Advanced Non-Small Cell Lung Cancer (NSCLC)and Other Solid Tumors with ROS1+ rearrangement
Conditions
Sponsors
Nuvalent, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients must meet all of the following criteria to be eligible to enroll in the study: 1.Age =18 years a.Phase 2 Cohort 2e only: Age =12 years and weighing > 40 kg. (Patients ages 12 to 17 will only be enrolled in countries and at sites where regulations allow.) 2.Disease criteria a.Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with documented ROS1 rearrangement, determined by testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab outside the United States (US) and using a local diagnostic test or a commercial test or by a regulatory agency approved test, such as fluorescence in situ hybridization (FISH) or next generation sequencing (NGS) or reverse transcription polymerase chain reaction (RT-PCR). The report from this test is required to be submitted for eligibility. b.Cohorts 2a, 2b, 2c and 2d: Histologically or cytologically confirmed locally advanced or metastatic NSCLC (excluding patients with transformation to non-NSCLC histology) with ROS1 rearrangement as determined by testing in a CLIA or equivalently accredited diagnostic lab using a local diagnostic test or a commercial test or by a regulatory agency approved test, such as FISH or NGS or RT-PCR. The report from this test is required to be submitted for eligibility. c. Cohort 2e: Histologically or cytologically confirmed locally advanced or metastatic solid tumor (including NSCLC not eligible for Cohorts 2a-2d) with ROS1 rearrangement as determined by testing in a CLIA or equivalently accredited diagnostic lab using a local diagnostic test or a commercial test or by a regulatory agency approved test, such as FISH or NGS or RT-PCR. The report from this test is required to be submitted for eligibility. 3. Prior anticancer treatment a.Phase 1: Patients with ROS1 fusion-positive NSCLC must have previously received at least 1 prior ROS1 TKI, while those with other ROS1-positive solid tumors must have progressed on any prior therapy (includes, but is not limited to, patients who have progressed on prior ROS1 TKIs). Any number of prior platinum-based chemotherapies with or without immunotherapy is allowed. ... d. Cohort 2c: Must have received 1 prior ROS1 TKI therapy (either crizotinib or entrectinib) and 1 prior platinum-based chemotherapy with or without immunotherapy ... 4. Phase 1: Must have evaluable disease (target or nontarget) according to RECIST 1.1 (Eisenhauer 2009, Appendix 2). Phase 2: Must have measurable disease, defined as =1 radiologically measurable target lesion according to RECIST 1.1. Note: Patients with CNS-only disease are eligible, provided that the disease is evaluable (Phase 1) or measurable (Phase 2) and does not meet Exclusion Criterion #11 ... 7. Adequate organ function and bone marrow reserve as indicated by the following laboratory values on last assessment prior to the first dose of study drug: a. Bone marrow function: absolute neutrophil count (ANC) =1500/µL; platelet count >75,000/µL; hemoglobin =8 g/dL (without transfusion). b. Renal function: estimated creatinine clearance =45 mL/min per Cockcroft-Gault formula, modified Cockcroft-Gault formula, or 24 hour creatinine clearance. c.Hepatic function: bilirubin <1.5×ULN, unless evidence of Gilbert Syndrome, in which the patient must have total bilirubin <3.0 mg/dL; aspartate aminotransferase and alanine aminotransferase =3.0×ULN (=5.0×ULN if liver metastases involvement). 8. All
Exclusion criteria
Exclusion criteria: Patients meeting any of the following criteria will be excluded from the study: 1. Patient’s cancer has a known oncogenic driver alteration other than ROS1. For example, NSCLC with a targetable mutation in EGFR, ALK, MET, RET, KRAS or BRAF; colorectal with an oncogenic KRAS, NRAS, or BRAF mutation. Investigators should discuss enrollment with the Sponsor regarding co-mutations. 2. Known allergy/hypersensitivity to excipients of NVL-520. 3. Major surgery within 4 weeks of first dose of study drug. Minor surgical procedures (eg, port insertion) are permitted, but with sufficient time for wound healing as deemed clinically appropriate. 4. Ongoing or recent anticancer therapy within the following timeframe prior to first dose of study drug (NVL-520 may be started within limits for prior TKI or chemotherapy if considered by the Investigator to be safe and within the best interest of the patient, with prior approval from the Sponsor): a. TKI or other anticancer therapy not listed below in exclusion criteria 4b or 4c: 450 msec (repeated demonstration on more than one assessment). Patient has a history of prolonged QT syndrome or Torsades de pointes. 