| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects with NTRK-Fusion-Positive Advanced or Metastatic Solid Tumors |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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
|
|
| E.2.2 | Secondary objectives of the trial |
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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
• Platelet count ≥ 75,000/mm3
• Hemoglobin ≥ 8 g/dL
• International normalized ratio (INR) ≤ 1.5 ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 ULN. Study subjects on therapeutic doses of anticoagulation medication must have INR and/or aPTT ≤ the upper limit of the therapeutic range for intended use
9. Ability to swallow capsules and no gastrointestinal issues that may impact absorption of oral medication
10. Women of child-bearing potential must agree to use highly effective contraceptive methods and avoid egg donation during the study treatment and for 4 months after the last dose of
PBI-200. A woman is considered to be of child-bearing potential unless she:
• has had a hysterectomy, bilateral tubal occlusion, or bilateral oophorectomy;
• is age ≥ 60 years and is amenorrhoeic; or
• is age < 60 years and has been amenorrhoeic for ≥ 12 months
11. For women of child-bearing potential: A negative serum pregnancy test during Screening and a negative pregnancy test (either serum or urine) predose on Day -2 (the first day of PBI-200
treatment)
12. Men of reproductive potential agree to use highly effective contraceptive methods and avoid sperm donation during the study treatment and for 4 months after the last dose of PBI-200. A
man is considered to be of child-producing potential unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy. |
|
| E.4 | Principal 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 with Medical Monitor approval.
13. Women who are pregnant or breastfeeding
14. Unwillingness or inability to comply with procedures required in this protocol
15. Currently receiving any other anticancer or investigational agent |
|
| E.5 End points |
| E.5.1 | 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)
parameters. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| This endpoint is to be measured throughout, until the end of the study |
|
| E.5.2 | 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 assessed via:
− AUC0-48h after single dose and AUC0-24h after 28 doses
− Cmax
− Tmax
− T1/2
− Vss/F
− CL/F |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Plasma PK of PBI-200 will be evaluated through Cycle 2 Day 2 for each subject. This equates to day 30. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Korea, Republic of |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit last subject (LVLS) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
