A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements

Metastatic Solid Tumors Clinical Trial

— TRIDENT-1  

Official 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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03093116
• Other study ID #: CA127-1024
• Secondary ID: CA127-1024TPX-00
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 7, 2017
• Est. completion date: February 29, 2028

Study information

• Verified date: February 2024
• Source: Turning Point Therapeutics, Inc.
• Contact: BMS Study Connect Contact Center www.BMSStudyConnect.com
• Phone: 855-907-3286
• Email: Clinical.Trials[@]bms.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

In Phase 2, study subjects will be enrolled into 6 distinct expansion (EXP) cohorts:

• EXP-1: ROS1 TKI-naïve ROS1+ NSCLC. Up to one prior line of chemotherapy OR immunotherapy is allowed

• EXP-2: 1 Prior ROS1 TKI AND 1 Platinum-based Chemotherapy ROS1+ NSCLC. Disease progression, or intolerant to one prior line of a ROS1 TKI. Must have received one prior line of platinum based chemotherapy OR one prior line of platinum based chemotherapy in combination with immunotherapy before or after a ROS1 TKI

• EXP-3: 2 Prior ROS1 TKIs AND NO Chemotherapy ROS1+ NSCLC. Disease progression, or intolerant to 2 prior lines of a ROS1 TKI treatment. No prior lines of chemotherapy or immunotherapy are allowed.

• EXP-4: 1 Prior ROS1 TKI and NO Chemotherapy or Immunotherapy. Disease progression or intolerant to one prior line of a ROS1 TKI. No prior lines of chemotherapy or immunotherapy are allowed.

• EXP-5: TRK TKI-naïve NTRK+ solid tumors. Any number of prior lines of chemo or immunotherapy is allowed.

• EXP-6: TRK TKI-pretreated NTRK+ solid tumors. Disease progression, or intolerant to 1 or 2 prior TRK TKIs. Any number of prior lines of chemo- or immunotherapy are allowed.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: February 29, 2028
• Est. primary completion date: February 29, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

PHASE 1

Key Inclusion Criteria:

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 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.

Related Conditions & MeSH terms

• Locally Advanced Solid Tumors
• Metastatic Solid Tumors
• Neoplasms

Intervention

Drug:
• Oral repotrectinib (TPX-0005)
Oral repotrectinib (TPX-0005) capsules.

