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Drug Interventions

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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 10/25/2020.

Phase II Anti-PD1 Epigenetic Therapy Study in NSCLC.

Clinicaltrials.gov identifier NCT01928576

Recruitment Status Recruiting

First Posted August 26, 2013

Last update posted July 21, 2020

Study Description

Brief summary:

Response Rate

  • Condition or Disease:Non-Small Cell Lung Cancer
    Epigenetic Therapy
  • Intervention/Treatment: Drug: Azacitidine
    Drug: Entinostat
    Drug: Nivolumab
  • Phase: Phase 2
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.

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 120 participants
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • 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.
  • Study Start Date: August 2013
  • Estimated Primary Completion Date: August 2022
  • Estimated Study Completion Date: August 2022
Arms and interventions
Arm Intervention/treatment
Experimental: Arm D
Anti-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 After a patient has completed 6 months of nivolumab, they can receive nivolumab every 4 weeks instead of every 2 weeks. The dose for Nivolumab every 4 weeks is 480mg.
Drug: Azacitidine


Drug: Entinostat


Drug: Nivolumab
Experimental: Arm E
Patients 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 After a patient has completed 6 months of nivolumab, they can receive nivolumab every 4 weeks instead of every 2 weeks. The dose for Nivolumab every 4 weeks is 480mg.
Drug: Azacitidine


Drug: Entinostat


Drug: Nivolumab
Experimental: Arm F
Patients 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 After a patient has completed 6 months of nivolumab, they can receive nivolumab every 4 weeks instead of every 2 weeks. The dose for Nivolumab every 4 weeks is 480mg.
Drug: Azacitidine


Drug: Entinostat


Drug: Nivolumab
Experimental: Arm C
Nivolumab 3mg/kg every 2 weeks until progression
Drug: Nivolumab
Outcome Measures
  • Primary Outcome Measures: 1. Objective Response [ Time Frame: 2 years ]
    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: 1. Progression free survival [ Time Frame: 2 years ]
    Number of months from the time of randomization until radiologic (per RECIST 1.1) or clinical progression or death, whichever comes first.
  • 2. Time to Progression [ Time Frame: 2 years ]
    Number of months from the time nivolumab begins until radiologic (per RECIST 1.1) or clinical progression is noted.
  • 3. Overall survival [ Time Frame: 2 years ]
    Number of months from the time of randomization until death. Estimation will be by the Kaplan-Meier method.
  • 4. Safety and tolerability as assessed by number of participants with adverse events [ Time Frame: 2 years ]
    Number of participants who experience adverse events as defined by CTCAE v4.0.
Eligibility Criteria
  • Ages Eligible for Study: 18 to 100 Years (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No
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. A CT scan of the abdomen and
pelvis is not required for patients with no disease in these areas.

- 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 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 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.

Contacts and Locations
Contacts

Contact: Julie Brahmer, MD 410-502-7159 brahmju@jhmi.edu

Contact: Elisabeth Prophet 443-287-2021 eprophe1@jhmi.edu

Locations

United States, California
University of Southern California
Los Angeles

United States, District of Columbia
Sibley Memorial Hospital
Washington

United States, Maryland
Julie Brahmer, MD
Baltimore

United States, Maryland
Julie Brahmer, MD
Baltimore

United States, Pennsylvania
UPMC Cancer Center- Hillman Cancer Center
Pittsburgh

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Rising Tide Foundation

Stand Up To Cancer

Bristol-Myers Squibb

Celgene

Syndax Pharmaceuticals, Inc.

Rhone-Poulenc Rorer

Investigators

Principal Investigator: Julie Brahmer, MD Johns Hopkins University

More Information
  • Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • ClinicalTrials.gov Identifier: NCT01928576 History of Changes
  • Other Study ID Numbers: J1353, NA_00084192, 119134, 117207, 121445, 119134, CA209-117
  • First Posted: August 26, 2013 Key Record Dates
  • Last Update Posted: July 21, 2020
  • Last Verified: July 2020
  • Additional relevant MeSH terms: Lung Neoplasms Carcinoma, Non-Small-Cell Lung