Single arm study with dose escalation Phase Ib cohort followed by a Phase II cohort. PAC-1
(PO) will be given daily on Days 1 through 21 of each cycle (28-day cycle). Entrectinib (PO)
will be given daily on Days 1 through 28 of each cycle. Response will be evaluated after
every 2 cycles. Treatment will continue until disease progression based on RECIST criteria or
1. Written informed consent and HIPAA authorization for release of personal health
information prior to registration. NOTE: HIPAA authorization may be included in the
informed consent or obtained separately. Patients must be willing and able to provide
written informed consent for this trial.
2. Age ≥ 18 years at the time of consent.
3. Histologically or cytologically confirmed metastatic uveal melanoma. Staging per AJCC
manual edition 8.
4. One or more lesions that could be accurately measured using Response Evaluation
Criteria in Solid Tumors (RECIST) 1.1.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix 1).
6. Demonstrate adequate organ function as defined in the table below. All screening labs
to be obtained within 14 days prior to registration.
- Leukocytes ≥ 2,000 µ/l
- Absolute Neutrophil Count (ANC) ≥ 1,500 K/mm3
- Platelets ≥ 100,000/µl
- Hemoglobin (Hgb) ≥ 9 g/dL
- Serum Creatinine ≤ 1.5 x ULN
- Calculated creatinine clearance ≥ 40 mL/min
- Total Bilirubin ≤ 1.5 mg/dL
- Aspartate aminotransferase (AST) ≤ 2.5 × ULN
- Alanine aminotransferase (ALT) ≤ 2.5 × ULN
- Alkaline Phosphatase ≤ 2.5 × ULN
- Partial Thromboplastin Time (PTT) < 1.5 × ULN
7. Subjects must have archival tissue (metastatic disease preferred) available or undergo
a biopsy prior to Cycle 1 Day 1 of treatment. Subjects that do not have archival
tissue or cannot undergo a biopsy are not eligible for the study.
8. Prior therapy is allowed but must have been completed 21 days prior to initiation of
protocol therapy and all toxicities must be < Grade 2.
9. Palliative radiation must have been completed 2 weeks prior to the initiation of study
10. Patient with known brain metastases must have been treated at least 2 weeks prior to
enrollment, be asymptomatic from brain metastases, stable on brain imaging, and not be
receiving a supra-physiologic dose of steroids (>10 mg prednisone daily or
11. Women of childbearing potential (WOCBP) must agree to use contraception as outlined in
Section 5.8 from the time of informed consent, during the study and for 3 months after
the last dose of study drug(s). Abstinence from heterosexual intercourse from the time
of informed consent, during study treatment and for 3 months after the last dose of
study drug(s) is an acceptable form of contraception. Women of childbearing potential
are those who have not been surgically sterilized or have not been free of menses >1
12. Male patients who are sexually active with WOCBP must agree to use contraception as
outlined in Section 5.8 from the time of initiation of study treatment, during the
study and for 3 months after the last dose of study drug(s). Abstinence from
heterosexual intercourse from the time of initiation of study treatment, during study
treatment and for 3 months after the last dose of study drug(s) is an acceptable form
13. The participant is capable of understanding and complying with the protocol and has
signed informed consent document.
1. Peripheral sensory neuropathy Grade ≥ 2 (per CTCAE v5.0).
2. Active gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short
gut syndrome) or other malabsorption syndromes that would reasonably impact drug
3. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
4. Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive
HBsAg result. 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. For patients with past HBV infection or resolved HBV infection (defined as the
presence of hepatitis B core antibody [HBcAb] and absence of HBsAg), the patient is
only eligible if they are negative for HBV DNA.
5. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase
inhibitor-induced pneumonitis. NOTE: Radiation-induced lung disorders are not included
in this exclusion criterion.
6. History of retinal pigmented epithelial detachment, central serous retinopathy, or
retinal vein occlusion in the unaffected eye; or intraocular pressure 21 mmHg or
uncontrolled glaucoma (irrespective of intraocular pressure) in the unaffected eye.
7. History of uncontrolled seizures.
8. History of ataxia.
9. Allergies and adverse drug reaction: History of allergy to study drug components.
10. Thromboembolic events requiring therapeutic anticoagulation. Concomitant
anticoagulation with oral anticoagulants (warfarin, direct thrombin or factor Xa
inhibitors), platelet inhibitors (e.g. Clopidogrel, high dose aspirin) is prohibited.
Low-dose aspirin (<100 mg/day), low-dose warfarin (<1 mg/day) and prophylactic low
molecular weight heparin (LMWH) or similar agent are permitted.
11. History of recent (within the past 3 months) symptomatic congestive heart failure or
ejection fraction ≤ 50% observed during screening for the study.
12. History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval >
450 milliseconds from ECGs performed at least 24 hours apart).
13. History of additional risk factors for torsades de pointes (e.g., family history of
long QT syndrome).
14. Cardiovascular disorders including unstable angina pectoris, clinically-significant
cardiac arrhythmias, myocardial infarction or stroke (including transient ischemic
attack [TIA], or other ischemic event) within 6 months prior to registration.
15. Active infection requiring intravenous systemic treatment.
16. Serious non-healing wound/ulcer/bone fracture within 28 days prior to registration.
17. Known uncontrolled, symptomatic brain metastasis or cranial epidural disease.
18. Known additional malignancies which require systemic treatment.
19. Inability to swallow intact tablets.
20. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or may interfere with the interpretation of study results and, in
the judgment of the Investigator, would make the patient inappropriate for entry into
this study or could compromise protocol objectives in the opinion of the Investigator
and/or the sponsor-investigator.