Clinical Trials /

Phase II Anti-PD1 Epigenetic Therapy Study in NSCLC.

NCT01928576

Description:

Response Rate

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Anti-PD1 Epigenetic Therapy Study in NSCLC.
  • Official Title: A Phase II Study of Epigenetic Therapy With Azacitidine and Entinostat With Concurrent Nivolumab in Subjects With Metastatic Non-Small Cell Lung Cancer.

Clinical Trial IDs

  • ORG STUDY ID: J1353
  • SECONDARY ID: NA_00084192
  • SECONDARY ID: 119134
  • SECONDARY ID: 117207
  • SECONDARY ID: 121445
  • SECONDARY ID: 119134
  • SECONDARY ID: CA209-117
  • NCT ID: NCT01928576

Conditions

  • Non-Small Lung Cancer, Epigenetic Therapy

Interventions

DrugSynonymsArms
Azacitidine5-AZA, VidazaArm D
EntinostatArm D
NivolumabOpdivoArm C

Purpose

Response Rate

Detailed Description

      Objective response rate to Nivolumab preceded by epigenetic priming. Response will be
      assessed by RECIST 1.1 criteria, baseline scans for this assessment will be the baseline
      scans done within 4 weeks of enrollment.
    

Trial Arms

NameTypeDescriptionInterventions
Arm CExperimentalNivolumab 3mg/kg every 2 weeks until progression
  • Nivolumab
Arm DExperimentalAnti-PD-1/PD-L1 treatment naïve patients only Every 28 days for 6 cycles Azacitidine 40mg/m2 days 1-5 and 8-10 Entinostat 5mg Days 3 and 10 Nivolumab 3mg/kg Days 1 and 15 Followed by: Nivolumab 3mg/kg every 2 weeks until progression
  • Azacitidine
  • Entinostat
  • Nivolumab
Arm EExperimentalPatients must have had refractory (Arm E=less than 24 weeks from first dose of anti-PD-1/PD-L1) disease during or after anti-PD-1 or anti-PD-L1 therapy and, in the opinion of the investigator, must be unlikely to benefit from nivolumab monotherapy. Every 28 days for 6 cycles Azacitidine 40mg/m2 days 1-5 and 8-10 Entinostat 5mg Days 3 and 10 Nivolumab 3mg/kg Days 1 and 15 Followed by: Nivolumab 3mg/kg every 2 weeks until progression
  • Azacitidine
  • Entinostat
  • Nivolumab
Arm FExperimentalPatients must have had recurrent (Arm F=more than 24 weeks from first dose of anti-PD1/PD-L1) disease during or after anti-PD-1 or anti-PD-L1 therapy and, in the opinion of the investigator, must be unlikely to benefit from nivolumab monotherapy. Every 28 days for 6 cycles Azacitidine 40mg/m2 days 1-5 and 8-10 Entinostat 5mg Days 3 and 10 Nivolumab 3mg/kg Days 1 and 15 Followed by: Nivolumab 3mg/kg every 2 weeks until progression
  • Azacitidine
  • Entinostat
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically proven stage IIIB, IV or recurrent non-small cell
             lung cancer. Patients must be willing to undergo a pre-treatment biopsy, either core
             needle biopsy or equivalent amount or via excisional specimen. (cytology specimen not
             acceptable for this purpose).

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional
             techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam. See
             Section 11 for the evaluation of measurable disease.

          -  Age >18 years. Because no dosing or adverse event data are currently available on the
             use of azacitidine with entinostat, or of Nivolumab, in patients <18 years of age,
             children are excluded from this study.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.

          -  Life expectancy of greater than 12 weeks.

          -  Patients must have adequate organ and marrow function.

          -  The effects of entinostat, azacitidine, and Nivolumab, on the developing human fetus
             are unknown. For this reason women of child-bearing potential and men must agree to
             use adequate contraception (hormonal or barrier method of birth control; abstinence)
             prior to study entry and for the duration of study participation and for up to 23
             weeks after the last dose of nivolumab. Should a woman become pregnant or suspect she
             is pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately. Men who are sexually active with women of
             childbearing potential must also use an adequate contraceptive method for up to 31
             weeks after fhe last dose of nivolumab.

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  All adenocarcinoma patients must be tested for ALK rearrangements and EGFR (Exon 19
             Deletion and Exon 21 L8585R Substitution) mutations and must have been treated with
             EGFR or ALK TKI therapy if found to have an actionable alteration. If patients are
             KRAS positive, testing for ALK rearrangements and EGFR mutations is not applicable.

          -  All patients should have been offered a platinum-based chemotherapy. For EGFR/ALK wild
             type patients, no more than two prior chemotherapy-based lines of therapy for advanced
             or metastatic NSCLC is permitted. For EGFR mutated or ALK translocated patients, no
             more than three prior lines of therapy for advanced or metastatic NSCLC is permitted.
             Patients who refuse platinum based chemotherapy, may be allowed to enroll if they meet
             all other criteria.

               -  Patients who received adjuvant or neoadjuvant platinum-doublet chemotherapy
                  (after surgery and/or radiation therapy) and developed recurrent or metastatic
                  disease within 6 months of completing therapy are eligible and the adjuvant or
                  neoadjuvant chemotherapy will count as a line of therapy as above.

