Locally Advanced Solid Tumor, Metastatic Solid Tumor
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGZidesamtinib (NVL-520)
Oral tablet of zidesamtinib (NVL-520)
Sponsors
Nuvalent Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years (Cohort 2e only: Age ≥12 years). 2. Disease Criteria: 1. Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with documented ROS1 rearrangement. 2. Phase 2: Cohorts 2a, 2b, 2c and 2d: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangement. 3. Phase 2: Cohort 2e: Histologically or cytologically confirmed locally advanced or metastatic solid tumor (other than NSCLC) with ROS1 rearrangement. 3. Prior anticancer treatment (except cohort 2a). 4. Phase 1: Must have evaluable disease (target or nontarget) according to RECIST 1.1. Phase 2: Must have measurable disease according to RECIST 1.1. 5. Adequate baseline organ function and bone marrow reserve.
Exclusion criteria
1. Patient's cancer has a known oncogenic driver alteration other than ROS1. 2. Known allergy/hypersensitivity to excipients of NVL-520. 3. Major surgery within 4 weeks of first dose of study drug. 4. Ongoing anticancer therapy. 5. Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) (Phase 1) | Within 28 days of last patient dosed during dose escalation | Highest dose with dose-limiting toxicity (DLT) rate ≤ 25% |
| Recommended Phase 2 Dose (RP2D) | Within 28 days of last patient dosed during dose escalation. | To determine the RP2D |
| Objective Response Rate (ORR) (Phase 2) | 2-3 years after first patient dosed. | To determine ORR as assessed by BICR |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average plasma concentration (Cavg) of NVL-520 | Pre-dose and up to 24 hours post-dose | To determine the average plasma concentration (Cavg) of NVL-520 |
| Time of maximum concentration (Tmax) of NVL-520 | Pre-dose and up to 24 hours post-dose | To determine the time of maximum concentration (Tmax) of NVL-520 |
| Area under the curve at the end of the dosing interval (AUCtau) of NVL-520 | Pre-dose and up to 24 hours post-dose | To determine the area under the curve at the end of the dosing interval (AUCtau) of NVL-520 |
| Area under the curve from time 0 to 24 (AUC0-24) of NVL-520 | Pre-dose and up to 24 hours post-dose | To determine the area under the curve from time 0 to 24 (AUC0-24) of NVL-520 |
| Area under the curve from time 0 to infinity (AUCinf) of NVL-520 | Pre-dose and up to 24 hours post-dose | To determine the area under the curve from time 0 to infinity (AUCinf) of NVL-520 |
| Oral clearance (CL/F) of NVL-520 | Pre-dose and up to 24 hours post-dose | To determine the oral clearance (CL/F) of NVL-520 |
| Volume of distribution (Vz/F) of NVL-520 | Pre-dose and up to 24 hours post-dose | To determine the volume of distribution (Vz/F) of NVL-520 |
| Half-life (t1/2) of NVL-520 | Pre-dose and up to 24 hours post-dose | To determine the half-life (t1/2) of NVL-520 |
| Objective response rate (ORR) | 2-3 years after first patient dosed | Determine ORR as assessed by BICR |
| Number of participants with treatment-emergent adverse events, as assessed by CTCAE, v5.0 | Approximately 3 years. | Incidence and severity of treatment-emergent adverse events (TEAEs) |
| Clinical benefit rate (CBR) | 2-3 years after first patient dosed | Determine CBR of NVL-520 |
| Time to response | 2-3 years after first patient dosed | Determine time to response of NVL-520 |
| Progression-free survival (PFS) | Approximately 3 years | Determine PFS of NVL-520 until radiographic disease progression or death |
| Overall survival (OS) | Approximately 3 years | Determine OS |
| Rate of CNS progression | Approximately 3 years | The incidence of CNS as first site of progression, alone or with concurrent extra-CNS progression |
| Intracranial objective response rate (IC-ORR) | Approximately 3 years | Determine the intracranial objective response rate |
| Quality of life assessment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) | 2-3 years after first patient dosed | 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. |
| 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) | 2-3 years after first patient dosed | 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. |
| Duration of response (DOR) | 2-3 years after first patient dosed | Determine DOR of NVL-520 until radiographic disease progression or death |
| Maximum plasma concentration (Cmax) of NVL-520 | Pre-dose and up to 24 hours post-dose | To determine the maximum plasma concentration (Cmax) of NVL-520 |
| Plasma concentration at the end of the dosing interval (Ctau) of NVL-520 | Pre-dose and up to 24 hours post-dose | To determine the plasma concentration at the end of the dosing interval (Ctau) of NVL-520 |
Countries
Australia, Belgium, Canada, France, Germany, Italy, Japan, Netherlands, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
Primary ContactNuvalent
Outcome results
None listed