Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03093116




Registration number
NCT03093116
Ethics application status
Date submitted
6/03/2017
Date registered
28/03/2017
Date last updated
7/02/2024

Titles & IDs
Public title
A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements
Scientific title
A Phase 1/2, Open-Label, Multi-Center, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity of TPX-0005 in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)
Secondary ID [1] 0 0
CA127-1024
Secondary ID [2] 0 0
CA127-1024
Universal Trial Number (UTN)
Trial acronym
TRIDENT-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Locally Advanced Solid Tumors 0 0
Metastatic Solid Tumors 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - Oral repotrectinib (TPX-0005)

Experimental: Repotrectinib (TPX-0005) - Phase 1
Oral repotrectinib (TPX-0005):
Phase 1a dose escalation, Phase 1b food-effect sub-study, and Phase 1c dose escalation with food, and Midazolam drug-drug interaction sub-study.
Phase 2
Oral repotrectinib (TPX-0005): 6 distinct expansion cohorts
EXP-1: ROS1 TKI-naïve ROS1+ NSCLC
EXP-2: 1 Prior ROS1 TKI and 1 Platinum based chemo ROS1+ NSCLC
EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO)
EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO)
EXP-5: TRK TKI-naïve NTRK+ solid tumors
EXP-6: TRK TKI-pretreated NTRK+ solid tumors


Treatment: Drugs: Oral repotrectinib (TPX-0005)
Oral repotrectinib (TPX-0005) capsules.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Dose limiting toxicities (DLTs) (Phase 1)
Timepoint [1] 0 0
Within 28 days of the first repotrectinib dose
Primary outcome [2] 0 0
Recommended Phase 2 Dose (RP2D) (Phase 1)
Timepoint [2] 0 0
Within 28 days of the last patient dosed in escalation
Primary outcome [3] 0 0
Overall Response Rate (ORR) Phase 2
Timepoint [3] 0 0
Two to three years after first dose of repotrectinib dose
Secondary outcome [1] 0 0
Maximum plasma concentration (CMAX) of repotrectinib (TPX-0005) (Phase 1)
Timepoint [1] 0 0
Up to 72 hours post dose
Secondary outcome [2] 0 0
Area under the plasma concentration time curve (AUC) of repotrectinib (TPX-0005) (Phase 1)
Timepoint [2] 0 0
Up to 72 hours post dose
Secondary outcome [3] 0 0
Area under the plasma concentration time curve (AUC) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)
Timepoint [3] 0 0
Up to 72 hours post dose
Secondary outcome [4] 0 0
Maximum plasma concentration (CMAX) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)
Timepoint [4] 0 0
Up to 72 hours post dose
Secondary outcome [5] 0 0
Area under the plasma concentration time curve (AUC) of midazolam(TPX-0005) (Phase 1)
Timepoint [5] 0 0
Up to 24 hours post dose
Secondary outcome [6] 0 0
Maximum plasma concentration (CMAX) of midazolam(TPX-0005) (Phase 1)
Timepoint [6] 0 0
Up to 24 hours post dose
Secondary outcome [7] 0 0
Plasma concentration of repotrectinib following administration at RP2D (Phase 2)
Timepoint [7] 0 0
Pre dose and 4 hours post dose
Secondary outcome [8] 0 0
Preliminary objective response rate (ORR) (Phase 1)
Timepoint [8] 0 0
Approximately three years
Secondary outcome [9] 0 0
Duration of response (DOR) (Phase 2)
Timepoint [9] 0 0
Approximately three years
Secondary outcome [10] 0 0
Clinical benefit rate (CBR) (Phase 2)
Timepoint [10] 0 0
Approximately three years
Secondary outcome [11] 0 0
Progression free survival (PFS) (Phase 2)
Timepoint [11] 0 0
Approximately three years
Secondary outcome [12] 0 0
Overall survival (OS) (Phase 2)
Timepoint [12] 0 0
Approximately three years
Secondary outcome [13] 0 0
Intracranial objective response rate (Phase 2)
Timepoint [13] 0 0
Approximately three years

Eligibility
Key inclusion criteria
PHASE 1

Key

1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on
Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by
protocol specified tests.

