Brigham Research Institute (BRI) - Brigham and Women's Hospital

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Participants must meet the following eligibility criteria at the time of screening to be
eligible to participate in the study:

Eligibility Criteria

1. Participants must have histologically confirmed adenoid cystic carcinoma (ACC) with
evidence of recurrent, metastatic or advanced, incurable disease arising from any
primary site

2. Activating mutation in the NOTCH signaling pathway

3. In Cohort 1 only, prior multitargeted VEGFR TKI or systemic therapy is permitted.

4. In Cohort 2 only, no prior multitargeted VEGFR TKI therapy is permitted, but prior
systemic chemotherapy as part of definitive or curative intent management is
permitted.

a. Any participant must obtain prior approval from insurance to reimburse for oral
Lenvatinib, or off-label drug assistance to secure Lenvatinib for the duration of
the study or agree to self-pay for oral Lenvatinib or obtain institutional
commitment from the study site to provide Lenvatinib.

5. Age 18 years or older

6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

7. Patients able and willing to swallow oral capsules or tablet medications.

8. At least one measurable lesion (RECIST v1.1)

9. Participant must have organ and marrow function as defined below within 14 days
prior to study registration (ULN=upper limit of normal per institution):

Absolute neutrophil count (ANC) ≥1.5 x 109/L Hemoglobin (Hgb) ≥9 g/dL (patients may
receive erythrocyte transfusions to achieve this hemoglobin level at the discretion
of the investigator. Initial treatment must not begin earlier than the day after the
erythrocyte transfusion).

Platelet count ≥100 x 109/L (without transfusion within the last 5 days) Serum
creatinine ≤1.5x ULN or serum creatinine clearance (CrCl) ≥50 mL/min (estimated by
Cockcroft-Gault formula) Serum aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) ≤3x ULN Total serum bilirubin ≤1.5x ULN (patients with
Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within
normal limits are permitted).

10. Baseline proteinuria with a urinalysis or urine dipstick value of 2+ requires a spot
urine protein/creatinine ratio of <0.3 (or 24-hour urine collection protein value
<300 mg/g) in Cohort 2 only

11. Participants with treated brain or CNS metastases are eligible if follow-up brain
imaging after CNS-directed therapy shows no convincing evidence of progression and
patients are neurologically stable with no new neurological deficits.

12. Female subjects of childbearing potential should have a negative serum pregnancy
test within 7 days before start of study treatment.

13. Female and male subjects of childbearing potential must agree to use an adequate
method of contraception to avoid pregnancy (with at least 99% certainty) from
screening through 90-days or 3-months post-treatment completion (see Appendix B).

14. Participants with a prior or concurrent malignancy whose natural history or
treatment does not have the potential to interfere with the safety or efficacy
assessment of the investigational regimen are eligible for this trial.

15. Patients who received chemotherapy must have recovered (CTCAE grade ≤1) from the
acute effects of chemotherapy except for residual alopecia or grade 2 peripheral
neuropathy. A washout period of at least 21 days is required between last
chemotherapy dose and start of therapy (provided the patient did not receive
radiotherapy).

Exclusion Criteria

1. Participant has untreated or clinically symptomatic CNS metastases and/or
carcinomatous meningitis

2. The patient has had major surgery within 14 days prior to study registration.

3. The patient has serious and/or uncontrolled preexisting medical condition(s) that,
in the judgment of the investigator, would preclude participation in this study (for
example, interstitial lung disease, severe dyspnea at rest or requiring oxygen
therapy, severe renal impairment, history of major surgical resection involving the
stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a
preexisting chronic condition resulting in baseline grade 2 or higher diarrhea).

4. Impairment of GI function or presence of GI disease that may significantly alter the
absorption of the study agents (e.g. ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

5. The patient has active systemic bacterial infection (requiring intravenous [IV]
antibiotics at time of initiating study treatment), fungal infection, or detectable
viral infection (such as known human immunodeficiency virus positivity or with known
active hepatitis B or C [for example, hepatitis B surface antigen positive].
Screening is not required for enrollment.

6. The patient has a personal history of any of the following conditions: syncope of
cardiovascular etiology, ventricular arrhythmia of pathological origin (including,
but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
cardiac arrest

7. Pregnant or lactating women. Pregnant women are excluded from this study because of
the potential for teratogenic or abortifacient effects. Because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of
the mother, breastfeeding should be discontinued.

8. Patients who received radiotherapy must have completed and fully recovered from the
acute effects of radiotherapy. A washout period of at least 14 days is required
between end of radiotherapy and start of therapy. Patients on anticoagulants that
require INR monitoring (such as warfarin). The patient has received an experimental
treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is
longer, or is currently enrolled in any other type of medical research judged by the
sponsor not to be scientifically or medically compatible with this study.

9. Corrected QTcF >450 msec for males and >470 msec for females in screening