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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)

Studio Clinico

Patologia: Neoplasie del polmone, Altre neoplasie

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: No

Fase di studio: 1, II

Richiesta mandatoria di tessuto: 

Linee di trattamento: Prima/N linee

Criteri di inclusione: 

PHASE 1
Key Inclusion Criteria:

- 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.
- ECOG PS 0-1.
- Age ≥18 (or age ≥ 20 of age as required by local regulation).
- Capability to swallow capsules intact (without chewing, crushing, or opening).
- 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.
- Prior cytotoxic chemotherapy is allowed.
- Prior immunotherapy is allowed.
- 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.
- Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria.
- 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
- Life expectancy ≥ 3 months.

PHASE 2
Key Inclusion Criteria

- 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.
- Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based local testing using either:
    a) 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
   b) 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.
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
- Age ≥12 (or age ≥ 20 as required by local regulation).
- 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.
- 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.
- 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
- Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria.
- 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
- Life expectancy ≥ 3 months.

Criteri di esclusione: 

Key Exclusion Criteria PHASE 1 and PHASE 2

- Concurrent participation in another therapeutic clinical trial.
- Symptomatic brain metastases or leptomeningeal involvement.
- 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.
- 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
- 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
- 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.
- Known active infections (bacterial, fungal, viral including HIV positivity).
- Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption.
- Peripheral neuropathy of CTCAE ≥grade 2.
- 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.

Schema di trattamento: 

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

Trattamento sperimentale: 

Oral Repotrectinib (TPX-0005)

Trattamento di controllo: 

NA

Obiettivi primari dello studio: 

- Dose limiting toxicities (DLTs) (Phase 1) [ Time Frame: Within 28 days of the first repotrectinib dose ]
    Define the dose limiting toxicities (DLTs) (Phase 1)

- Recommended Phase 2 Dose (RP2D) (Phase 1) [ Time Frame: Within 28 days of the last patient dosed in escalation ]
    To determine the RP2D (Phase 1)

- Overall Response Rate (ORR) Phase 2 [ Time Frame: Two to three years after first dose of repotrectinib dose ]
    To determine the confirmed ORR of repotrectinib (TPX-0005) as assessed by Blinded Independent Central Review (Phase 2)

Centri partecipanti

Nord Italia

IRCCS Ca' Granda Ospedale Maggiore Policlinico
Via Francesco Sforza 35 - 20122 Milano - MI
NB: Phase 2

Riferimento: Dr.ssa Claudia Bareggi
Telefono: 0255032660
Email: claudia.bareggi@policlinico.mi.it

 

IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI
NB: Phase 2

Riferimento: Dr. Roberto Ferrara
Telefono: 0223903648
Email: roberto.ferrara@istitutotumori.mi.it

 

Centro di Riferimento Oncologico
Via Franco Gallini 2 - 33081 Aviano - PN
NB: Phase 2

Riferimento: Dr.ssa Alessandra Bearz
Telefono: 0434659294
Email: abearz@cro.it

 

AUSL/IRCCS di Reggio Emilia
Viale Risorgimento 80 - 42123 Reggio nell'Emilia - RE
Arcispedale Santa Maria Nuova - NB: Phase 2

 

Centro Italia

Istituto Nazionale Tumori “Regina Elena”
Via Elio Chianesi 53 - 00144 Roma - RM
Oncologia Medica 1 - NB: Phase 2

Riferimento: Prof. Federico Cappuzzo
Telefono: 0652665698
Email: federico.cappuzzo@ifo.gov.it

 

AO S. Maria Terni
Via Tristano di Joannuccio 1 - 05100 Terni - TR
NB: Phase 2

Riferimento: Dr. Sergio Bracarda
Telefono: 0744205631
Email: s.bracarda@aospterni.it

 

Sud Italia e isole

AO “V. Cervello”
Via Trabucco 180 - 90146 Palermo - PA
NB: Phase 2

Informazioni Generali

Protocollo

Numero di iscrizione a registro: NCT03093116

Data di inserimento: 09.11.2021

Promotore

Turning Point Therapeutics, Inc.

Principal Investigator ITALIA

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Riferimento: Dr. Roberto Ferrara

Telefono: 0223903648

Email: roberto.ferrara@istitutotumori.mi.it

Localita: Milano

 

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