A Phase 1/2 Study of the Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor NVL-655 in Patients with Advanced NSCLC and Other Solid Tumors (ALKOVE-1)

1. Age >=18 years
a. Phase 2 Cohort 2f 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 except 2f: 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.
c. Phase 2 Cohort 2f: 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 inflammatory myofibroblastic tumors,
esophageal squamous cell carcinoma, renal medullary carcinoma, renal
cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, papillary
thyroid carcinoma, cholangiocarcinoma, spitzoid tumors, neuroblastoma,
and anaplastic thyroid cancer. 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 (ceritinib,
alectinib, or brigatinib) as the only prior ALK TKI; no prior
investigational agents targeting ALK; <= 2 prior lines of chemotherapy
and/or immunotherapy.
c. Phase 2 Cohort 2b: 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib,
brigatinib or lorlatinib; excluding patients who received lorlatinib as the
1st ALK TKI); no prior investigational agents targeting ALK; <= 2 prior
lines of chemotherapy and/or immunotherapy.
d. Phase 2 Cohort 2c: Lorlatinib as the only prior ALK TKI; no prior
investigational agents targeting ALK. Up to 1 prior line of chemotherapy
and/or immunotherapy received prior to lorlatinib is allowed.
e. Phase 2 Cohort 2d: Treatment naïve to ALK TKI therapy. Up to 1 prior
line of chemotherapy and/or immunotherapy is allowed.
f. Phase 2 Cohort 2e: Any number of prior ALK TKIs, chemotherapy
and/or immunotherapy; not eligible for other Phase 2 cohorts.
g. Phase 2 Cohort 2f: >=1 prior systemic anticancer therapy, or for whom
no satisfactory standard therapy exists
4. Phase 1: Must have evaluable disease (target or nontarget)
according to RECIST 1.1. 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. ECOG PS of 0 or 1
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: ANC >=1500/µL; platelet count
>75,000/µL;
hemoglobin >=8 g/dL (without transfusion)
b. Renal function: estimated creatinine clearance >=60 mL/min
c. Hepatic function: bilirubin <1.5×ULN, unless evidence of Gilbert
Syndrome, in which the patient must have total bilirubin <3.0 mg/dL;
AST and ALT <=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. WOCBP must be surgically sterile or be willing to abstain from sexual
activity or use a highly effective contraceptive method (CTFG 2020) from
the time of signing the 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).
For criteria #10 please refer to protocol.

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 therapy not listed in exclusion criteria 4b or 4c below: <5 half-lives
or <7 days, whichever is longer.
b. Chemotherapy, 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 quantitative HBV DNA results greater
than the lower limits of detection of the assay. Active Hepatitis C is
defined by a 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:
a. Within 3 months of enrollment: cerebral vascular accident/stroke;
myocardial infarction; unstable angina; Grade >= 3 atrial fibrillation.
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
(excluding atrial fibrillation).
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, or localized and presumed cured breast
or prostate cancer. Patients on long-term anti-hormonal therapy for a
prior malignancy are allowed if the malignancy has not been active
within the prior 2 years.
15. Concomitant use (within 12 days of first dose of study drug) of
strong CYP3A4 inducers or strong CYP3A4 inhibitors.
16. Manifestation of malabsorption due to prior gastrointestinal
surgery, disease, or other illness that could affect oral absorption,
distribution, metabolism, or excretion of the study drug.
17. Patient is pregnant or breastfeeding. WOCBP must have a negative
serum pregnancy test at Screening and negative serum or urine test
prior to first dose of study drug.
18. Patient is actively receiving systemic treatment or direct medical
intervention on another therapeutic clinical study.
19. Any evidence of current ILD or pneumonitis or a prior history of ILD
or non-infectious pneumonitis.
20. Any medical condition or laboratory abnormality that in the opinion
of the Investigator or Sponsor would pose a risk to study patient or
confound the ability to interpret study results.