Clinical trial NCT04901806: Study of PBI-200 in Subjects With NTRK-Fusion-Positive Solid Tumors
Official title: A Phase 1/2 Study of PBI-200 in Subjects With NTRK-Fusion-Positive Advanced or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Solid Tumor, Adult
Brain Tumor, Primary
Desmoplastic Small Round Cell Tumor
Keywords: NTRK
NTRK Fusion
Resistance Mutation
Lead sponsor: Pyramid Biosciences
Sponsor class: INDUSTRY
First posted: 2021-05-26
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose Escalation: Single-subject cohorts will be enrolled initially, until a subject has a Grade 2 or greater adverse event (AE), at which time a 3+3 design will be utilized. Dose escalation will continue until the maximum-tolerated dose (MTD) is reached, or the Recommended Phase 2 Dose (RP2D) is established.

Cohort Expansion: Two cohorts will be opened to accrual. Cohort A will enroll subjects with a non-brain primary tumor and Cohort B will enroll subjects with a primary brain tumor.
Primary purpose: TREATMENT

Brief summary: This is a first-in-human, open-label, multicenter, dose-escalation, safety, PK, and biomarker study of PBI-200 in subjects with NTRK-fusion-positive advanced or metastatic solid tumors.

Detailed description: This is a first-in-human, open-label, multicenter, dose-escalation, safety, PK, and biomarker study of PBI-200 in subjects with NTRK-fusion-positive advanced or metastatic solid tumors. Phase 1 will also include subjects with NTRK-amplified advanced or metastatic solid tumors or refractory EWSR1-WT1-fusion-positive desmoplastic small round cell tumors (DSRCTs).

Phase 1 is the dose-escalation portion of the study in which the evaluation of safety and tolerability and establishing the RP2D are primary objectives. Once the RP2D has been established, two expansion cohorts will open to accrual, a Non-Brain Primary Tumor cohort and a Primary Brian Tumor cohort.

Although this was intended to be a Phase 1/2 trial, the trial was terminated without proceeding to Phase 2.

Eligibility criteria: Key Inclusion Criteria:

* 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 Note: Subjects with any grade of malignant glioma previously treated with systemic therapy are eligible.

Phase 1

* NTRK-gene amplified, locally advanced or metastatic solid tumor
* EWSR1-WT1-positive DSRCTs.
* Subjects with NTRK-fusion-positive solid tumors other than primary brain 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.

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 a documented resistance mutation(s) (e.g., solvent front, gatekeeper or xDFG mutation). 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. Biopsies of brain tumors are not required for eligibility.

Key Exclusion Criteria:

* Cytotoxic chemotherapy, biologic agent, investigational agent, or radiation therapy ≤ 3 weeks prior to the first dose of PBI-200 (6 weeks for nitrosoureas).

  * 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.
* Small-molecule kinase inhibitors or hormonal agents ≤ 14 days and within 5 half-lives prior to the first dose of PBI-200.

Primary outcomes:
measure: Phase 1: Number of patients with AEs
timeFrame: Through study completion, estimated as an average of 36 months
measure: Phase 1: Recommended Phase 2 Dose
timeFrame: Approximately 12 months
measure: Phase 2: Cohort A - Overall Response Rate (ORR)
timeFrame: Through study completion, estimated as an average of 36 months
measure: Phase 2: Cohort B - ORR
timeFrame: Through study completion, estimated as an average of 36 months
Secondary outcomes:
measure: Phase 1: Area under the plasma drug concentration-time curve from 0 to 24 hours after one dose and after 28 doses
timeFrame: 29 days
measure: Phase 1: ORR
timeFrame: Through study completion, estimated as an average of 36 months
measure: Duration of Response (DoR)
timeFrame: Through study completion, estimated as an average of 36 months
measure: Progression-free Survival
timeFrame: Through study completion, estimated as an average of 36 months
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: John Wayne Cancer Institute at St. Johns Health Center
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Denver
country: United States
facility: Sarah Cannon Research Institute at HealthONE
state: Colorado
city: Lake Mary
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center (University of Miami)
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Hawthorne
country: United States
facility: Westchester Medical Center
state: New York
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Copenhagen
country: Denmark
facility: Rigshospitalet, University Hospital of Copenhagen
city: Bordeaux
country: France
facility: Institut Bergonie
city: Lyon
country: France
facility: Centre Léon Bérard
city: Paris
country: France
facility: Hopital Europeen Georges Pompidou
city: Poitiers
country: France
facility: CHU Poitiers - Hopital la Miletrie
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Frankfurt am Main
country: Germany
facility: Dr. Senckenberg Institute of Neurooncology
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
city: Herne
country: Germany
facility: Marienhospital Herne
city: Pok Fu Lam
country: Hong Kong
facility: Queen Mary Hospital
city: Sha Tin
country: Hong Kong
facility: Prince of Wales Hospital
city: Ancona
country: Italy
facility: Azienda Ospedaliero Universitaria delle Marche
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale Tumori
city: Milano
country: Italy
facility: IRCCS (IEO) Istituto Europeo di Oncologia
city: Napoli
country: Italy
facility: IRCCS Istituto Nazionale Tumori Fondazione Pascale
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Verona
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hosptial
state: Gyeonggi-do
city: Suwon-si
country: Korea, Republic of
facility: The Catholic University of Korea St. Vincent Hosptial
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Severance Hosptial, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Soul St. Mary's Hosptial
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d Hebron
city: L'Hospitalet De Llobregat
country: Spain
facility: ICO l Hospitalet
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sant Cugat Del Vallès
country: Spain
facility: Hospital General de Catalunya
city: Manchester
country: United Kingdom
facility: The Christie
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital Institute Cancer Research
Study officials:
affiliation: Pyramid Biosciences
name: Chief Medical Officer
role: STUDY_DIRECTOR
References: