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: Capsule, soft
INN or Proposed INN: (R)-5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl) pyrazolo[1,5-
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: • 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 malignant glioma previously treated with systemic therapy are eligible. 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 the subject has declined treatment with available marketed TRK inhibitors. • 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 with Medical Monitor approval. • Subjects with primary brain tumors may have received prior treatment with a TRK inhibitor but this is not required. For these subjects who have previously been treated with a TRK inhibitor, 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 ongoing neurologic signs, symptoms, or a history of seizures due to their intracranial tumor or on antiseizure medication must be approved for enrollment by the Medical Monitor. 5. Age = 18 years at the time of signing the informed consent form (ICF) 6. Has provided written informed consent 7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1. Subjects with PS = 2 may be approved by the Medical Monitor. 8. Acceptable liver, renal, hematologic, and coagulation function • Bilirubin = 1.5x ULN • AST, ALT = 3.0x ULN • Serum creatinine = 1.5x ULN and/or an estimated creatinine clearance of = 45 ml/min based on the Cockcroft-Gault formula • Absolute neutrophil count = 1000/mm3
Exclusion criteria
Exclusion criteria: 1. Cytotoxic chemotherapy, biologic agent, investigational agent, or radiation therapy = 3 weeks prior to the first dose of PBI-200 (6 weeks for nitrosoureas). The interval may be reduced to 2 weeks for bone-only radiation therapy or investigational agents not expected to be associated with AEs after 2 weeks of last administration, with Medical Monitor approval. a. Subjects with either primary brain tumors or brain metastasis must have completed brain radiation therapy 12 weeks prior to the brain MRI obtained within 4 weeks of the first dose of PBI-200. The Medical Monitor may approve 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 2. Small-molecule kinase inhibitors or hormonal agents = 14 days and within 5 half-lives prior to the first dose of PBI-200 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 unless approved by the Medical Monitor 5. Subjects with leptomeningeal disease (primary or metastatic) unless approved by the Medical Monitor 6. Major surgery = 6 weeks or minor surgery = 14 days prior to the first dose of PBI-200 7. 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 PBI-200 • Unstable angina within = 13 weeks prior to the first dose of PBI-200 unless the underlying disease has been corrected by procedural intervention e.g., stent, bypass • Severe aortic stenosis • Uncontrolled arrhythmia. Medical Monitor approval of subjects with an arrhythmia is required • Congenital long QT syndrome. Medical Monitor approval is required • 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, and not taking antimicrobial treatment for = 3 days prior to the first dose of PBI-200 8. 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 9. 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 PBI-200 10. Human immunodeficiency virus (HIV) infection 11. Active hepatitis B or C infection 12. Has a history of another malignancy, unless the subject has been treated with curative intent for this malignancy. Medical Monitor approval for enrollment is required for subjects with a history of another malignancy. Study subjects with early-stage prostate cancer on active surveillance may be enrolled
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 in subjects with NTRK-fusion-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 Phase 2: • To evaluate the antitumor activity of PBI-200 in subjects with NTRK-fusion-positive advanced or metastatic refractory solid tumors as follows: Cohort A: Non-Brain Primary Tumors • ORR based on RECIST v1.1 by Independent Radiology Review Cohort B: Primary Brain Tumors • ORR based on RANO criteria by Independent Radiology Review;Secondary Objective: Phase 1: • Evaluate the pharmacokinetics (PK) of PBI-200 • Evaluate the antitumor activity of PBI-200 as follows: Subjects with Non-Brain Primary Tumors • Objective response rate (ORR), duration or response (DoR), and progression-free survival (PFS) based on RECIST version 1.1 by Investigator Assessment and by Independent Radiology Review (IRR). • Intracranial ORR (IORR), intracranial DoR (IDoR), and intracranial PFS (IPFS) based on Response Assessment in Neuro-oncology – Brain Metastases (RANO-BM) by Investigator Assessment and by Independent Radiology Review for subjects with measurable brain metastasis by RANO-BM during Screening Subjects with Primary Brain Tumors • ORR, DoR, and PFS based on Response Assessment in Neuro-oncology (RANO) criteria by Investigator Assessment and by IRR Phase 2 • To evaluate antitumor activity based on RECIST v1.1, RANO and/or RANO-BM • To confirm the safety and tolerability • To further evaluate the PK;Primary end point(s): • Safety as assessed by the incidence of adverse events (AEs) and changes in physical examinations, vital signs, clinical laboratory assessments, Eastern Cooperative Oncology Group (ECOG) performance status, and electrocardiogram (ECG) p | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1 Dose-Escalation • Plasma PK of PBI-200 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) after 28 doses. - Maximum concentration (Cmax) - Time to maximum concentration (Tmax) - Half-life (T1/2) - Apparent steady state volume of distribution (Vss/F) - Apparent clearance (CL/F) • Preliminary antitumor activity for subjects with non-brain primary tumors (ORR, DoR, PFS) based on RECIST v1.1 by Investigator assessment and Independent Radiology Review. Intracranial antitumor activity (IORR, IDoR, and IPFS) based on RANO-BM by Investigator assessment and Independent Radiology Review. • 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 Phase 2 Cohort Expansion Primary Endpoints Cohort A: Non-Brain Primary Tumors • Antitumor (ORR) activity based on RECIST v1.1 by Independent Radiology Review • 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 • Antitumor activity (ORR) based on RANO criteria by Independent Radiology Review Secondary Endpoints • Antitumor activity: • Antitumor activity (DoR, PFS) based on RANO criteria by Independent Radiology Review • Antitumor activity (ORR, DoR, and PFS) based on RANO criteria by Investigator assessment • Safety as assessed by the incidence of treatment-emergent AEs (TEAEs) and changes in physical examinations, vital signs, clinical laboratory assessments, ECOG performance status, and ECG parameters. • Plasma PK of PBI-200 as ass | — |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, Italy, Korea, Republic of, Spain, United Kingdom, United States
Contacts
Public ContactClinical Trial Information Desk
Pyramid Biosciences
Outcome results
None listed