Multiple Adjunct Therapies to Improve Immunotherapy Treatment in Patients With Locally Advanced or Metastatic Melanoma or Advanced Hepatocellular Cancer

Inclusion Criteria:

* Histologically or cytologically confirmed locally advanced or metastatic melanoma or advanced hepatocellular cancer (HCC); histologic/cytologic confirmation not required for HCC
* Eligible and planned to begin therapy with PD1/PDL-1 inhibitors as standard of care first-line therapy, either as monotherapy or in combination with other approved immune checkpoint inhibitors or bevacizumab
* Age ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Absolute neutrophil count ≥ 1,000/mcl
* Hemoglobin ≥ 8.0 g/dL
* Platelets ≥ 75,000/mcl
* Total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN in Gilbert's syndrome
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 × ULN for patients without liver metastasis ≤ 5 × ULN for patients with liver metastasis
* Creatinine clearance \> 30 mL/min per Cockcroft-Gault
* Females of childbearing potential must agree to sexual abstinence (defined below) or be willing to use a highly effective method of contraception from the start of therapy through 90 days after the completion of therapy.

Non-childbearing potential is defined as:

* Postmenopausal, defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
* Surgically sterile. Surgical sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.

Acceptable highly effective birth control methods include:

* Oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation
* Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation
* Intrauterine device
* Intrauterine hormone-releasing system
* Bilateral tubal occlusion
* Vasectomized partner (provided that partner is the sole sexual partner of the female of reproductive potential and that the vasectomized partner has received medical assessment of the surgical success)
* Sexual abstinence. In the context of this study sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse from the start of therapy through 90 days after the completion of therapy

  * Males who have female partners of childbearing potential must agree to use a highly effective method of contraception from the start of therapy through 90 days after the completion of therapy
  * Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

* Prior systemic anticancer therapy for locally advanced or metastatic disease. Therapy in the neoadjuvant or adjuvant setting is allowed if the last dose of neo/adjuvant therapy is at least 6 months prior to first dose of study treatment
* A known history or autoimmune disease requiring systemic immunosuppressive therapy; or any disease process requiring systemic immunosuppressive therapy (e.g. high-dose steroids defined as ≥ 10 mg prednisone or equivalent per day).

  * Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed
* History of grade ≥ 3 immune-related adverse event(s) associated with prior immunotherapy, unless these events did not require hospitalization, were manageable with medical therapy, and adequately resolved within 14 days
* Medical requirement for beta blockers or histamine 1 (H1) blockers
* Has active central nervous system (CNS) metastases and/or any history of leptomeningeal disease

  * Note: Patients with previously treated brain metastases may participate provided they are radiologically stable (i.e. no evidence of progression for ≥ 4 weeks by repeat imaging performed during study screening), clinically stable, and not requiring steroid treatment within 14 days prior to first dose of study treatment
* Has received a live vaccine administered within 28 days of planned treatment start or while participating in the study
* Patients must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants
* History of or current condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate
* Contraindications to the use of beta-blockers, including but not limited to unstable angina pectoris, uncontrolled heart failure (Grade III or IV), hypotension (systolic blood pressure \< 100 mmHg), bradycardia
* Patients must not be receiving other concomitant biologic therapy, hormonal therapy, chemotherapy, other anti-cancer therapy or any other investigational agents while on this protocol