An Exploratory Study of Pembrolizumab Plus Entinostat in Non-Inflamed Stage III/IV Melanoma

NCT03765229 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: LCCC1729
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

Cancers develop in two different ways. First, cancer cells can become invisible to the immune system by stop having proteins on their surface that are required for the immune system to recognize them. In this scenario, tumors do not attract any immune cells (e.g. white blood cells) whatsoever or they do not attract specialized white blood cells against cancer cells, called lymphocytes. White blood cells are the type of immune cells that attack foreign cells, such as cancer cells or normal cells infected with viruses or bacteria. Second, cancer cells can still grow side-to-side with white blood cells but are able to hide from them. As a result, the white blood cells cannot find and attack the cancer cells. Different types of cancers have different chance of having immune cells in the tumor. For example, the possibility that immune cells are within skin melanomas is almost 50% whereas the possibility in melanoma of the eye is only 10%. As a result, the first goal of this study is to understand whether entinostat can make a melanoma tumor more visible to the immune system. To see whether entinostat makes tumor more visible to the immune system, participants will have a mandatory tumor biopsy 3 weeks after starting entinostat therapy. Tumor tissue collected before and after participating in this study will be compared to see if there are more immune cells in the tumor after receive entinostat. The second goal of the study is to see if giving a combination of entinostat and pembrolizumab can shrink melanoma tumors of patients who did not have immune cells in tumors prior to treatment. The study will determine how many subjects cancer has become better or not changed 6 months after subjects have started treatment on the study. We will also determine what type of side effects occur in subjects receiving entinostat and pembrolizumab to look at the safety of this combination. The investigators will also look at any changes in the DNA of melanoma before the study begins. As a result of these changes in DNA, there are often see differences in the proteins that work to create other proteins. In addition, the study will look into how entinostat may make melanoma cells more visible to the immune system by comparing proteins in tumors before and after treatment. Finally, the study will see if this treatment changes the numbers and types of immune cells that are found in the blood by comparing blood at different time points while patients are on the study.

Conditions

Melanoma

Keywords

PD-1

Outcome Measures

Primary Outcomes (1)

• Number of Conversions of Non-inflamed to Inflamed Melanoma

  Number of subjects with conversion from non-inflamed Tumor-infiltrating lymphocyte / Tumor-associated lymphocyte (TIL/TAL) absent before treatment to TIL/TAL present after treatment was assessed by histopathologic analysis. Representative 5-micron thick formalin fixed paraffin embedded sections collected from baseline and on-treatment (entinostat-alone, day 21 of the trial) were stained with hematoxylin and eosin on day 21 (on-treatment biopsy).

  3 weeks after start of treatment

Secondary Outcomes (3)

• Overall Response Rate

  9 weeks

• Progression-Free Survival

  6 months

• Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination

  9 weeks

Study Arms (1)

Single Arm: Entinostat + Pembrolizumab

EXPERIMENTAL

Subjects in this trial will be administered entinostat, 5mg PO, once weekly (D1, D8, D15 of a 21-day cycle) starting on day 1 of study treatment. Pembrolizumab, 200 mg will be administered intravenously (IV) every 3 weeks and initiated at cycle 2 after the mandatory research tumor biopsy in the end of cycle 1, beginning of cycle 2 (day 21±2 days),. Combination therapy with both agents will continue if subject is receiving clinical benefit from therapy for up to 27 weeks (8 cycles of combination therapy or approximately 6 months). Study therapy will be discontinued for intolerable toxicity, disease progression or for other reasons at the discretion of the investigator.

Drug: Entinostat; Drug: Pembrolizumab

Interventions

Entinostat DRUG

Oral drug 5 mg taken once weekly for up to nine 3-week (21 day) cycles. Take on an empty stomach i.e., at least 2 hours after a meal and at least 1 hour before the next meal. On days when entinostat is administered on the same day as pembrolizumab, entinostat should be taken before the pembrolizumab infusion.

Single Arm: Entinostat + Pembrolizumab

Pembrolizumab DRUG

200 mg IV starting on Day 22 (cycle 2, Day 1) given every 3 weeks for up to 8 cycles.

