Clinical Trials /

Ph1b/2 Dose-Escalation Study of Entinostat With Pembrolizumab in NSCLC With Expansion Cohorts in NSCLC, Melanoma, and Colorectal Cancer

NCT02437136

Description:

The purpose of this study is to determine the safety and tolerability of entinostat used in combination with pembrolizumab in patients with Non-small Cell Lung Cancer. Additionally the purpose of the study is to assess how effective entinostat and pembrolizumab are in combination in patients with Non-small Cell Lung Cancer, Melanoma, and Mismatch-Repair Proficient Colorectal Cancer

Related Conditions:
  • Colorectal Carcinoma
  • Melanoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ph1b/2 Dose-Escalation Study of Entinostat With Pembrolizumab in NSCLC With Expansion Cohorts in NSCLC, Melanoma, and Colorectal Cancer
  • 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

Clinical Trial IDs

  • ORG STUDY ID: SNDX-275-0601
  • NCT ID: NCT02437136

Conditions

  • Non-Small Cell Lung Cancer
  • Melanoma
  • Mismatch Repair-Proficient Colorectal Cancer

Interventions

DrugSynonymsArms
entinostatSNDX-275, MS-275Ph 2 NSCLC (squamous or adeno)
pembrolizumabKeytruda, MK-3475, SCH 900475Ph 2 NSCLC (squamous or adeno)

Purpose

The purpose of this study is to determine the safety and tolerability of entinostat used in combination with pembrolizumab in patients with Non-small Cell Lung Cancer. Additionally the purpose of the study is to assess how effective entinostat and pembrolizumab are in combination in patients with Non-small Cell Lung Cancer, Melanoma, and Mismatch-Repair Proficient Colorectal Cancer

Detailed Description

      SNDX-275-0601 is an open-label, Phase 1b/2 study evaluating the combination of entinostat
      plus pembrolizumab in patients with advanced metastatic or recurrent NSCLC or melanoma or
      mismatch repair-proficient colorectal cancer. The study has 2 phases, a Dose
      Escalation/Confirmation Phase (Phase 1b) and an Expansion Phase (Phase 2). An additional
      cohort (Entinostat Monotherapy Immune Correlate [EMIC] Cohort) evaluating single agent
      entinostat for 2 weeks followed by the combination will also be evaluated in patients with
      NSCLC in the Phase 2 expansion phase.

      Toxicities will be assessed by the Investigator using the United States (US) National Cancer
      Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

      Dose Confirmation: The prospective MTD/RP2D identified in the Dose Escalation Phase will be
      confirmed in 9 patients in Dose Confirmation Cohort(s) to obtain additional AE, immune
      correlate, and anti-tumor activity data on entinostat in combination.

      Phase 2 (Expansion): In the Expansion Phase, entinostat in combination will be evaluated
      using the RP2D identified in the Dose Escalation/Confirmation Phase. Up to 3 Expansion
      Cohorts consisting of distinct subsets of patients with solid tumor cancers may be explored.
      Expansion cohorts may include:

        1. Cohort 1: NSCLC

        2. Cohort 2: Patients with NSCLC (any histology) who have previously been treated and
           responded and then progressed on either a PD-1 or PD-L1-blocking antibody

        3. Cohort 3: Patients with melanoma who have previously been treated with and unequivocally
           progressed on either a PD-1 or PD-L1-blocking antibody

        4. Cohort 4: Patients with CRC (mismatch repair-proficient) who have not been previously
           treated with a PD-1 or PD-L1 blocking antibody

      EMIC Cohort: 15 NSCLC patients Stage 2 of Cohort 1 will be randomly assigned to participate.
    

Trial Arms

NameTypeDescriptionInterventions
Ph 2 NSCLC (squamous or adeno)ExperimentalCohort 1: Patients with Non-Small Cell Lung Cancer, with squamous cell or adenocarcinoma histology who have not been treated with a PD-1 or PD-L-1 blocking antibody (entinostat + pembrolizumab)
  • entinostat
  • pembrolizumab
Ph 2 NSCLC pre-treated PD-1/LD-L1ExperimentalCohort 2: Patients with NSCLC (any histology) who have previously been treated with and unequivocally progressed on either a PD-1 or PD-L1-blocking antibody (entinostat + pembrolizumab)
  • entinostat
  • pembrolizumab
Ph 2 Melanoma pre-treated PD-1/PD-L1ExperimentalCohort 3: Patients with melanoma who have previously been treated with and unequivocally progressed on either a PD-1 or PD-L1-blocking antibody (entinostat + pembrolizumab)
  • entinostat
  • pembrolizumab
Ph 2 Mismatch Repair-Proficient CRCExperimentalCohort 4: Patients with CRC (mismatch repair-proficient) who have not been previously treated with a PD-1 or PD-L1 blocking antibody
  • entinostat
  • pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

        Patients 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 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.