Locations

Country	Name	City	State
Australia	Local Institution - 6103	Adelaide	South Australia
Australia	Local Institution - 6102	Camperdown	New South Wales
Australia	Local Institution - 6101	Melbourne	Victoria
Belgium	Local Institution - 4802	Antwerp
Belgium	Local Institution - 4801	Leuven
Canada	Local Institution - 2202	Edmonton	Alberta
Canada	Local Institution - 2203	Ontario
Canada	Local Institution - 2204	Ottawa
Canada	Local Institution - 2201	Toronto	Ontario
Canada	Local Institution - 6503	Toronto	Ontario
Canada	Local Institution - 2205	Vancouver	British Columbia
China	Beijing Cancer Hospital	Beijing	Beijing
China	Local Institution - 6702	Beijing	Beijing
China	Local Institution - 6714	Changchun	Jilin
China	Jilin Cancer Hospital/Medical Oncology Department	Changchun City
China	Jilin Cancer Hospital/Medical Oncology Department	Changchun City
China	Hunan Cancer Hospital-thoracic oncology II	Changsha	Hunan
China	Local Institution - 6705	Changsha	Hunan
China	The Third Xiangya Hospital of Central South University/Department of Respiratory and Critical Care Medicine	Changsha
China	West China Hospital Sichuan University/Lung cancer center	Chengdu
China	Sichuan Cancer Hospital/Medical Oncology Department	Chengdu City	Sichuan
China	Local Institution - 6716	Chongqing	Sichuan
China	Daping Hospital, the Third Affiliated Hospital of Third Military Medical University /Cancer Center	Daping	Chongqing
China	Local Institution - 6719	Fuzhou	Fujian
China	Guangdong Provincial People'S Hospital	Guangzhou	Guangdong
China	The First Affiliated Hospital of Guangzhou Medical University-Pneumology department	Guangzhou	Guangdong
China	Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University	Hangzhou	Zhejiang
China	The First Affiliated Hospital - Zhejiang University School of Medicine	Hangzhou
China	Zhejiang Cancer Hospital-Oncology	Hangzhou	Zhejiang
China	The Affiliated Tumor Hospital of Harbin Medical University	Harbin	Heilongjiang
China	Local Institution - 6704	Hefei
China	Nanjing Drum Tower hospital	Nanjing	Jiangsu
China	Shanghai Chest Hospital	Shanghai
China	Shanghai Chest Hospital	Shanghai
China	Local Institution - 6504	Shatin	Hong Kong
China	Local Institution - 6742	Shenyang	Liaoning
China	Local Institution - 6505	Shenzhen	Guangdong
China	Shanxi Bethune Hospital	Taiyuan	Shanxi
China	Weifang People's Hospital/Medical Oncology Department	Weifang City
China	Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology/Cancer Center Department	Wuhan
China	Tangdu Hospital	Xi'an	Shan3xi
China	The First Affiliated hospital of Xiamen University-oncology	Xiamen	Fujian
China	XuZhou Central Hospital/Oncology Department	Xuzhou City	Jiangsu
China	Henan Cancer Hospital/The 1st pneumology department	Zhengzhou
Denmark	Local Institution - 4901	Copenhagen
France	Local Institution - 4207	Brest
France	Local Institution - 4204	Dijon Cedex
France	Local Institution - 4206	Grenoble Cedex 9
France	Local Institution - 4201	Marseille	Bouches-du-Rhône
France	Local Institution - 4205	Nice
France	Local Institution - 4208	Poitiers
France	Local Institution - 4203	St Mande
France	Local Institution - 4202	Villejuif
Germany	Local Institution - 4704	Berlin
Germany	Local Institution - 4703	Dresden
Germany	Local Institution - 4702	Heidelberg
Germany	Local Institution - 4701	Koln
Hong Kong	Local Institution - 6501	Hong Kong
Hong Kong	Local Institution - 6502	Hong Kong
Hungary	Local Institution - 5101	Budapest
Hungary	Local Institution - 5103	Budapest
Italy	Local Institution - 4301	Milano	MI
Italy	Local Institution - 4306	Milano
Italy	Local Institution - 4307	Palermo
Italy	Local Institution - 4303	Pordenone
Italy	Local Institution - 4305	Reggio Emilia
Italy	Local Institution - 4308	Roma
Italy	Local Institution - 4302	Terni
Japan	Local Institution - 6604	Chuo-ku	Tokyo
Japan	National Cancer Center Hospital East	Kashiwa
Japan	Local Institution - 6608	Nagoya-shi
Japan	Local Institution - 6602	Osaka
Japan	Local Institution - 6605	Osaka-shi	Osaka
Japan	Local Institution - 6607	Sapporo-shi	Hokkaido
Japan	Local Institution - 6609	Toon	Ehime
Japan	Local Institution - 6603	Yokohama	Kanagawa
Japan	Local Institution - 6606	Yonago	Tottori
Korea, Democratic People's Republic of	Local Institution - 6305	Seoul
Korea, Republic of	Local Institution - 6306	Cheongju-si
Korea, Republic of	Local Institution - 6308	Hwasun-eup, Hwasun-gun	Jeonnam
Korea, Republic of	Local Institution - 6301	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Local Institution - 6302	Seoul
Korea, Republic of	Local Institution - 6303	Seoul	Seoul-teukbyeolsi [Seoul]
Korea, Republic of	Local Institution - 6304	Seoul
Korea, Republic of	Local Institution - 6307	Seoul
Netherlands	Local Institution - 4502	Amsterdam
Netherlands	Local Institution - 4501	Groningen
Poland	Local Institution - 4601	Gdansk
Poland	Local Institution - 4604	Lublin
Poland	Local Institution - 4605	Poznan
Poland	Local Institution - 4603	Szczecin
Poland	Local Institution - 4602	Warszawa
Singapore	Local Institution - 6401	Singapore
Singapore	Local Institution - 6402	Singapore
Spain	Local Institution - 4101	Barcelona
Spain	Local Institution - 4102	Barcelona
Spain	Local Institution - 4103	Madrid
Spain	Local Institution - 4104	Madrid
Spain	Local Institution - 4105	Madrid
Spain	Local Institution - 4106	Madrid
Spain	Local Institution - 4108	Pamplona
Spain	Local Institution - 4107	Valencia
Taiwan	Local Institution - 6201	Taiepi
Taiwan	Local Institution - 6203	Tainan
Taiwan	Local Institution - 6202	Taipei
United Kingdom	Local Institution - 4401	London
United Kingdom	Local Institution - 4402	London
United Kingdom	Local Institution - 4404	London
United Kingdom	Local Institution - 4403	Manchester