               -  Subjects with recurrent disease > 6 months after adjuvant or neoadjuvant
                  platinum-based chemotherapy, who also subsequently progressed during or after a
                  platinum-doublet regimen given to treat the recurrences, are eligible and do not
                  count as another line of therapy for advanced disease.

               -  Subjects who received pemetrexed, bevacizumab, or erlotinib as maintenance
                  therapy (nonprogressors with platinum-based doublet chemotherapy) and
                  subsequently progressed after maintenance therapy, are eligible and do not count
                  as a line of therapy. However, subject who received a tyrosine kinase inhibitor
                  after failure of a prior platinum-based therapy, that tyrosine kinase inhibitor
                  therapy would count as an additional line of therapy.

               -  Patients who have been treated with prior standard of care PD-1/L1 agents, alone
                  or in combination with chemotherapy, are eligible. Patients previously treated on
                  clinical trials with non PD-1/PD-L1 immunotherapy agents are eligible. Patients
                  who have been treated with a PD-1/L1 agent in more than 1 line of therapy (as
                  standard of care or in clinical trial) are not eligible.

          -  Arm-specific eligibility criteria

               -  Arm D: Anti-PD-1/PD-L1 treatment naïve patients only

               -  Arm E & F: Anti-PD-1/PD-L1 treatment experienced patients: Patients must have had
                  refractory (Arm E=less than 24 weeks from first dose of anti-PD-1/PD-L1) or
                  recurrent (Arm F=more than 24 weeks from first dose of anti-PD-1/PD-L1) disease
                  during or after anti-PD-1 or anti-PD-L1 therapy and, in the opinion of the
                  investigator, must be unlikely to benefit from nivolumab monotherapy.

          -  Patients must have disease amenable to biopsy at the time of enrollment as biopsies
             are required for study participation.

        Exclusion Criteria:

          -  Any active history of a known autoimmune disease. Subjects with vitiligo, type 1
             diabetes mellitus, residual hypothyroidism requiring hormone replacement, or
             conditions not expected to recur in the absence of an external trigger are permitted
             to enroll.

          -  Subjects with a history of interstitial lung disease that has required intubation in
             the past (i.e. such as Asthma or COPD).

          -  Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 2 weeks earlier.

          -  Patients who are receiving any other anticancer therapy.

          -  Patients with uncontrolled brain metastases. Patients with brain metastases must have
             stable neurologic status following local therapy (surgery or radiation) for at least 2
             weeks without the use of steroids or on stable or decreasing dose of < 10mg daily
             prednisone (or equivalent), and must be without neurologic dysfunction that would
             confound the evaluation of neurologic and other adverse events. Patients with a
             history of carcinomatous meningitis are not eligible.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to entinostat, azacitidine, or Nivolumab.

          -  Known or suspected hypersensitivity to azacitidine or mannitol

          -  Uncontrolled inter-current illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Pregnant women are excluded from this study because entinostat, azacitidine, and
             Nivolumab are agents with the potential for teratogenic or abortifacient effects.
             Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with entinostat, azacitidine, or Nivolumab
             breastfeeding should be discontinued if the mother is treated on this protocol.

          -  HIV-positive patients are excluded. (Patients cannot have known history of HIV.
             Testing for it at baseline is not required unless it is suspected they may have it).

          -  Patients with active hepatitis B or hepatitis C are excluded. (Patients cannot have
             known history of hepatitis B or hepatitis C. Testing for it at baseline is not
             required unless it is suspected they may have it).

          -  Patients with a condition requiring systemic treatment with either corticosteroids
             (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
             days of randomization. Inhaled or topical steroids and adrenal replacement steroid
             doses > 10 mg daily prednisone equivalent, are permitted in the absence of active
             autoimmune disease.

          -  Patients with malabsorption in the small intestine or other conditions that would
             preclude administration of oral medication.

          -  Prior therapy with DNA methyltransferase therapy or HDAC inhibitor therapy.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response
Time Frame:2 years
Safety Issue:
Description:Percentage of participants with response to combination Nivolumab and epigenetic therapy. Response will be assessed by RECIST 1.1 criteria, where complete response (CR)= disappearance of all target lesions, partial response (PR) is =>30% decrease in sum of diameters of target lesions, progressive disease (PD) is >20% increase in sum of diameters of target lesions, stable disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions.

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:2 years
Safety Issue:
Description:Number of months from the time of randomization until radiologic (per RECIST 1.1) or clinical progression or death, whichever comes first.
Measure:Time to Progression
Time Frame:2 years
Safety Issue:
Description:Number of months from the time nivolumab begins until radiologic (per RECIST 1.1) or clinical progression is noted.
Measure:Overall survival
Time Frame:2 years
Safety Issue:
Description:Number of months from the time of randomization until death. Estimation will be by the Kaplan-Meier method.
Measure:Safety and tolerability as assessed by number of participants with adverse events
Time Frame:2 years
Safety Issue:
Description:Number of participants who experience adverse events as defined by CTCAE v4.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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