Clinical trial NCT02437136: Ph1b/2 Dose-Escalation Study of Entinostat With Pembrolizumab in Non-small Cell Lung Cancer (NSCLC) With Expansion Cohorts in NSCLC, Melanoma, and Colorectal Cancer (CRC)
Official title: A Phase 1b/2, Open-label, Dose Escalation Study of Entinostat in Combination With Pembrolizumab in Patients With Non-small Cell Lung Cancer, With Expansion Cohorts in Patients With Non-small Cell Lung Cancer, Melanoma, and Mismatch Repair-Proficient Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Non-Small Cell Lung Cancer
Melanoma
Mismatch Repair-Proficient Colorectal Cancer
Lead sponsor: Syndax Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-05-07
Enrollment: 191
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the safety and tolerability of entinostat used in combination with pembrolizumab in participants with NSCLC. Additionally, the purpose of the study is to assess how effective entinostat and pembrolizumab are in combination in participants with NSCLC, Melanoma, and Mismatch-Repair Proficient CRC.


Eligibility criteria: Inclusion Criteria:

Participants with NSCLC:

1. Has histologically- or pathologically-confirmed recurrent/metastatic NSCLC.
2. If has adenocarcinoma, required to have previously been tested for anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) mutations, with results available for collection in this study, and, if positive, has been treated with prior epidermal growth factor receptor (EGFR) or ALK therapy.
3. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and experienced documented, unequivocal progressive disease by either RECIST 1.1 or clinical assessment. Additional requirements related to prior treatments applied and may have been dependent on mutational status.
4. Participants with NSCLC enrolled in Cohort 1 of the Expansion Phase should not have been previously treated with a PD-1/PD-L1-blocking antibody.

   Participants in Expansion Phase, Cohorts 2 (NSCLC) and 3 (Melanoma):
5. Previously treated with a PD-1/PD-L1-blocking antibody and experienced documented, unequivocal radiographic progression of disease by irRECIST, or similar criteria during or within 12 weeks after last dose of such treatment. Participants must have received at least 6 weeks of PD-1/PD-L1 therapy for Cohort 2 and at least 8 weeks of PD-1/PD-L1 therapy for Cohort 3.

   Participants with Melanoma:
6. In addition to having been previously treated with a PD-1/PD-L1-blocking antibody, has a histologically- or cytologically-confirmed diagnosis of unresectable or metastatic melanoma and experienced unequivocal progressive disease during treatment with a Serine/threonine-protein kinase B-Raf (BRAF) inhibitor if BRAF V600 mutation-positive. Treatment with BRAF inhibitor may occur after treatment with the checkpoint inhibitor.

   Participants in Expansion Phase, Cohort 4 (CRC):
7. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and experienced documented, unequivocal progressive disease by either RECIST 1.1 or clinical assessment. Must have documented mismatch repair-proficient colon cancer as determined by either immunohistochemistry for mismatch repair proteins or polymerase chain reaction (PCR)-based functional microsatellite instability. Participants with CRC enrolled in Cohort 4 should not have been previously treated with a PD-1/PD-L1-blocking antibody (that is, pembrolizumab, nivolumab, MEDI4736, or GNE PDL1 \[MPDL3280A\]).

   All Participants:
8. Aged 18 years or older on the day written informed consent is given.
9. If has brain metastases, must have stable neurologic status following local therapy for at least 4 weeks without the use of steroids or on stable or decreasing dose of ≤10 milligrams (mg) daily prednisone (or equivalent), and must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs.
10. Evidence of locally recurrent or metastatic disease based on imaging studies within 28 days before the first study drug dose:

    * At least 1 measurable lesion ≥20 mm by conventional techniques or ≥10 mm by spiral computed tomography (CT) scan or magnetic resonance imaging (MRI), with the last imaging performed within 28 days before the first study drug dose. If there is only 1 measurable lesion and it is located in previously irradiated field, it must have demonstrated unequivocal progression according to RECIST, version 1.1.
11. If receiving radiation therapy, has a 2-week washout period following completion of the treatment prior to receiving the first study drug dose and continues to have at least 1 measurable lesion, per above criterion.
12. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
13. Has acceptable renal and hepatic function and stable hematologic and coagulation status.
14. Female participants must not be pregnant. If a participants is of childbearing potential, the participant must agree to use effective contraception, as defined in the protocol, during the study and for 120 days after the last dose of study drug.
15. If male, agrees to use an adequate method of contraception starting from the first dose of study drug through 120 days after the last dose of study drug.
16. Experienced resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except alopecia). If participant underwent major surgery or radiation therapy of \>30 gray (Gy), they must have recovered from the toxicity and/or complications from the intervention.
17. Willing to have fresh tumor samples collected during screening and at other time points designated as mandatory, per the Schedule of Study Assessments.
18. Able to understand and give written informed consent and comply with study procedures.

