| 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 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 |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| 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 (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 anticoagulation medication must have INR and/or aPTT ≤ the
upper limit of the therapeutic range for intended use
9. Ability to swallow capsules or tablets 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 6 months after the last dose of study treatment. Due to the potential interaction of PBI-200 and ritonavir with CYP3A substrates such as oral contraceptives, women using hormonal methods of contraception must also use a second non-hormonal highly effective method. A woman is considered to be of child-bearing potential unless she:
• has had a hysterectomy, bilateral salpingectomy, 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 study treatment)
12. Men of reproductive potential agree to use highly effective
contraceptive methods and avoid sperm donation during the study
treatment and for 6 months after the last dose of study treatment. 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, 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], and T1 [tumor invades lamina
propria]), and asymptomatic localized prostate cancer with no
requirement for systemic therapy (or requiring only hormonal therapy) and with normal prostate-specific antigen values within ≥12 months prior to enrollment.
12. Women who are pregnant or breastfeeding.
13. Unwillingness or inability to comply with procedures required in this protocol.
14. Currently receiving any other anticancer or investigational agent.
15. Subjects that are taking narrow therapeutic index (NTI) oral P-gp
substrate drugs unless the subject can safely discontinue these
medications or change to comparable medications that are not NTI substrate drugs of P-gp.
16. Subjects with known hypersensitivity (e.g., toxic epidermal necrolysis or Stevens-Johnson syndrome) to ritonavir, PBI-200, or any of the ingredients or excipients in either drug. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1: Dose Escalation
• Safety as assessed by the incidence of adverse events (AEs) and changes in vital signs, clinical laboratory assessments, Eastern
Cooperative Oncology Group (ECOG) performance status, and
electrocardiogram (ECG) parameters.
Phase 2: Cohort Expansion
- Cohort A: Non-Brain Primary Tumors
• Antitumor (ORR) activity based on RECIST v1.1 by Independent
Radiology Review
- Cohort B: Primary Brain Tumors
• Antitumor activity (ORR) based on RANO criteria by Independent
Radiology Review Secondary Endpoints |
|
| 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 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
• 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 vital signs, clinical laboratory assessments, ECOG performance status, and ECG parameters.
• Plasma PK of PBI-200 and its metabolite PBI-200-M15 as appropriate, as assessed via:
− AUC0-48h after single dose and AUC0-24h after steady state
− Cmax
− Tmax
− T1/2
− Vss/F
− CL/F
• 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 for subjects 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Plasma PK of PBI-200 will be evaluated through Cycle 6 Day 1 and an additional PK sample should be collected upon assessment of disease progression (prior to discontinuation of study drug). |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Hong Kong |
| Korea, Republic of |
| Singapore |
| United States |
| Denmark |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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