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

PRIMARY OBJECTIVE:

I. Compare levels of biomarkers of immunomodulation, specifically interleukin (IL)-8, interferon gamma (IFN-y), effector T cells (Teff)/regulatory T cell (Treg) ratio, over a 12-week period, in peripheral blood of patients undergoing standard of care PD-1/PD-L1-containing immunotherapy regimens for advanced cancers randomized to Arm A or Arm B.

SECONDARY OBJECTIVE:

I. Evaluate the safety and tolerability of the combination of: magnesium, vitamin D supplements; desloratadine; propranolol in patients undergoing morning infusion of standard of care PD-1/PD-L1-containing immunotherapy regimens in Arm A.

EXPLORATORY OBJECTIVES:

I. Compare additional biomarkers of immunomodulation (including \[incl.\] cytokines, metabolites, select metal ion levels, flow cytometry, circulating tumor deoxyribonucleic acid \[ctDNA\]) over a 12-week period, in peripheral blood of patients undergoing standard of care PD-1/PD-L1-containing immunotherapy regimens for advanced cancers randomized to Arm A or Arm B.

II. Compare the preliminary clinical benefit using time to next treatment (TTNT) in patients undergoing standard of care PD-1/PD-L1-containing immunotherapy regimens for advanced cancers randomized to Arm A or Arm B.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive standard of care PD-1/PD-L1-containing immunotherapy infusion, starting before 12 PM, desloratadine orally (PO) once daily (QD), propranolol PO twice daily (BID), magnesium intravenously (IV) if magnesium level is below 1.9, and vitamin D PO QD if vitamin D level is below 30. Additional IV or oral magnesium and vitamin D supplementation may be administered at the investigator's discretion per standard of care. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan or magnetic resonance imaging (MRI) and blood sample collection throughout the study.

ARM B: Patients receive standard of care PD-1/PD-L1-containing immunotherapy, starting at standard of care time. Magnesium and vitamin D levels are checked with any supplementation per investigator discretion and institutional practice, without a prespecified goal level. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and blood sample collection throughout the study.

After completion of study treatment, patients are followed up every 3 months.

• Biospecimen Collection (Procedure), also known as Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection: Undergo blood sample collection
• Cholecalciferol (Dietary supplement), also known as 9,10-Secocholesta-5,7,10(19)-trien-3-ol, Calciol, Delsterol, Vitamin D3: Given PO
• Computed Tomography (Procedure), also known as CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography: Undergo CT scan
• Desloratadine (Drug), also known as Clarinex, Sch 34117: Given PO
• Immunotherapy (Other), also known as Immunological, Immunological Therapy, Immunologically Directed Therapy: Given standard of care immunotherapy
• Infusion Procedure (Procedure), also known as Infused, Infusion: Immunotherapy infusion given prior to 12 PM
• Infusion Procedure (Procedure), also known as Infused, Infusion: Infusion given per standard of care timing
• Magnesium Sulfate (Drug), also known as Magnesium SO4, Magnesium Sulfate whiskers, MAGNESIUM SULFATE, UNSPECIFIED FORM: Given IV
• Magnetic Resonance Imaging (Procedure), also known as Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI: Undergo MRI
• Propranolol (Drug), also known as 1-[(1-Methylethyl)amino]-3-(1-naphthalenyloxy)-2-propanol: Given PO

Primary outcomes

• Change in interleukin-8 levels [From baseline to 12 weeks]: The estimand for the null hypothesis will be the estimate of the difference in the average characteristics at week 12 stratified by the disease group. The null hypothesis will be tested at the 0.05 level. Tests of the null hypothesis will be conducted using the t-test. Departures from the normal distribution of the estimand will be assessed using the Shapiro-Wilk test.
• Change in interferon-gamma levels [From baseline, up to 12 weeks]: The estimand for the null hypothesis will be the estimate of the difference in the average characteristics at week 12 stratified by the disease group. The null hypothesis will be tested at the 0.05 level. Tests of the null hypothesis will be conducted using the t-test. Departures from the normal distribution of the estimand will be assessed using the Shapiro-Wilk test.
• Change in effector T cells (Teff)/regulatory T cell (Treg) ratio [From baseline, up to 12 weeks]: The estimand for the null hypothesis will be the estimate of the difference in the average characteristics at week 12 stratified by the disease group. The null hypothesis will be tested at the 0.05 level. Tests of the null hypothesis will be conducted using the t-test. Departures from the normal distribution of the estimand will be assessed using the Shapiro-Wilk test.

Secondary outcomes

• Incidence of grade ≥ 3 treatment related adverse events (AEs) [From baseline, up to 12 weeks]: Will report the frequency of treatment-related AEs, treatment-emergent SAEs during treatment with immunoadjuvant treatment for patients randomized to Arm A and through the first 12 protocol weeks for Arm B. For each evaluable patient, the maximum grade of each Common Terminology Criteria for Adverse Events (CTCAE) version 6 codable toxicity will be determined. For any AE event that occurs in at least one patient at grade 3 or greater, the rate of occurrence will be compared between the two randomized groups using the exact conditional test of proportions.
• Incidence of immune related AEs [From baseline, up to 12 weeks]: Will report the frequency of immune related AEs during treatment for patients randomized to Arm A and through the first 12 protocol weeks for Arm B using Common Terminology Criteria for Adverse Events (CTCAE) version 6.
• Incidence of serious AEs [From baseline, up to 12 weeks]: Will report the frequency of serious AEs during treatment for patients randomized to Arm A and through the first 12 protocol weeks for Arm B using Common Terminology Criteria for Adverse Events (CTCAE) version 6.

Sex: All, ages: 18 Years to any

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

• Diana Hanna, Principal investigator, University of Southern California

NIH grants: P30CA014089