Phase 1/2, dose escalation and expansion study designed to evaluate the safety and tolerability of zidesamtinib (NVL-520), determine the recommended phase 2 dose (RP2D), and evaluate the antitumor activity in patients with advanced ROS1-positive (ROS1+) NSCLC and other advanced ROS1-positive solid tumors. Phase 1 will determine the RP2D and, if applicable, the maximum tolerated dose (MTD) of zidesamtinib in patients with advanced ROS1-positive solid tumors. Phase 2 will determine the objective response rate (ORR) as assessed by Blinded Independent Central Review (BICR) of zidesamtinib at the RP2D. Secondary objectives will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and clinical benefit rate (CBR) of zidesamtinib in patients with advanced ROS1-positive NSCLC and other solid tumors.
In Phase 2, study patients will be enrolled into 5 distinct expansion cohorts: * Cohort 2a: ROS1-positive NSCLC naïve to Tyrosine Kinase Inhibitor (TKI) therapy and up to 1 prior chemotherapy and/or immunotherapy. * Cohort 2b: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy. * Cohort 2c: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy. * Cohort 2d: ROS1-positive NSCLC treated with ≥2 prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy. * Cohort 2e: ROS1-positive solid tumor and progressed on any prior therapy.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
359
Oral tablet of zidesamtinib (NVL-520)
UCI Medical Center
Orange, California, United States
RECRUITINGStanford Medicine
Palo Alto, California, United States
RECRUITINGUC Davis Comprehensive Cancer Center
Sacramento, California, United States
RECRUITINGUniversity of Colorado Cancer Center
Denver, Colorado, United States
Maximum Tolerated Dose (MTD) (Phase 1)
Highest dose with dose-limiting toxicity (DLT) rate ≤ 25%
Time frame: Within 28 days of last patient dosed during dose escalation
Recommended Phase 2 Dose (RP2D)
To determine the RP2D
Time frame: Within 28 days of last patient dosed during dose escalation.
Objective Response Rate (ORR) (Phase 2)
To determine ORR as assessed by BICR
Time frame: 2-3 years after first patient dosed.
Number of participants with treatment-emergent adverse events, as assessed by CTCAE, v5.0
Incidence and severity of treatment-emergent adverse events (TEAEs)
Time frame: Approximately 3 years.
Maximum plasma concentration (Cmax) of NVL-520
To determine the maximum plasma concentration (Cmax) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Plasma concentration at the end of the dosing interval (Ctau) of NVL-520
To determine the plasma concentration at the end of the dosing interval (Ctau) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Average plasma concentration (Cavg) of NVL-520
To determine the average plasma concentration (Cavg) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Time of maximum concentration (Tmax) of NVL-520
To determine the time of maximum concentration (Tmax) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Area under the curve at the end of the dosing interval (AUCtau) of NVL-520
To determine the area under the curve at the end of the dosing interval (AUCtau) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Area under the curve from time 0 to 24 (AUC0-24) of NVL-520
To determine the area under the curve from time 0 to 24 (AUC0-24) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Area under the curve from time 0 to infinity (AUCinf) of NVL-520
To determine the area under the curve from time 0 to infinity (AUCinf) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Oral clearance (CL/F) of NVL-520
To determine the oral clearance (CL/F) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Volume of distribution (Vz/F) of NVL-520
To determine the volume of distribution (Vz/F) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Half-life (t1/2) of NVL-520
To determine the half-life (t1/2) of NVL-520
Time frame: Pre-dose and up to 24 hours post-dose
Objective response rate (ORR)
Determine ORR as assessed by BICR
Time frame: 2-3 years after first patient dosed
Duration of response (DOR)
Determine DOR of NVL-520 until radiographic disease progression or death
Time frame: 2-3 years after first patient dosed
Clinical benefit rate (CBR)
Determine CBR of NVL-520
Time frame: 2-3 years after first patient dosed
Time to response
Determine time to response of NVL-520
Time frame: 2-3 years after first patient dosed
Progression-free survival (PFS)
Determine PFS of NVL-520 until radiographic disease progression or death
Time frame: Approximately 3 years
Overall survival (OS)
Determine OS
Time frame: Approximately 3 years
Rate of CNS progression
The incidence of CNS as first site of progression, alone or with concurrent extra-CNS progression
Time frame: Approximately 3 years
Intracranial objective response rate (IC-ORR)
Determine the intracranial objective response rate
Time frame: Approximately 3 years
Quality of life assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
EORTC QLQ-C30 measures cancer patients' physical, psychological, and social functions. Scale ranges from: 1, "Not at all"; 2, "A little"; 3, "Quite a bit"; to 4, "Very much." Higher score for the functioning scales and global health status denotes a better level of functioning, while higher scores on the symptom and single-item scales indicate a higher level of symptoms.
Time frame: 2-3 years after first patient dosed
Quality of life assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 29 module (EORTC QLQ-LC29)
EORTC-QLQ-LC29 measures the quality of life in patients with lung cancer. Symptom scale ranges from: 1, "Not at all"; 2, "A little"; 3, "Quite a bit"; to 4, "Very much." For symptoms scales, higher scores indicated greater symptom burden.
Time frame: 2-3 years after first patient dosed
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Georgetown University Medical Center
Washington D.C., District of Columbia, United States
RECRUITINGUniversity of Miami
Coral Gables, Florida, United States
RECRUITINGUniversity of Chicago
Chicago, Illinois, United States
RECRUITINGMass General Hospital
Boston, Massachusetts, United States
RECRUITINGDana-Farber Cancer Institute
Boston, Massachusetts, United States
RECRUITINGHenry Ford Cancer Institute
Detroit, Michigan, United States
RECRUITING...and 53 more locations