Melanoma
Conditions
Keywords
PD-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.
Detailed description
This is an exploratory (n=10-12 evaluable patients), open-label, single-arm, phase II study in patients with 'non-inflamed' unresectable regional or distant metastatic melanomas irrespective of prior treatment with PD-1/PD-L1 pathway inhibitors. The primary endpoint is to assess the incidence of histopathologic conversion of non-inflamed melanomas from patients with metastatic melanoma to 'inflamed' melanoma following single-agent entinostat priming (entinostat monotherapy). More specifically, patients with metastatic melanomas that have no evidence of tumor-infiltrating or tumor-associated lymphocytes (TIL/TAL), based on standard hematoxylin and eosin (H&E) staining of representative tumor sections (non-inflamed melanomas) will receive weekly entinostat for 3 weeks in cycle 1 (entinostat monotherapy; 5mg PO, qwk on D1, D8, D15 of cycle 1; cycle length = 21 days). Mandatory tumor tissue biopsies will be performed in the end of cycle 1, beginning of cycle 2 (day 21±2 days), immediately before treatment with concurrent entinostat (once weekly × 3) and pembrolizumab (200 mg q3wks) in cycles 2-9 (see section 5.2.1 drug dosing schema). Correlative studies will be performed at baseline and in the end of cycle 1, beginning of cycle 2 (day 21±2 days) to assess whether: (a) 3 weeks of entinostat monotherapy converts TIL/TAL-absent melanomas to TIL/TAL-present by histopathologic (H&E stain) analysis, (b) 3 weeks of single-agent entinostat induces changes in gene expression profiling by assessing distinct signatures as defined by RNA-sequencing signatures (RNA-seq; 'immune-high', innate anti-PD-1 resistance, and epigenetic 1-3), (c) 3 weeks of single-agent entinostat induces changes in histone-accessible DNA by performing formaldehyde-assisted isolation of regulatory elements (FAIRE)4, (d) conversion of non-inflamed to inflamed melanomas by single-agent entinostat and/or antitumor response to the entinostat-pembrolizumab combination is associated with a baseline signature that consists of distinct somatic mutation gene profile, global histone modification profile in melanoma tissue or peripheral blood mononuclear cells (PBMC), and/or abundance of entinostat targets in melanoma cells (HDAC 1, 2, 3, and 11). Up to 12 evaluable patients will be treated with entinostat plus pembrolizumab for up to 27 weeks (approximately 6 months) based on clinical benefit. Patients who continue to have clinical benefit at 27 weeks may continue therapy with pembrolizumab or any other PD-1/PD-L1 inhibitor, as per standard of care.Secondary exploratory endpoints involve: (a) assessment of antitumor response of entinostat administered concurrently with pembrolizumab at week 10 (or earlier if patient progresses), based on response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). (b) assessment of the progression-free survival (PFS) rate at 27 weeks (approximately 6 months) of the entinostat-pembrolizumab combination. (c) determine the safety of the entinostat-pembrolizumab combination in patients with metastatic melanoma per NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE). (d) assessment of other exploratory biomarkers in tumor tissue and peripheral blood.
Interventions
DRUGEntinostat
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.
DRUGPembrolizumab
200 mg IV starting on Day 22 (cycle 2, Day 1) given every 3 weeks for up to 8 cycles.
Sponsors
Syndax Pharmaceuticals
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* 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, * If male, agrees to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of entinostat, * See section 5.6.2 for information on acceptable methods of contraception. * Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to Grade ≤1 (except alopecia or neuropathy) by CTCAE v5.0. Exceptions are patients who may have developed autoimmune-type side effects that require permanent hormonal replacement from previous therapies. * If the patient underwent major surgery or radiation therapy, these procedures must have occurred at least 15 days prior to the first dose of entinostat. In addition, patients must have recovered from the toxicity and/or complications from the intervention to Grade ≤1. * Subjects must be willing and able to comply with study procedures based on the judgment of the investigator or protocol designee.
