Phase II Anti-PD1 Epigenetic Priming Study in NSCLC. (NA_00084192)
Verified August 2013 by Sidney Kimmel Comprehensive Cancer Center
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
First received: August 21, 2013
Last updated: August 23, 2013
Last verified: August 2013
Non-Small Lung Cancer, Epigenetic Therapy
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
||A Randomized Phase II Study of Epigenetic Priming With Azacitidine and Entinostat or Oral Azacitidine Alone Prior to Nivolumab in Subjects With Recurrent Metastatic Non-Small Cell Lung Cancer.
Primary Outcome Measures:
Secondary Outcome Measures:
- Progression free survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Progression-free survival (overall) will be measured from the time of randomizationuntil radiologic or clinical progression is noted. Estimation will be by the Kaplan-Meier method.
- Time to Progression [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Time to progression (nivolumab) on nivolumab will be measured from the time nivolumab begins until radiologic or clinical progression is noted. Estimation will be by the Kaplan-Meier method.
- Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Overall survival will be measured from the time of randomization until death. Estimation will be by the Kaplan-Meier method.
- Safety and tolerability [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
Toxicities observed in both phases of the study will be assessed by CTCAE 4.0 criteria. We will tabulate toxicities and compare the two treatment groups via methods appropriate for categorical data.
| Estimated Enrollment:
| Study Start Date:
| Estimated Study Completion Date:
| Estimated Primary Completion Date:
||January 2015 (Final data collection date for primary outcome measure)
Experimental: Arm B
CC-486 300 mg Days 1-21 for 28 days times 2 cycles followed by Nivolumab 3 mg/kg every 2 weeks until progression.
Other Name: Oral Azacitidine
Active Comparator: Arm A
Azacitidine 40mg/m2 Subcutaneous Days 1-6, 8-10, + Entinostat 8 mg Oral Days 3 & 10 for 28 Days times 2 cycles followed by Nivolumab 3 mg/kg every 2 weeks until progression.
Other Name: 5-AZA, Vidaza
Other Name: Entinostat
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.
|Ages Eligible for Study:
||18 Years and older
|Genders Eligible for Study:
|Accepts Healthy Volunteers:
- Patients must have histologically proven stage IIIB, IV or recurrent non-small cell lung cancer. Patients must have a pre-treatment tumor specimen available for correlative studies, either core needle biopsy or excisional specimen (cytology specimen not acceptable for this purpose). Patients with no available archived specimen must be willing to undergo a pre-treatment tumor biopsy.
- 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.
- Patients must have received at least one platinum based chemotherapy, and not more than three, prior therapies for stage IIIB/IV disease.
- 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.
- 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.
- Patients with documented EGFR or ALK mutations must have been treated with prior EGFR or ALK therapy as well as a platinum containing doublet.
- All adenocarcinoma patients will be tested for ALK rearrangements and EGFR (Exon 19 Deletion and Exon 21 L8585R Substitution) mutations and must have been treated with prior EGFR or ALK therapy as well as a platinum containing doublet.
- 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. Patients requiring continuous supplemental oxygen are excluded to avoid possible complications from pneumonitis.
- 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.
- Patients with advanced malignant hepatic tumors.
- 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 with active hepatitis B or hepatitis C are excluded.
- 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 anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody therapies, any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways, DNA methyltransferase therapy or HDAC inhibitor therapy.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01928576
|Julie Brahmer, MD
|Baltimore, Maryland, United States, 21287 |
|Contact: Julie Brahmer, MD 410-502-7159 firstname.lastname@example.org |
|Contact: Charles P. Raines, CRNP, MSN 410-502-3696 email@example.com |
|Phillip Dennis, MD, PhD
|Johns Hopkins at Bayview Medical Center, Maryland, United States, 21224 |
|Contact: Phillip Dennis, MD, PhD 410-550-9250 firstname.lastname@example.org |
|Contact: Jessica Wakefield 410-550-2751 email@example.com |
Sidney Kimmel Comprehensive Cancer Center
No publications provided
||Sidney Kimmel Comprehensive Cancer Center
History of Changes
|Other Study ID Numbers:
|Study First Received:
||August 21, 2013
||August 23, 2013
||United States: Food and Drug Administration
United States: Institutional Review Board
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on July 20, 2014
Respiratory Tract Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Molecular Mechanisms of Pharmacological Action