 3 days prior to the first dose of study treatment 7. Subjects taking sensitive substrates of CYP2B6, CYP2C8, CYP2C9 and CYP3A unless the subject can safely discontinue these medications or change to comparable medications that are not sensitive substrates of these CYPs. 8. Subjects that are taking strong CYP3A inhibitors or inducers unless the subject can safely discontinue these medications or change to comparable medications that are not strong inhibitors or inducers of CYP3A at least 5 half-lives or 7 days prior to the first dose of study treatment. 9. Human immunodeficiency virus (HIV) infection. 10. Active hepatitis B or C infection. 11. Previous or concurrent cancer that is distinct in the primary site or histology from the solid tumors under evaluation within 3 years before start of study treatment except for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors (Ta [noninvasive tumor], Tis [carcinoma in situ],
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • Phase 1: - To determine the safety and tolerability, maximum tolerated dose (MTD), and dose limiting toxicities (DLTs) of PBI-200 alone and coadministered with ritonavir (PBI-200/ritonavir) in subjects with NTRKfusion-positive or NTRK-amplified advanced or metastatic refractory solid tumors or refractory EWSR1-WT1-fusion-positive desmoplastic small round cell tumors (DSRCTs). - To establish the Recommended Phase 2 Dose (RP2D) of PBI- 200/ritonavir • Phase 2: - To evaluate the antitumor activity of PBI-200 in subjects with NTRKfusion-positive advanced or metastatic refractory solid tumors as follows: Cohort A: Non-Brain Primary Tumors - Objective response rate (ORR) based on RECIST v1.1 by Independent Radiology Review (IRR) Cohort B: Primary Brain Tumors - ORR based on Response Assessment in Neuro-Oncology (RANO) criteria by IRR;Secondary Objective: Phase 1: - To evaluate the pharmacokinetics (PK) of PBI-200 and metabolite PBI-200-M15 - To evaluate the antitumor activity of PBI-200 as follows: Non-Brain Primary Tumors - ORR, duration or response (DoR), and progression-free survival (PFS) based on RECIST v1.1 by Inv Assessment and by IRR. - Intracranial ORR (IORR), DoR (iDoR), and PFS (IPFS) based on RANO-BM by Inv Assessment and by IRR for subjects with measurable brain metastasis at Screening Primary Brain Tumors - ORR, DoR, and PFS based on RANO criteria by Inv Assessment and by IRR • Phase 2 - Non-Brain Primary Tumors -- DoR and PFS based on RECIST v1.1 by IRR -- IORR, iDoR, and IPFS based on RANO-BM by IRR for subjects with measurable brain mets at Screening - Primary Brain Tumors -- DoR and PFS based on RANO criteria by IRR - To evaluate antitumor activity by Inv Assessment - To confirm the safety and tolerability of PBI-200 at the RP2D - To further evaluate the PK of PBI-200 and metabolite PBI-200-M15;Primary end point(s): Phase 1: Dose Escalation • Safety as assessed by the incidence of adverse events (AEs) and changes in vital signs, clinica | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1 Dose-Escalation • Plasma PK of PBI-200 and metabolite PBI-200-M15 as assessed via: - Area under the plasma drug concentration-time curve from 0 to 48 hours (AUC0-48h) after one dose and 0 to 24 hours (AUC0-24h) at steady state. - Maximum concentration (Cmax) - Time to maximum concentration (Tmax) - Half-life (T1/2) - Apparent steady state volume of distribution of PBI-200 (Vss/F) - Apparent clearance (CL/F) of PBI-200 • Preliminary antitumor activity for subjects with non-brain primary tumors -- Subjects with Non-Brain Primary Tumors --- ORR, DoR and PFS based on RECIST v1.1 by Investigator assessment and Independent Radiology Review. --- Intracranial ORR (IORR), iDoR, and IPFS based on RANO-BM by Investigator assessment and Independent Radiology Review for subjects with measurable brain metastasis by RANO-BM during Screening. -- Subjects with Primary Brain Tumors --- Preliminary antitumor activity for subjects with primary brain tumors based on RANO criteria by Investigator assessment and Independent Radiology Review as assessed via ORR, DoR, and PFS • Exploratory Endpoints - ORR, DoR and PFS based on RECIST v 1.1 and IORR, iDoR and IPFS for subjects with Non-Brain Primary Tumors and ORR, DoR and PFS based on RANO criteria for subjects with Primary Brain Tumors in patients with resistance mutations to prior TRK inhibitors - Response assessment of non-measurable intracranial lesions - Plasma PK of ritonavir at steady state as assessed by AUC0-24,ss, Cmax,ss, Cmin and Tmax Phase 2 Cohort Expansion Cohort A: Non-Brain Primary Tumors • Antitumor activity (DoR, PFS) based on RECIST v1.1 by Independent Radiology Review • Intracranial antitumor activity (IORR, iDoR, and IPFS) based on RANO-BM by Independent Radiology Review • Antitumor activity (ORR, DoR, PFS) based on RECIST v1.1 by Investigator assessment. Intracranial antitumor activity (IORR, iDoR, and IPFS) based on RANO-BM by Investigator assessment Cohort B: Primary Brain Tumors • An | — |
Countries
Australia, Denmark, France, Germany, Hong Kong, Italy, Korea, Republic of, Singapore, Spain, United Kingdom, United States
Contacts
Public ContactClinical Trial Information Desk
Pyramid Biosciences
Outcome results
None listed