Also known as: Keytruda

Single Arm: Entinostat + Pembrolizumab

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years at the time of consent.
• Subject has provided informed consent and Health Insurance Portability and Accountability Act (HIPAA) prior to initiation of any study-specific activities/procedures.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2.
• Histologically confirmed metastatic (regional or distant) melanoma of any subtype (cutaneous, mucosal, ocular).
• American Joint Committee on Cancer (AJCC) stage unresectable III or stage IV disease that is measurable by RECIST v1.1 criteria.
• Must agree to undergo one on-treatment tumor biopsy on day 22 (±2 days) of the study. Subjects for whom fresh samples cannot be safely provided (e.g., inaccessible tumor for biopsy or has metastatic lung lesion(s) as the only site of metastatic disease) will not be eligible for study participation.
• Must have available archival tissue and subjects have consented to allow collection of archived tumor blocks from previous surgeries confirming or treating unresectable stage III or distant metastatic disease. If more than one archived tumor blocks are available, two blocks have to be analyzed for the presence of Tumor-infiltrating lymphocyte/Tumor-associated lymphocyte (TIL/TALS). Archived tumor tissues must fulfill the following criteria based on two representative Hematoxylin \& Eosin (H\&E)-stained tissue sections: (1) the tumor surface area must be at least 1cm (squared), (2) no more than 20% of necrosis, (3) the ratio of viable tumor cells to tumor-associated stroma should be at least 60/40, (4) if TILs are present based on H\&E stained sections, they must be ≤ 1% of the total number of cells in the specimen; the amount of tissue should be ≥ 1 cm2.
• The study pathologists must sign off on the eligibility of archived tumor blocks before study enrollment. If archival tissue is unavailable or insufficient, fresh biopsy should be performed to confirm unresectable stage III or distant metastatic disease.
• Previous treatment with immune checkpoint inhibitors and chemotherapies is allowed on condition that the last treatment is at least 28 days prior to first dose of entinostat. Previous treatment with targeted therapies (e.g. Mitogen-activated protein kinase inhibitors) is allowed on condition that the last treatment was administered at least 15 days prior to first dose of entinostat).
• Demonstrate adequate organ function as defined in the protocol table; all screening labs to be obtained within 21 days prior to entinostat treatment.
• \*Note: Hematology and other lab parameters that are ≤ grade 2 but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered Adverse events (AEs) unless they meet criteria for dose modification(s) of study medication outlined by the protocol in Section 5.3.1 and/or worsen from baseline during therapy.
• A female of childbearing potential must have a negative serum pregnancy test during screening and a negative urine pregnancy test within 3 days prior to receiving the first dose of study drug. If the screening serum test is done within 3 days prior to receiving the first dose of study drug, a urine test is not required. A female of childbearing potential must agree to use effective contraception during the study and for 120 days after the last dose of study drug. A female of non-childbearing potential defined as (by other than medical reasons):
• ≥45 years of age and has not had menses for \>2 years,
• Amenorrheic for \<2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation,
• Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure; otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last dose of entinostat,

You may not qualify if:

• Is receiving systemic steroid therapy or any other form of immunosuppressive therapy for autoimmune side effects related to previous use of immunotherapies for melanoma. Exceptions include episodic (up to 7 days) use of systemic steroids for common conditions while on study treatment (e.g. Chronic obstructive pulmonary disease (COPD) exacerbation, poison ivy), use of corticosteroids as replacement doses for adrenal or pituitary insufficiency.
• Has a known history of tuberculosis (Bacillus Tuberculosis) or human immunodeficiency virus (HIV 1/2 antibodies).
• Hypersensitivity to pembrolizumab or any of its excipients. Allergy to benzamide or inactive components of entinostat.
• Has known history of biopsy-proven (non-infectious) pneumonitis that required systemic steroids, or any evidence of current pneumonitis.
• Conditions that would preclude adequate absorption of oral medications (malabsorption, significant nausea and vomiting, resection of \>100-cm of proximal small bowel, resection of \>200-cm of distant small bowel).
• 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, including but not limited to:
• i. Myocardial infarction or arterial thromboembolic events within 6 months prior to screening or severe or unstable angina, New York Heart Association (NYHA) Class III of IV disease, or a QT corrected for heart rate interval \> 470 msec,
• ii. Uncontrolled hypertension (\>150/90 in more than 60% of recorded BP measurements taken on 5 or more separate occasions, within 3 weeks of the first dose of entinostat; at least 3 recorded measurements required on each occasion) or diabetes mellitus (HbA1c \>9.0 within 15 days from first dose of entinostat),
• iii. Active infection requiring systemic antibiotic therapy by the first day of entinostat treatment,
• iv. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• If female, is pregnant or breastfeeding, or, if male, 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.
• Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid \[qualitative\]). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBs Ag) are eligible. HBV DNA test must be performed in these patients prior to study treatment if known history of viral hepatitis. Patients positive for hepatitis C virus (HCV) antibody are eligible, only if polymerase chain reaction is negative for HCV RNA.
• 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.
• History of prior malignancy, with the exception of the following:
• Non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma in situ of the cervix,

Sponsors & Collaborators

• UNC Lineberger Comprehensive Cancer Center: lead
• Syndax Pharmaceuticals: collaborator

Study Sites (1)

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599, United States

Location

Related Links

• University of North Carolina Lineberger Comprehensive Cancer Center Clinical Trials

MeSH Terms

Conditions

Melanoma

Interventions

entinostat; pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Melahat G. Canter MD MS, Clinical Trial Analyst
• Organization: University of North Carolina Lineberger Comprehensive Cancer Center

Melahat_Canter@med.unc.edu

(919) 962-0000

Study Officials

• Stergios Moschos, MD

  UNC Lineberger Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 15, 2018
• First Posted: December 5, 2018
• Study Start: March 22, 2019
• Primary Completion: December 31, 2022
• Study Completion: July 31, 2023
• Last Updated: January 10, 2024
• Results First Posted: January 10, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)