A Phase 1/2 Study of PBI-200 in Subjects with NTRK-Fusion-Positive Advanced or Metastatic Solid Tumors
- Conditions
- 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: 20.0Level: SOCClassification code 10029104Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps)System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2021-001029-32-IT
- Lead Sponsor
- Pyramid Biosciences
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 74
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
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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method