United Kingdom	Local Institution - 4405	Sutton
United States	University Of Michigan	Ann Arbor	Michigan
United States	ThedaCare	Appleton	Wisconsin
United States	University Cancer and Blood Center	Athens	Georgia
United States	University Of Colorado Denver	Aurora	Colorado
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Central Care Cancer Center	Bolivar	Missouri
United States	Dana Farber Cancer Institute.	Boston	Massachusetts
United States	Massachusetts General Hospital,	Boston	Massachusetts
United States	Gabrail Cancer Center	Canton	Ohio
United States	University of Chicago	Chicago	Illinois
United States	Trihealth Cancer Institute	Cincinnati	Ohio
United States	Cleveland Clinic Main Campus	Cleveland	Ohio
United States	Colombus Regional Research Institute	Columbus	Georgia
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Henry Ford Transplant Institute	Detroit	Michigan
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	City Of Hope	Duarte	California
United States	Virginia Cancer Specialists, PC	Fairfax	Virginia
United States	Adventist Health Glendale	Glendale	California
United States	Southeastern Medical Oncology Center	Goldsboro	North Carolina
United States	Memorial Healthcare System	Hollywood	Florida
United States	MD Anderson Cancer Center	Houston	Texas
United States	Oncology Consultants, P.A.	Houston	Texas
United States	Lumi Research	Kingwood	Texas
United States	UC San Diego Health	La Jolla	California
United States	Pacific Shores Medical Group	Long Beach	California
United States	Baptist Memorial Hospital Baptist Cancer Center	Memphis	Tennessee
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Laura & Isaac Perlmutter Cancer Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	UC Irvine Medical Center	Orange	California
United States	Illinois Cancer Care	Peoria	Illinois
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Washington University Infusion Center Pharmacy	Saint Louis	Missouri
United States	Regions Hospital - Cancer Care Center	Saint Paul	Minnesota
United States	St Joseph Heritage Healthcare	Santa Rosa	California
United States	University of Washington-Seattle Cancer Care Alliance	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida
United States	Georgetown University Medical Center - Lombardi Comprehensive Cancer Center	Washington	District of Columbia
United States	The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Turning Point Therapeutics, Inc.	Zai Lab (Shanghai) Co., Ltd.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  China,  Denmark,  France,  Germany,  Hong Kong,  Hungary,  Italy,  Japan,  Korea, Democratic People's Republic of,  Korea, Republic of,  Netherlands,  Poland,  Singapore,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose limiting toxicities (DLTs) (Phase 1)	Define the dose limiting toxicities (DLTs) (Phase 1)	Within 28 days of the first repotrectinib dose
Primary	Recommended Phase 2 Dose (RP2D) (Phase 1)	To determine the RP2D (Phase 1)	Within 28 days of the last patient dosed in escalation
Primary	Overall Response Rate (ORR) Phase 2	To determine the confirmed ORR of repotrectinib (TPX-0005) as assessed by Blinded Independent Central Review (Phase 2)	Two to three years after first dose of repotrectinib dose
Secondary	Maximum plasma concentration (CMAX) of repotrectinib (TPX-0005) (Phase 1)	To determine the maximum plasma concentration (CMAX) of repotrectinib (TPX-0005)	Up to 72 hours post dose
Secondary	Area under the plasma concentration time curve (AUC) of repotrectinib (TPX-0005) (Phase 1)	To determine the area under the plasma concentration time curve (AUC) of repotrectinib	Up to 72 hours post dose
Secondary	Area under the plasma concentration time curve (AUC) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)	To determine the area under the plasma concentration time curve (AUC) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)	Up to 72 hours post dose
Secondary	Maximum plasma concentration (CMAX) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)	To determine the maximum plasma concentration (CMAX) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)	Up to 72 hours post dose
Secondary	Area under the plasma concentration time curve (AUC) of midazolam(TPX-0005) (Phase 1)	To determine the area under the plasma concentration time curve (AUC) of midazolam(TPX-0005) (Phase 1)	Up to 24 hours post dose
Secondary	Maximum plasma concentration (CMAX) of midazolam(TPX-0005) (Phase 1)	To determine the maximum plasma concentration (CMAX) of midazolam(TPX-0005) (Phase 1)	Up to 24 hours post dose
Secondary	Plasma concentration of repotrectinib following administration at RP2D (Phase 2)	To evaluate the plasma concentration of repotrectinib following administration at RP2D (Phase 2)	Pre dose and 4 hours post dose
Secondary	Preliminary objective response rate (ORR) (Phase 1)	To determine the preliminary objective response rate (ORR) by Blinded Independent Central Review (BICR) (Phase 1)	Approximately three years
Secondary	Duration of response (DOR) (Phase 2)	To determine the DOR of repotrectinib (TPX-0005) (Phase 2)	Approximately three years
Secondary	Clinical benefit rate (CBR) (Phase 2)	To determine the CBR of repotrectinib (TPX-0005) (Phase 2)	Approximately three years
Secondary	Progression free survival (PFS) (Phase 2)	To determine the PFS (Phase 2)	Approximately three years
Secondary	Overall survival (OS) (Phase 2)	To determine the OS (Phase 2)	Approximately three years
Secondary	Intracranial objective response rate (Phase 2)	To determine the intracranial objective response rate (Phase 2)	Approximately three years

External Links

•   BMS Clinical Trial Information
•   BMS Clinical Trial Patient Recruiting