Pembrolizumab and Tretinoin in Treating Patients with Stage III-IV Melanoma

Status: Active

Description

This pilot phase I / Ib trial studies the side effects and best dose of tretinoin when given together with pembrolizumab in treating patients with stage III-IV melanoma. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Tretinoin is a vitamin A derivative that may alter immune response. Giving pembrolizumab and tretinoin may work better in treating patients with stage III-IV melanoma.

Eligibility Criteria

Inclusion Criteria

  • Diagnosis of advanced melanoma (unresectable stage III or stage IV melanoma)
  • Planned standard treatment with pembrolizumab
  • Be willing and able to provide written informed consent for the trial
  • State willingness to comply with all study procedures and be available for the duration of the trial
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 10 days of treatment initiation)
  • Platelets >= 100,000/mcL (performed within 10 days of treatment initiation)
  • Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (performed within 10 days of treatment initiation)
  • Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated (creatinine clearance should be calculated per institutional standard) creatinine clearance >= 60 mL/min for patient with creatinine levels > 1.5 X institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl])
  • Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 10 days of treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (performed within 10 days of treatment initiation)
  • Albumin >= 2.5 mg/dL (performed within 10 days of treatment initiation)
  • Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
  • Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

Exclusion Criteria

  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
  • Has a known history of active TB (Bacillus tuberculosis)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent; subjects with chronic conditions such as vision changes from plaque radiation therapy for ocular melanoma or prior hearing loss that is not reasonably expected to be exacerbated by the investigational product may be included * Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Has known history of, or any evidence of active, non-infectious pneumonitis
  • Has an active infection requiring systemic therapy
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Has received a live vaccine within 30 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
  • Has known sensitivity to retinoic acid derivatives
  • Has a medical history of allogenic stem cell transplant or received a solid organ transplant

Locations & Contacts

Colorado

Aurora
University of Colorado Hospital
Status: Active
Contact: Martin D. McCarter
Phone: 303-724-2725
Fort Collins
Poudre Valley Hospital
Status: Approved
Contact: Steven Robert Schuster
Phone: 970-493-6337
Email: steven.schuster@uchealth.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of pembrolizumab and tretinoin (ATRA).

SECONDARY OBJECTIVES:

I. Describe the safety and toxicity of combined treatment with pembrolizumab and all-trans retinoic acid (ATRA) (brand name VESANOID) in melanoma patients.

II. To assess the anti-tumor activity in terms of the reduction in myeloid-derived suppressor cell (MDSC) (immunosuppressive myeloid-derived suppressor cells) frequency and suppressive function (measured as a continuous variable) in peripheral blood of advanced melanoma patients undergoing pembrolizumab and VESANOID combination therapy.

III. To assess the anti-tumor activity in terms of progression free survival.

EXPLORATORY OBJECTIVES:

I. To determine the clinical outcomes with tumor-specific T cell responses.

OUTLINE: This is a dose-escalation study of tretinoin.

Patients receive tretinoin orally (PO) on days -1, 0, and 1, and pembrolizumab intravenously (IV) over 30 minutes on day 0. Treatment with tretinoin repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Treatment with pembrolizumab repeats every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 90 days, and then every 12 weeks for up to 2 years.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
University of Colorado Hospital

Principal Investigator
Martin D. McCarter

Trial IDs

Primary ID 16-1080
Secondary IDs NCI-2017-01775
Clinicaltrials.gov ID NCT03200847