• This is a first-in-human, Phase 1/2, multicenter, open-label, dose escalation and expansion study designed to evaluate the safety and tolerability of NVL-655

NVL-655 15mg QD

• RP2D and, if applicable, the MTD as determined by incidence of DLTs during Cycle 1, overall safety profile, PK, pharmacodynamics, and preliminary efficacy

• 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.
• Phase 2 Cohorts 2a, 2b, and 2c: Histologically or cytologically confirmed locally advanced or metastatic NSCLC (excluding patients with documented transformation to non-NSCLC histology) 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.
Prior anticancer treatment
• Phase 2 Cohort 2a: 1 prior 2nd generation ALK TKI (ceritinib, alectinib, or brigatinib)
• Phase 2 Cohort 2b: 2-3 prior 1st or 2nd generation ALK TKIs (crizotinib, ceritinib, alectinib, or brigatinib)
• Phase 2 Cohort 2c: 2-3 prior ALK TKIs, with lorlatinib received in the 2nd or 3rd line of therapy
• Phase 2 Cohort 2d: ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists
• 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.

• Cohort 2A and 2C are recruiting, cohort 2B and 2E are closed.

• 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 anticancer therapy not listed below in exclusion criteria 4b or 4c: <5 half-lives or <7days, whichever is longer.
b. Chemotherapy, antibody-drug conjugates (ADCs), or other antibodies:
c. Immunotherapy or cellular therapy <28days
• Ongoing or recent radiation therapy within the following timeframe prior to first dose of study drug:
a. Radiation therapy (except palliative radiation to relieve bone pain) <14days
b. Palliative radiation to relieve bone pain <48 hours
c. Stereotactic or small field brain irradiation <7days
d. Whole brain radiation <14days