A Phase 1/2 Study of the Highly Selective ROS1 Inhibitor NVL-520 in Patients with Advanced NSCLC and Other Solid Tumors (ARROS-1)

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 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 whohave progressed on prior ROS1 TKIs). Any
number of prior platinum-based chemotherapies with or without immunotherapy is
allowed. b. Cohort 2a: Must be nai*ve to TKI therapy and up to one prior
platinum-based chemotherapy (with or without immunotherapy). c. Cohort 2b: Must
have received 1 prior ROS1 TKI therapy (either crizotinib or entrectinib) and
no prior platinum-based chemotherapy or immunotherapy. 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). e. Cohort
2d: Must have received at least 2 prior ROS1 TKI therapies and up to 1 prior
platinum-based chemotherapy (with or without immunotherapy). f. Cohort 2e: Must
have progressed on any prior therapy (includes, but is not limited to, patients
who have progressed on prior ROS1 TKIs). 4. Phase 1: Must have evaluable
disease (target or nontarget) according to RECIST 1.1 (Eisenhauer et al, 2009;
Appendix 3). 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. 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 approved for enrollment after
consultation with the Sponsor*s Medical Monitor. 6. Eastern Cooperative
Oncology Group (ECOG) performance status (PS) of 0, 1 or 2 (Oken et al, 1982).
Patients with ECOG PS2 require approval by Sponsor*s medical monitor. 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 >=60 mL/min per Cockroft-Gault formula, modified
Cockroft-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
clinically relevant toxicities related to prior anticancer therapy must have
recovered to Grade <=1 or baseline (except alopecia or ototoxicity). 9. Women of
childbearing potential (WOCBP) must be surgically sterile or be willing to
abstain from sexual activity or use an effective contraceptive method from the
time of signing the informed consent form (ICF) through at least 6 months after
the last administration of study drug (or longer, if required by local or
country-specific guidance). Male patients with pregnant or non-pregnant WOCBP
partners must use male contraception (condom) from the time of signing the ICF
through at least 4 months after the last administration of study drug (or
longer, if required by local or country-specific guidance). Refer to Section
8.3.2 for acceptable methods of contraception. 10. Provide written informed
consent and willing and able to comply with requirements of the study protocol.
Phase 2 Cohort 2e only: Assent must be obtained for patients <18 years old (or
for minors who have not reached the age of consent, as defined by local
regulations) and a parent/guardian must provide written consent.

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, 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: <5 half-lives or <7 days, whichever is longer b.
Chemotherapy, antibody-drug conjugates (ADCs), or other antibodies: <21 days.
c. Immunotherapy or cellular therapy <28 days 5. 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) <14 days.
b. Palliative radiation to relieve bone pain <48 hours. c. Stereotactic or
small field brain irradiation <7 days. d. Whole brain radiation <14 days. 6.
Prior high-dose chemotherapy requiring stem cell rescue. 7. Uncontrolled
clinically relevant bacterial or fungal infection requiring systemic therapy.
8. Has known active tuberculosis or active Hepatitis B or C. Active Hepatitis B
is defined as a known positive HBsAg result and known quantitative HBV DNA
results greater than the lower limits of detection of the assay. Active
Hepatitis C is defined by a known positive Hep C Ab result and known
quantitative HCV RNA results greater than the lower limits of detection of the
assay. 9. Patient has a QTcF >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: