Prostaglandin Inhibition and Immune Checkpoint Blockade in Melanoma

Prostaglandin Inhibition and Programmed Cell Death Protein 1 (PD-1)/Cytotoxic T-lymphocyte-Associated Protein 4 (CTLA4) Blockade in Melanoma

This phase II trial studies how well pembrolizumab, ipilimumab, and aspirin work in treating patients with melanoma that has spread to other places in the body or cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread. Aspirin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab, ipilimumab, and aspirin may work better in treating patients with melanoma.

Study Overview

• Status: Completed
• Conditions: Stage III Cutaneous Melanoma; Stage IIIA Cutaneous Melanoma; Stage IIIB Cutaneous Melanoma; Stage IIIC Cutaneous Melanoma; Stage IV Cutaneous Melanoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Aspirin; Biological: Ipilimumab; Biological: Pembrolizumab

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the overall response rate (ORR) by week 12 in patients with stage III unresectable/stage IV melanoma.

SECONDARY OBJECTIVES:

I. To determine the median progression free survival, overall survival, and toxicity profile of the combination of ipilimumab, pembrolizumab and high dose aspirin in patients with stage III unresectable/IV melanoma.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, ipilimumab IV over 60 minutes on day 1 for courses 1-4, and aspirin orally (PO) twice daily (BID) on days 1-21. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of Califonia, San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have histologically confirmed melanoma that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Leukocytes >= 3,000/microliter (mcL)
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin within normal institutional limits
• Total bilirubin =< 1.5 X institutional upper limit
• Aspartate aminotransferase (AST) [serum glutamic-oxaloacetic transaminase (SGOT)] =< 2.5 X institutional upper limit of normal
• Alanine aminotransferase (ALT) [serum glutamate pyruvate transaminase (SGPT)] =< 2.5 X institutional upper limit of normal
• Creatinine =< 1.5 X upper limit of normal (ULN)
• Women of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study drug; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Women 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
• Men 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
• Ability to understand a written informed consent document, and the willingness to sign it

Exclusion Criteria:

• Any mental or physical condition or disease or past medical history that mitigates against following the protocol
• History of active autoimmune diseases such as but not limited to Crohn?s disease, ulcerative colitis, Sjogren's syndrome, requiring active immune suppression; patient may have hay fever or controlled asthma
• Any solid organ transplant or bone marrow transplant
• Any other disseminated malignancy. Exceptions include: localized prostate cancer, basal or squamous cell skin cancer, localized cervical cancer, and localized breast cancer.
• Uncontrolled central nervous system (CNS) metastasis; patients with CNS metastasis can be eligible if definitively treated with radiotherapy or surgery
• Any coexistent medical condition interfering with drug absorption
• History of gastritis or malabsorption syndrome or aspirin intolerance or allergy
• Live vaccination within the last 30 days
• History of multiple sclerosis, type 1 diabetes mellitus (DM) or Guillain-Barre syndrome
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (pembrolizumab, ipilimumab, aspirin); Patients receive pembrolizumab IV over 30 minutes on day 1, ipilimumab IV over 60 minutes on day 1 for courses 1-4, and aspirin PO BID (orally, twice a day) on days 1-21. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Aspirin; Given PO; Other Names: Aspergum; Ecotrin; Empirin; Entericin; Extren; Measurin; Acetylsalicylic Acid (ASA); Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Defined as the proportion of subjects for whom the best overall response at week 12 is confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST). Point estimates of ORR and 95% confidence intervals will be provided. Only participants with confirmed response are included in this analysis.	Up to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Reported Treatment-related Adverse Events	Number of participants with reported treatment-related adverse events defined as having an attribution of definite, possible, and probable according to Common Terminology Criteria for Adverse Events (CTCAE) version 4 will be reported.	Within 30 days after last dose of study drug, up to 3 years
Proportion of Participants With Progression-free Survival (PFS) at 6 Months	PFS at 6 months is defined as the proportion of subjects alive and progression-free 6 months (182 days) after study day 1.	Up to 6 months (182 days)
Median Duration of PFS	Duration of PFS is defined as the time from the study day 1 to the earlier of disease progression or death due to any cause. The analysis of PFS will include only objective progression events per RECIST and clinical progression determined by the investigator may not be considered disease progression. The median duration of PFS will be estimated using the Kaplan-Meier methods with the associated 95% confidence interval.	Up to 3 years
Median Overall Survival (OS)	Duration of OS is defined as the time from study day 1 to death due to any cause. For subjects who are alive at the time of data cutoff or are permanently lost to follow-up, duration of OS will be right censored at the date the subject was last known to be alive. The median duration of OS will be estimated using the Kaplan-Meier methods with the associated 95% confidence interval.	Up to 3 years

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Adil Daud, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2018
• Primary Completion (Actual): April 30, 2020
• Study Completion (Actual): June 30, 2022

Study Registration Dates

• First Submitted: January 5, 2018
• First Submitted That Met QC Criteria: January 5, 2018
• First Posted (Actual): January 11, 2018

Study Record Updates

• Last Update Posted (Actual): October 13, 2022
• Last Update Submitted That Met QC Criteria: September 19, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Skin Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Aspirin; Pembrolizumab; Ipilimumab
• Other Study ID Numbers: 17854; NCI-2017-02441 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No