Clinical trial NCT02644369: Study of the Effects of Pembrolizumab in Patients With Advanced Solid Tumors
Official title: Investigator-initiated Phase II Study of Pembrolizumab Immunological Response Evaluation
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Squamous Cell Cancer of Head and Neck
Triple Negative Breast Cancer
Epithelial Ovarian Cancer
Malignant Melanoma
Advanced Solid Tumors
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-12-31
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a phase 2 study whose main purpose is to evaluate gene changes and immune biomarkers in patients with solid tumors during treatment with pembrolizumab and in relation to response to treatment.

Pembrolizumab is a monoclonal antibody that is designed to block a protein called programmed cell death 1 ligand 1 (PD-L1) which will allow the body's immune system to kill the cancer cells.

Detailed description: This study will involve treatment with pembrolizumab, tests and procedures done for safety, and the collection of archival tumor tissue, fresh tumor biopsies, and blood samples for biomarker research (including genetic testing).

Eligibility criteria: Inclusion Criteria:

* Be willing and able to provide written informed consent/assent for the trial.
* Be 18 years of age or older on day of signing informed consent.
* Have histologically or cytologically-documented, locally-advanced, or metastatic solid malignancy that is incurable and has either (a) failed prior standard therapy, (b) for which no standard therapy exists, or (c) standard therapy is not considered appropriate by the patient and treating physician. There is no limit to the number of prior treatment regimens.
* Have one of the following advanced (unresectable and/or metastatic) solid tumor indications:

  * Squamous cell cancer of head and neck
  * Triple negative breast cancer
  * Epithelial ovarian cancer
  * Malignant melanoma
  * Advanced solid tumors
* Have measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.
* Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Patients for whom newly-obtained samples cannot be provided (e.g. inaccessible or patient safety concern) will not be eligible for this study.
* Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
* Demonstrate adequate organ function.
* Negative pregnancy test for female patients of childbearing potential.
* Must use approved methods of birth control during the course of the study and for 120 days after the last dose of study drug.

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 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 from adverse events due to a previously administered agent.
* Has a known additional malignancy that is progressing or requires active treatment.
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Has active autoimmune disease that has required systemic treatment in the past 2 years
* 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 patient's participation for the full duration of the trial, or is not in the best interest of the patient 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 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., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
* Has received a live vaccine within 30 days of planned start of study therapy.

Primary outcomes:
measure: Changes in genomic and immune biomarkers that will be measured in blood and tumor pre-treatment, on-treatment and at progression (progression biopsies only done for those who have complete or partial responses, or stable disease for more than 4 months)
timeFrame: 5 years
Secondary outcomes:
measure: Overall response rate
timeFrame: 5 years
measure: Changes in circulating tumor DNA genomic biomarkers
timeFrame: 5 years
measure: Changes in radiomic imaging parameters
timeFrame: 5 years
measure: Correlation between tumor genomic profiles and radiomic imaging signatures
timeFrame: 5 years
measure: Changes in immune cell subsets in the blood and tumor microenvironment
timeFrame: 5 years
measure: Positive predictive value and negative predictive value of in vitro predictive assay for Pembrolizumab response
timeFrame: 5 years
measure: Distribution of drug tumor penetration using a mass spectrometry assay
timeFrame: 5 years
measure: Baseline tumor RNA expression profile for immune inhibitory genes
timeFrame: 5 years
measure: Comparison of baseline tumor RNA expression profile for immune inhibitory genes with clinical outcome (response)
timeFrame: 5 years
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
Study officials:
affiliation: Princess Margaret Cancer Centre
name: Lillian Siu, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Iafolla MAJ, Yang C, Chandran V, Pintilie M, Li Q, Bedard PL, Hansen A, Lheureux S, Spreafico A, Razak AA, Hakgor S, Giesler A, Pugh TJ, Siu LL. Predicting Toxicity and Response to Pembrolizumab Through Germline Genomic HLA Class 1 Analysis. JNCI Cancer Spectr. 2020 Dec 29;5(1):pkaa115. doi: 10.1093/jncics/pkaa115. eCollection 2021 Feb.
citation: Bratman SV, Yang SYC, Iafolla MAJ, Liu Z, Hansen AR, Bedard PL, Lheureux S, Spreafico A, Razak AA, Shchegrova S, Louie M, Billings P, Zimmermann B, Sethi H, Aleshin A, Torti D, Marsh K, Eagles J, Cirlan I, Hanna Y, Clouthier DL, Lien SC, Ohashi PS, Xu W, Siu LL, Pugh TJ. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer. 2020 Sep;1(9):873-881. doi: 10.1038/s43018-020-0096-5. Epub 2020 Aug 3.