10. Patients with clinically significant cardiovascular disease as follows: a. Within 3 months of enrollment: cerebral vascular accident/stroke; myocardial infarction; unstable angina; uncontrolled atrial fibrillation of any grade b. History of congestive heart failure (New York Heart Association Classification Class =II); second-degree or third-degree atrioventricular block (unless paced) or any atrioventricular block with PR consistently >220 msec; or ongoing cardiac dysrhythmias of NCI-CTCAE Grade =2. 11. Patient has central nervous system (CNS) metastases or a primary CNS tumor that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a patient requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks preceding C1D1. Asymptomatic leptomeningeal carcinomatosis is allowed. 12. Symptomatic spinal cord compression. 13. Patients with moderate to severe cognitive impairment or psychiatric disturbances that would compromise the patient’s ability to comply with study requirements in the Investigator’s opinion. 14. Evidence of active malignancy (other than current ROS1-positive solid malignancy) requiring systemic therapy w
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: English Phase 1 Primary Objective • To determine the RP2D and, if applicable, the maximum tolerated dose (MTD) of NVL-520 in patients with advanced ROS1-positive solid tumors Phase 2 Primary Objective • To evaluate the ORR of NVL-520 at the RP2D in patients with advanced ROS1-positive NSCLC;Secondary Objective: Phase 1 - Secondary Objectives • To evaluate the overall safety and tolerability of NVL-520 • To characterize the PK profile of NVL-520 • To evaluate preliminary antitumor activity of NVL-520 in patients with advanced ROS1 positive solid tumors Phase 2 - Secondary Objectives • To assess additional measures of clinical efficacy in patients with ROS1-positive NSCLC • To assess clinical efficacy in patients with non-NSCLC ROS1-positive solid tumors • To evaluate the intracranial antitumor activity of NVL-520 at the RP2D in patients with advanced ROS1-positive NSCLC and other solid tumors • To characterize the safety and tolerability of NVL-520 at the RP2D • To confirm the PK profile of NVL-520 and metabolite M9 at the RP2D • To assess treatment-related symptoms and general health status using validated instruments of patient-reported outcomes (PROs) in patients treated with NVL-520;Primary end point(s): Phase 1 • RP2D and, if applicable, the MTD as determined by incidence of DLTs during Cycle 1, overall safety profile, PK, PD, and preliminary efficacy Phase 2 • ORR per RECIST 1.1 - Defined as the proportion of patients with a confirmed CR or PR according to RECIST 1.1 per Blinded Independent Central Review (BICR);Timepoint(s) of evaluation of this end point: Table 1: Schedule of Assessments Phase 1 and Phase 2 (All Cohorts) Assessments/Procedures Table 2: Schedule of Pharmacokinetic Sampling Timepoints (Phase 1 and Phase 2) • DOR per RECIST 1.1 • CBR per RECIST 1.1 • Incidence and severity of TEAEs and changes in clinically relevant laboratory parameters • Pharmacokinetic parameters of NVL-520 - Cmax, Cmax - dose normalized, Ctau, Cavg, | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Incidence and severity of treatment-emergent adverse events (TEAEs) and changes in clinically relevant laboratory parameters • Pharmacokinetic parameters of NVL-520 - Maximum plasma concentration (Cmax); Cmax – dose normalized, plasma concentration at the end of the dosing interval (Ctau); average plasma concentration (Cavg); time of maximum concentration (Tmax); area under the curve at the end of the dosing interval (AUCtau); AUCtau – dose normalized, area under the curve from time 0 to 24 (AUC0-24); AUC0-24 – dose normalized, area under the curve from time 0 to infinity (AUCinf); AUCinf – dose normalized; oral clearance (CL/F); volume of distribution (Vz/F); and half-life (t1/2) • Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Phase 2 • DOR per RECIST 1.1 • CBR per RECIST 1.1 • Incidence and severity of TEAEs and changes in clinically relevant laboratory parameters • Pharmacokinetic parameters of NVL-520 - Cmax, Cmax - dose normalized, Ctau, Cavg, Tmax, AUCtau, AUCtau - dose normalized, AUC0-24, AUC0-24 – dose normalized, AUCinf, AUCinf – dose normalized, CL/F, Vz/F, t1/2 • PFS per RECIST 1.1 • Overall survival (OS);Timepoint(s) of evaluation of this end point: Table 1: Schedule of Assessments Phase 1 and Phase 2 (All Cohorts) Assessments/Procedures Table 2: Schedule of Pharmacokinetic Sampling Timepoints (Phase 1 and Phase 2) | — |
Countries
Australia, Belgium, Canada, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Singapore, Spain, Taiwan, United Kingdom, United States
Contacts
Public ContactGosia Riley
Nuvalent, Inc.
Outcome results
None listed