          4. Patients with NSCLC enrolled in Cohort 1 of the Expansion Phase should not have been
             previously treated with a PD-1/PD-L1-blocking antibody

             Patients in Expansion Phase, Cohorts 2 and 3

          5. Previously treated with a PD-1/PD-L1-blocking antibody and experienced experienced
             documented, unequivocal radiographic progression of disease by irRECIST, or similar
             criteria during or within 12 weeks after last dose of such treatment. Patients must
             have received at least 6 weeks of PD-1/PD-L1 therapy for Cohort 3.

             Patients with Melanoma:

          6. In addition to having been previously treated with a PD-1/PD-L1-blocking antibody
             (inclusion #5), has a histologically- or cytologically-confirmed diagnosis of
             unresectable or metastatic melanoma and experienced unequivocal progressive disease
             during treatment with a BRAF inhibitor if BRAF V600 mutation-positive. Treatment with
             BRAF inhibitor may occur AFTER treatment with the checkpoint inhibitor.

             Patients in Expansion Phase, Cohort 4 (Colorectal Cancer)

          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 PCR-based
             functional microsatellite instability. Patients with colorectal cancer enrolled in
             Cohort 4 should not have been previously treated with a PD-1/PD-L1-blocking antibody
             (i.e., pembrolizumab, nivolumab, MEDI36MEDI4376, or GNE PDL1 [MPDL3280A])

             All Patients

          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 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 CT scan or 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 measureable lesion, per above criterion.

         12. ECOG performance status of 0 or 1.

         13. Has acceptable, applicable laboratory parameters.

         14. Female subjects must not be pregnant.

         15. If male, agrees to use an adequate method of contraception

        15. Experienced resolution of toxic effect(s) of the most recent prior chemotherapy to
        Grade 1 or less (except alopecia). If patient underwent major surgery or radiation therapy
        of >30 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:

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

          1. Diagnosis of immunodeficiency or receiving systemic steroid therapy 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 (i.e.,
             with disease modifying agents, corticosteroids, or immunosuppressive drugs).
             Replacement therapy (e.g., 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 pembroluzumab.

          6. History or current evidence of any condition, therapy, or laboratory abnormality that
             might confound the results of the study, interfere with the patient'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 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: Patients 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 (i.e., ≤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 (i.e., ≤Grade 1 or at baseline)
             from AEs due to a previously administered agent.

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

             Note: If patient 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 (e.g., hepatitis B surface antigen-reactive) or hepatitis C
             (e.g., 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, no history of uncontrolled ascites, defined as
             symptomatic ascites and/or repeated paracenteses for symptom control in the past 3
             months
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants taking 3mg entinostat weekly with Adverse Events as a Measure of Safety and Tolerability
Time Frame:In approximately 3-4 months after 3-6 patients have enrolled and been on study for 1 cycle
Safety Issue:
Description:Ph 1 Dose Escalation - All patients within each dose escalation cohort are to complete C1, have safety assessments performed through C2D1, and be assessed for DLT before enrollment of the next cohort may commence.

Secondary Outcome Measures

Measure:Clinical Benefit Rate (CBR)
Time Frame:At 6 months of treatment for each of the 3 Dose Escalation (Ph 2 cohorts) as applicable
Safety Issue:
Description:CBR is Complete Response + Partial Response + Stable Disease for each patient after 6 months of study treatment
Measure:Progression-free survival (PFS) @ 6mo
Time Frame:At 6 months of treatment for each of the 3 Dose Escalation (Ph 2 cohorts) as applicable
Safety Issue:
Description:PFS status in each patient after 6 months of study treatment. PFS is defined as the number of months from the date of the first dose of study drug to the earliest of documented PD or death due to any cause without prior progression.
Measure:Progression-free survival (PFS)
Time Frame:In approximately 3 years
Safety Issue:
Description:PFS status in each patient. PFS is defined as the number of months from the date of the first dose of study drug to the earliest of documented PD or death due to any cause without prior progression.
Measure:Overall survival (OS)
Time Frame:In approximately 3 years
Safety Issue:
Description:OS status in each patient. OS is defined as the number of months from the first dose of study drug to the date of death due to any cause.
Measure:Duration of Response (DOR)
Time Frame:In approximately 3 years
Safety Issue:
Description:DOR will be calculated for patients who achieve a CR or PR and is defined as the number of months from the start date of the response (and subsequently confirmed) to the first date that recurrent disease or PD is documented.
Measure:Time to Response (TTR)
Time Frame:In approximately 3 years
Safety Issue:
Description:TTR status in each patient.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Syndax Pharmaceuticals

Last Updated

September 20, 2017