2. ECOG PS 0-1.

3. Age =18 (or age = 20 of age as required by local regulation).

4. Capability to swallow capsules intact (without chewing, crushing, or opening).

5. At least 1 measurable target lesion according to RECIST version 1.1. CNS-only
measurable disease as defined by RECIST version 1.1 is allowed.

6. Prior cytotoxic chemotherapy is allowed.

7. Prior immunotherapy is allowed.

8. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
therapy to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Version 4.03 Grade less than or equal to 1.

9. Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.

10. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) =1500/mm3 (1.5 × 109/L); Platelets (PLTs) =100,000/mm3 (100 × 109/L);
Hemoglobin = 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN;
Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present
Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are
present; Serum calcium, magnesium, and potassium Normal or CTCAE grade = 1 with or
without supplementation

11. Life expectancy = 3 months.

PHASE 2 Key Inclusion Criteria

1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) that harbors a ROS1, or NTRK1-3 gene
fusion.

2. Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based
local testing using either:

1. a next-generation sequencing (NGS) or quantitative polymerase chain reaction
(qPCR) test will be accepted to determine molecular eligibility.

• Adequate tumor tissue needs to be sent to the Sponsor designated central
diagnostic laboratory for retrospective confirmation by a central diagnostic
laboratory test selected by the Sponsor.

OR

2. a fluorescence in situ hybridization (FISH) test AND prospective confirmation of
fusion status by a central diagnostic laboratory test selected by the Sponsor
PRIOR to enrollment will be accepted to determine molecular eligibility.

- Adequate tumor tissue must be sent to the Sponsor designated central
diagnostic laboratory for prospective confirmation by a central diagnostic
laboratory test selected by the Sponsor PRIOR to enrollment.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.

4. Age =12 (or age = 20 as required by local regulation).

5. Willing and able to provide written institutional review board (IRB)/institutional
ethics committee-approved Informed Consent or an Assent signed by a parent or legal
guardian for subjects age 12 to 17.

6. At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed
by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to
enrollment. Subjects with CNS-only measurable disease =10 mm as defined by RECIST
(v1.1) are eligible.

7. Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3
rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all
inclusion and exclusion criteria are met.

i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based
chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv.
EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+
solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors

8. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.

9. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) =1500/mm3 (1.5 × 109/L); Platelets (PLTs) =100,000/mm3 (100 × 109/L);
Hemoglobin = 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases
(ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline
phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present;
Serum calcium, magnesium, and potassium Normal or CTCAE grade = 1 with or without
supplementation

10. Life expectancy = 3 months.

Key
Minimum age
12 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria PHASE 1 and PHASE 2

1. Concurrent participation in another therapeutic clinical trial.

2. Symptomatic brain metastases or leptomeningeal involvement.

3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the
skin, or any in situ carcinoma that has been completely resected, requiring therapy
within the previous 2 years.

4. Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy
(except palliative to relieve bone pain) within 2 weeks of study entry. Palliative
radiation (=10 fractions) must have been completed at least 48 hours prior to study
entry

5. Clinically significant cardiovascular disease (either active or within 6 months prior
to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure (New York Heart Association
Classification Class = II), cerebrovascular accident or transient ischemic attack,
symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac
dysrhythmias of NCI CTCAE grade =2

6. Any of the following cardiac criteria:

Mean resting corrected QT interval (ECG interval measured from the onset of the QRS
complex to the end of the T wave) for heart rate (QTcF) > 470 msec obtained from 3
ECGs, using the screening clinic ECG machine-derived QTc value Any clinically
important abnormalities in rhythm, conduction or morphology of resting ECG (e.g.,
complete left bundle branch block, third degree heart block, second degree heart
block, PR interval > 250 msec) Any factors that increase the risk of QTc prolongation
or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT
syndrome, family history of long QT syndrome, or any concomitant medication known to
prolong the QT interval.

7. Known active infections (bacterial, fungal, viral including HIV positivity).

8. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact drug absorption.