Exclusion Criteria:

Participants meeting any of the following criteria are not eligible for study participation:

1. Diagnosis of immunodeficiency or receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
2. Active autoimmune disease that has required systemic treatment in past 2 years (that is, with disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (for example, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
3. History of interstitial lung disease (ILD).
4. Allergy to benzamide or inactive components of entinostat.
5. History of allergies to any active or inactive ingredients of pembrolizumab or severe hypersensitivity (≥Grade 3) to pembrolizumab.
6. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator, including, but not limited to:

   * Myocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTc interval \> 470 milliseconds (msec).
   * Uncontrolled heart failure or hypertension, uncontrolled diabetes mellitus, or uncontrolled systemic infection.
   * Another known additional malignancy that is progressing or requires active treatment (excluding adequately treated basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia \[CIN\]/cervical carcinoma in situ or melanoma in situ, or ductal carinoma in situ of the breast). Prior history of other cancer is allowed, as long as there is no active disease within the prior 5 years.
   * Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
   * Active infection requiring systemic therapy.
   * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.

   Note: Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging \[using the identical imaging modality for each assessment, either MRI or CT scan\] for at least 4 weeks prior to the first dose of study drug and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 2 weeks prior to the first dose of study drug or are on stable or decreasing dose of ≤10 mg daily prednisone (or equivalent). This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
7. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
8. 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.
9. Received a live virus vaccination within 30 days of the first dose of treatment.
10. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to baseline or who has not recovered (that is, ≤Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier.
11. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study baseline or who has not recovered (that is, ≤Grade 1 or at baseline) from AEs due to a previously administered agent.

    Note: Participants with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this criterion and may qualify for the study.

    Note: If participant underwent major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
12. Received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte-colony stimulating factor \[G-CSF\], granulocyte macrophage-colony stimulating factor \[GM-CSF\], or recombinant erythropoietin) within 4 weeks prior to the first dose of study drug.
13. Currently receiving treatment with any other agent listed on the prohibited medication list such as valproic acid, or other systemic cancer agents within 14 days of the first dose of treatment.
14. If female, is pregnant, breastfeeding, or expecting to conceive, or if male, expect to father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study drug.
15. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
16. Known active hepatitis B (for example, hepatitis B surface antigen-reactive) or hepatitis C (for example, hepatitis C virus ribonucleic acid \[qualitative\]).
17. For CRC expansion cohort, no prior history of malignant bowel obstruction requiring hospitalization in the 6 months prior to enrollment
18. For the CRC expansion cohort, history of uncontrolled ascites, defined as symptomatic ascites and/or repeated paracenteses for symptom control in the past 3 months.

Primary outcomes:
measure: Phase 2: Objective Response Rate (ORR), as Assessed Using Immune Response RECIST (irRECIST)
timeFrame: From date of randomization to date of progression (up to 765 days)
Secondary outcomes:
measure: Phase 2: Clinical Benefit Rate (CBR), as Assessed Using irRECIST
timeFrame: 6 months
measure: Phase 2: CBR, as Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
timeFrame: 6 months
measure: Phase 2: Progression Free Survival (PFS), as Assessed Using irRECIST
timeFrame: 6 months
measure: Phase 2: PFS, as Assessed Using RECIST 1.1
timeFrame: 6 months
measure: Phase 2: PFS Duration, as Determined by the Local Investigator Using irRECIST
timeFrame: From date of randomization to PD or death due to any cause (up to 765 days)
measure: Phase 2: PFS Duration, as Determined by the Local Investigator Using RECIST 1.1
timeFrame: From date of randomization to PD or death due to any cause (up to 765 days)
measure: Phase 2: Overall Survival
timeFrame: From date of randomization to the date of death (up to 765 days)
measure: Phase 2: Duration of Response, as Assessed Using irRECIST
timeFrame: From start date of CR or PR to date of progression (up to 765 days)
measure: Phase 2: Duration of Response, as Assessed Using RECIST 1.1
timeFrame: From start date of CR or PR to date of progression (up to 765 days)
measure: Phase 2: Time to Response, as Assessed Using irRECIST
timeFrame: From the date of randomization to date of PR or CR (up to 765 days)
measure: Phase 2: Time to Response, as Assessed Using RECIST 1.1
timeFrame: From the date of randomization to date of PR or CR (up to 765 days)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), AEs Resulting in the Permanent Discontinuation of Study Drug, and Death
timeFrame: From first dose of study drug up to 765 days
measure: Phase 1b: Number of Participants With at Least One Dose Limiting Toxicities (DLTs)
timeFrame: Day 1 through Day 21 (Cycle 1)
measure: Phase 1b: Recommended Phase 2 Dose (RP2D)
timeFrame: Day 1 through Day 21 (Cycle 1)
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Baltimore
country: United States
facility: University of Maryland, Marlene and Stewart Greenbaum Cancer Center
state: Maryland
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institution
state: Massachusetts
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: The University of North Carolina at Chapel Hill
state: North Carolina
city: Easton
country: United States
facility: St Luke's University Health Network
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Pasi A Janne, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.
citation: Hellmann MD, Janne PA, Opyrchal M, Hafez N, Raez LE, Gabrilovich DI, Wang F, Trepel JB, Lee MJ, Yuno A, Lee S, Brouwer S, Sankoh S, Wang L, Tamang D, Schmidt EV, Meyers ML, Ramalingam SS, Shum E, Ordentlich P. Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti-PD-(L)1 Therapy. Clin Cancer Res. 2021 Feb 15;27(4):1019-1028. doi: 10.1158/1078-0432.CCR-20-3305. Epub 2020 Nov 17.