Exclusion criteria
All subjects meeting any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Conversions of Non-inflamed to Inflamed Melanoma | 3 weeks after start of treatment | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 9 weeks | Radiographic response will be measured by Response Evaluation Criteria In Solid Tumors (RECIST) Criteria for Complete Response (CR), disappearance of all target lesions or Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. The Overall Response rate will be the percentage of subjects with CR or PR at 9 weeks after the start of treatment. |
| Progression-Free Survival | 6 months | Progression Free Survival is measured as the rate of patients who are progression-free from the date of enrollment on study to the date of documented progression per RECIST 1.1. criteria or death. Per RECIST 1.1, Progressive Disease (PD), is a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination | 9 weeks | Type of AEs that occur in subjects enrolled who receive at least one dose of therapy will be reported based on the NCI Common Terminology Criteria for Adverse Events v5.0 (NCI-CTCAE v.5.0). The NCI-CTCAE is a descriptive terminology utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. |
Countries
United States
Participant flow
Pre-assignment details
Subjects were enrolled in the study between 03/22/2019-05/24/2022, at one cancer center in the United States. A total of 11 participants consented, were found eligible and started to study. During the screening period, 22 subjects were consented to and 11 subjects did not enroll in the study since 10 of them were deemed not eligible and 1 subject expired.
Participants by arm
| Arm | Count |
|---|---|
| Single Arm: Entinostat + Pembrolizumab 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.
Entinostat: 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.
Pembrolizumab: 200 mg IV starting on Day 22 (cycle 2, Day 1) given every 3 weeks for up to 8 cycles. | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Single Arm: Entinostat + Pembrolizumab |
|---|---|
| Age, Continuous | 58.36 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 11 |
| other Total, other adverse events | 11 / 11 |
| serious Total, serious adverse events | 5 / 11 |
Outcome results
Primary
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).
Time frame: 3 weeks after start of treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm: Entinostat + Pembrolizumab | Number of Conversions of Non-inflamed to Inflamed Melanoma | Tumor-infiltrating lymphocyte increased | 3 Participants |
| Single Arm: Entinostat + Pembrolizumab | Number of Conversions of Non-inflamed to Inflamed Melanoma | Tumor-infiltrating lymphocyte not increased | 7 Participants |
Secondary
Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination
Type of AEs that occur in subjects enrolled who receive at least one dose of therapy will be reported based on the NCI Common Terminology Criteria for Adverse Events v5.0 (NCI-CTCAE v.5.0). The NCI-CTCAE is a descriptive terminology utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Time frame: 9 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm: Entinostat + Pembrolizumab | Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination | fatigue | 11 Participants |
| Single Arm: Entinostat + Pembrolizumab | Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination | nausea | 6 Participants |
| Single Arm: Entinostat + Pembrolizumab | Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination | vomiting | 3 Participants |
| Single Arm: Entinostat + Pembrolizumab | Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination | diarrhea | 7 Participants |
| Single Arm: Entinostat + Pembrolizumab | Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination | anorexia | 3 Participants |
| Single Arm: Entinostat + Pembrolizumab | Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination | musculoskeletal pain | 5 Participants |
| Single Arm: Entinostat + Pembrolizumab | Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination | cytopenia | 2 Participants |
| Single Arm: Entinostat + Pembrolizumab | Number of Participant With Adverse Events During the Concurrent Pembrolizumab-entinostat Combination | anemia | 8 Participants |
Secondary
Overall Response Rate
Radiographic response will be measured by Response Evaluation Criteria In Solid Tumors (RECIST) Criteria for Complete Response (CR), disappearance of all target lesions or Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions. The Overall Response rate will be the percentage of subjects with CR or PR at 9 weeks after the start of treatment.
Time frame: 9 weeks
Population: Subjects started to the study treatment and response evaluation per RECIST was completed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm: Entinostat + Pembrolizumab | Overall Response Rate | Stable Disease or Progression | 8 Participants |
| Single Arm: Entinostat + Pembrolizumab | Overall Response Rate | Complete Response or Partial Response | 3 Participants |
Secondary
Progression-Free Survival
Progression Free Survival is measured as the rate of patients who are progression-free from the date of enrollment on study to the date of documented progression per RECIST 1.1. criteria or death. Per RECIST 1.1, Progressive Disease (PD), is a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: 6 months
Population: Subjects who started the study treatment and tumor response was evaluated, median follow-up time 14.3 (2.5-36.8) months.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm: Entinostat + Pembrolizumab | Progression-Free Survival | Alive with no evidence of disease | 1 Participants |
| Single Arm: Entinostat + Pembrolizumab | Progression-Free Survival | Alive with disease | 3 Participants |
| Single Arm: Entinostat + Pembrolizumab | Progression-Free Survival | Died from disease | 7 Participants |