9. Peripheral neuropathy of CTCAE =grade 2.

10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4
interstitial fibrosis or interstitial lung disease including a history of pneumonitis,
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,
obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior
radiation pneumonitis are not excluded.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
7/03/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
29/02/2028
Actual
Sample size
Target
500
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 0 0
Local Institution - 6102 - Camperdown
Recruitment hospital [2] 0 0
Local Institution - 6103 - Adelaide
Recruitment hospital [3] 0 0
Local Institution - 6101 - Melbourne
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
5042 - Adelaide
Recruitment postcode(s) [3] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
District of Columbia
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Georgia
Country [6] 0 0
United States of America
State/province [6] 0 0
Illinois
Country [7] 0 0
United States of America
State/province [7] 0 0
Maryland
Country [8] 0 0
United States of America
State/province [8] 0 0
Massachusetts
Country [9] 0 0
United States of America
State/province [9] 0 0
Michigan
Country [10] 0 0
United States of America
State/province [10] 0 0
Minnesota
Country [11] 0 0
United States of America
State/province [11] 0 0
Missouri
Country [12] 0 0
United States of America
State/province [12] 0 0
New Jersey
Country [13] 0 0
United States of America
State/province [13] 0 0
New York
Country [14] 0 0
United States of America
State/province [14] 0 0
North Carolina
Country [15] 0 0
United States of America
State/province [15] 0 0
Ohio
Country [16] 0 0
United States of America
State/province [16] 0 0
Pennsylvania
Country [17] 0 0
United States of America
State/province [17] 0 0
Tennessee
Country [18] 0 0
United States of America
State/province [18] 0 0
Texas
Country [19] 0 0
United States of America
State/province [19] 0 0
Virginia
Country [20] 0 0
United States of America
State/province [20] 0 0
Washington
Country [21] 0 0
United States of America
State/province [21] 0 0
Wisconsin
Country [22] 0 0
Belgium
State/province [22] 0 0
Antwerp
Country [23] 0 0
Belgium
State/province [23] 0 0
Leuven
Country [24] 0 0
Canada
State/province [24] 0 0
Alberta
Country [25] 0 0
Canada
State/province [25] 0 0
British Columbia
Country [26] 0 0
Canada
State/province [26] 0 0
Ontario
Country [27] 0 0
Canada
State/province [27] 0 0
Ottawa
Country [28] 0 0
China
State/province [28] 0 0
Beijing
Country [29] 0 0
China
State/province [29] 0 0
Chongqing
Country [30] 0 0
China
State/province [30] 0 0
Fujian
Country [31] 0 0
China
State/province [31] 0 0
Guangdong
Country [32] 0 0
China
State/province [32] 0 0
Heilongjiang
Country [33] 0 0
China
State/province [33] 0 0
Hong Kong
Country [34] 0 0
China
State/province [34] 0 0
Hunan
Country [35] 0 0
China
State/province [35] 0 0
Jiangsu
Country [36] 0 0
China
State/province [36] 0 0
Jilin
Country [37] 0 0
China
State/province [37] 0 0
Liaoning
Country [38] 0 0
China
State/province [38] 0 0
Shan3xi
Country [39] 0 0
China
State/province [39] 0 0
Shanxi
Country [40] 0 0
China
State/province [40] 0 0
Sichuan
Country [41] 0 0
China
State/province [41] 0 0
Zhejiang
Country [42] 0 0
China
State/province [42] 0 0
Changchun City
Country [43] 0 0
China
State/province [43] 0 0
Changsha
Country [44] 0 0
China
State/province [44] 0 0
Chengdu
Country [45] 0 0
China
State/province [45] 0 0
Hangzhou
Country [46] 0 0
China
State/province [46] 0 0
Hefei
Country [47] 0 0
China
State/province [47] 0 0
Shanghai
Country [48] 0 0
China
State/province [48] 0 0
Weifang City
Country [49] 0 0
China
State/province [49] 0 0
Wuhan
Country [50] 0 0
China
State/province [50] 0 0
Zhengzhou
Country [51] 0 0
Denmark
State/province [51] 0 0
Copenhagen
Country [52] 0 0
France
State/province [52] 0 0
Bouches-du-Rhône
Country [53] 0 0
France
State/province [53] 0 0
Brest
Country [54] 0 0
France
State/province [54] 0 0
