Advanced Non-Small Cell Lung Cancer (NSCLC) and Other Solid Tumors with ALK rearrangement or activating ALK mutation.
Conditions
Sponsors
Nuvalent, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age =18 years a. Phase 2 Cohort 2d only: Age =12 years and weighing >40 kg. (Patients age 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 a documented ALK rearrangement or activating ALK mutation detected by certified assay (i.e. CLIA in the US). The report from this test is required to be submitted for eligibility. b. Phase 2 Cohorts 2a, 2b, and 2c: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with a documented ALK rearrangement detected by certified assay (i.e. CLIA in the US). The report from this test is required to be submitted for eligibility. c. Phase 2 Cohort 2d: Any other histologically or cytologically confirmed locally advanced or metastatic solid tumor with a documented ALK rearrangement or activating ALK mutation detected by certified assay, including but not limited to anaplastic large cell lymphoma, inflammatory myofibroblastic tumors, diffuse large B-cell lymphoma, esophageal squamous cell carcinoma, renal medullary carcinoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, cholangiocarcinoma, spitzoid tumors, neuroblastoma, anaplastic thyroid cancer, and patients with NSCLC not eligible for Cohorts 2a-c. The report from this test is required to be submitted for eligibility. 3. Prior anticancer treatment: a. Phase 1: Patients with ALK fusion-positive NSCLC must have previously received =1 ALK TKI, one of which must be a 2nd or 3rd generation TKI (ceritinib, alectinib, brigatinib, or lorlatinib). Patients with other solid tumors must have previously received =1 prior systemic anticancer therapy or be those for whom no satisfactory standard therapy exists. b. Phase 2 Cohort 2a: 1 prior 2nd generation ALK TKI c. Phase 2 Cohort 2b: 2-3 prior 1st or 2nd generation ALK TKIs (crizotinib, ceritinib, alectinib, or brigatinib) d. Phase 2 Cohort 2c: 2-3 prior ALK TKIs, with lorlatinib received in the 2nd or 3rd line of therapy e. Phase 2 Cohort 2d: =1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists f. All patients except Phase 2 Cohort 2d: = 2 prior lines of chemotherapy and/or immunotherapy in the locally advanced or metastatic setting. Patients who have received >2 prior lines of chemotherapy and/or immunotherapy in the locally advanced or metastatic setting may be enrolled in Phase 2 Cohort 2d. g. Phase 2 Cohorts 2a, 2b and 2c: No prior investigational agents targeting ALK. Patients who previously received investigational agents targeting ALK may be enrolled in Phase 1 and Phase 2 Cohort 2d. 4. Phase 1: Must have evaluable disease (target or nontarget) according to RECIST 1.1 (Appendix 3). Phase 2: Must have measurable disease, defined as =1 radiologically measurable target lesion according to RECIST 1.1 (Appendix 3). 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. 5. Pre-treatment tumor tissue (archived, if available, or a fresh biopsy) submitted for central analysis. It is preferable that submitted tumor tissue be obtained during or after the most recent disease progression. If appropriate tissue is not available, and if biopsy is not considered safe and medically feasible by the Investigator, the patient may be appr
Exclusion criteria
Exclusion criteria: 1. Patient’s cancer has a known oncogenic driver alteration other than ALK. Investigators should discuss enrollment with the Sponsor regarding co-mutations. 2. Known allergy/hypersensitivity to excipients of NVL-655. 3. Major surgery within 4 weeks of the first dose of study drug. Minor surgical procedures (e.g., 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-655 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 non-chemotherapy/non-immunotherapy anticancer agents 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 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 ALK-positive solid malignancy) requiring systemic therapy within the prior 2 years. Exceptions: nonmelanoma skin cancer, in situ melanoma, in situ cervical cancer, papillary thyroid cancer, ductal carcinoma in situ of the breast, or localized and presumed cured prostate cancer. Patients on long-term anti-hormonal therapy for a prior malignancy are allowed if the malignancy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - To evaluate the efficacy of NVL-655 at the RP2D in patients with advanced ALK-positive NSCLC, including those with ALK resistance mutations, and other solid tumors.;Secondary Objective: - To assess additional measures of clinical efficacy in patients with ALK-positive NSCLC, including those with ALK resistance mutations, and other solid tumors; - To evaluate the intracranial antitumor activity of NVL-655 at the RP2D in patients with advanced ALK-positive NSCLC and other solid tumors; - To characterize the safety and tolerability of NVL-655 at the RP2D. To confirm the PK profile of NVL-655 at the RP2D.;Primary end point(s): RP2D and, if applicable, the MTD as determined by incidence of DLTs during Cycle 1, overall safety profile, PK, PD, and preliminary efficacy.;Timepoint(s) of evaluation of this end point: Table 1: Schedule of Assessments Phase 1 and Phase 2 (All Cohorts) Table 2: Schedule of Pharmacokinetic Sampling Timepoints (Phase 1 and Phase 2) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Incidence and severity of TEAEs and changes in clinically relevant laboratory parameters; PK parameters of NVL-655: 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; and t1/2; ORR: Defined as the percent of patients with a CR or PR according to RECIST 1.1 per Investigator assessment; DOR: In responders, defined as the time from first Investigator-assessed response per RECIST 1.1 to radiographic disease progression or death; IC-ORR: In patients with measurable metastatic CNS disease at baseline, defined as the proportion of patients with a confirmed intracranial response (IC-CR or IC-PR) per investigator, based on assessment of up to 5 intracranial target lesions according to RECIST 1.1 principles; IC-DOR: In patients with intracranial response, defined as the time from first Investigator-assessed IC-response per RECIST 1.1 to radiographic IC-disease progression or death; CBR: Defined as the percent of patients with a confirmed CR or PR, or SD of at least 24 weeks duration according to RECIST 1.1 per Investigator assessment; Time to response: Defined as the time from first dose to first confirmed radiographic response according to RECIST 1.1 per Investigator assessment; PFS: Defined as the time from first dose to radiographic disease progression per RECIST 1.1 based on Investigator assessment or death. ;Timepoint(s) of evaluation of this end point: Table 1: Schedule of Assessments Phase 1 and Phase 2 (All Cohorts) Table 2: Schedule of Pharmacokinetic Sampling Timepoints (Phase 1 and Phase 2) | — |
Countries
Australia, Belgium, Canada, France, Germany, Netherlands, Spain, United Kingdom, United States
Contacts
Public ContactTina Kehrig
Nuvalent, Inc.
Outcome results
None listed