Dijon Cedex
Country [55] 0 0
France
State/province [55] 0 0
Grenoble Cedex 9
Country [56] 0 0
France
State/province [56] 0 0
Nice
Country [57] 0 0
France
State/province [57] 0 0
Poitiers
Country [58] 0 0
France
State/province [58] 0 0
St Mande
Country [59] 0 0
France
State/province [59] 0 0
Villejuif
Country [60] 0 0
Germany
State/province [60] 0 0
Berlin
Country [61] 0 0
Germany
State/province [61] 0 0
Dresden
Country [62] 0 0
Germany
State/province [62] 0 0
Heidelberg
Country [63] 0 0
Germany
State/province [63] 0 0
Koln
Country [64] 0 0
Hong Kong
State/province [64] 0 0
Hong Kong
Country [65] 0 0
Hungary
State/province [65] 0 0
Budapest
Country [66] 0 0
Italy
State/province [66] 0 0
MI
Country [67] 0 0
Italy
State/province [67] 0 0
Milano
Country [68] 0 0
Italy
State/province [68] 0 0
Palermo
Country [69] 0 0
Italy
State/province [69] 0 0
Pordenone
Country [70] 0 0
Italy
State/province [70] 0 0
Reggio Emilia
Country [71] 0 0
Italy
State/province [71] 0 0
Roma
Country [72] 0 0
Italy
State/province [72] 0 0
Terni
Country [73] 0 0
Japan
State/province [73] 0 0
Ehime
Country [74] 0 0
Japan
State/province [74] 0 0
Hokkaido
Country [75] 0 0
Japan
State/province [75] 0 0
Kanagawa
Country [76] 0 0
Japan
State/province [76] 0 0
Osaka
Country [77] 0 0
Japan
State/province [77] 0 0
Tokyo
Country [78] 0 0
Japan
State/province [78] 0 0
Tottori
Country [79] 0 0
Japan
State/province [79] 0 0
Kashiwa
Country [80] 0 0
Japan
State/province [80] 0 0
Nagoya-shi
Country [81] 0 0
Korea, Republic of
State/province [81] 0 0
Jeonnam
Country [82] 0 0
Korea, Republic of
State/province [82] 0 0
Seoul-teukbyeolsi [Seoul]
Country [83] 0 0
Korea, Republic of
State/province [83] 0 0
Cheongju-si
Country [84] 0 0
Korea, Republic of
State/province [84] 0 0
Seoul
Country [85] 0 0
Netherlands
State/province [85] 0 0
Amsterdam
Country [86] 0 0
Netherlands
State/province [86] 0 0
Groningen
Country [87] 0 0
Poland
State/province [87] 0 0
Gdansk
Country [88] 0 0
Poland
State/province [88] 0 0
Lublin
Country [89] 0 0
Poland
State/province [89] 0 0
Poznan
Country [90] 0 0
Poland
State/province [90] 0 0
Szczecin
Country [91] 0 0
Poland
State/province [91] 0 0
Warszawa
Country [92] 0 0
Singapore
State/province [92] 0 0
Singapore
Country [93] 0 0
Spain
State/province [93] 0 0
Barcelona
Country [94] 0 0
Spain
State/province [94] 0 0
Madrid
Country [95] 0 0
Spain
State/province [95] 0 0
Pamplona
Country [96] 0 0
Spain
State/province [96] 0 0
Valencia
Country [97] 0 0
Taiwan
State/province [97] 0 0
Taiepi
Country [98] 0 0
Taiwan
State/province [98] 0 0
Tainan
Country [99] 0 0
Taiwan
State/province [99] 0 0
Taipei
Country [100] 0 0
United Kingdom
State/province [100] 0 0
London
Country [101] 0 0
United Kingdom
State/province [101] 0 0
Manchester
Country [102] 0 0
United Kingdom
State/province [102] 0 0
Sutton

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Turning Point Therapeutics, Inc.
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Zai Lab (Shanghai) Co., Ltd.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the
maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose
(RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an
ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction.

Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded
Independent Central Review (BICR) of repotrectinib in each subject population expansion
cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene
rearrangement. The secondary objective will include the duration of response (DOR), time to
response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit
rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a
ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03093116
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Bristol-Myers Squibb
Address 0 0
Bristol-Myers Squibb
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
BMS Study Connect Contact Center www.BMSStudyConnect.com
Address 0 0
Country 0 0
Phone 0 0
855-907-3286
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03093116