Adenocarcinoma of the Lung, Lung Cancer, Non-Squamous Non-Small Cell Lung Cancer (NSCLC), Squamous Cell Lung Cancer
Conditions
Keywords
Nivolumab, BMS-936558-01, Anti-PD-1 Antibody, Docetaxel, Pemetrexed, Gemcitabine
Brief summary
This is a randomized phase II study assessing the activity of single agent chemotherapy combined with nivolumab (Arm A) compared to single agent chemotherapy alone (Arm B) in squamous or non-squamous NSCLC subjects with primary resistance to prior PD-1 or PDL-1 inhibitor. The single agent chemotherapy chosen is at the discretion of the site investigator and may include pemetrexed, gemcitabine or taxotere. Institutional standards should be used for administration of the single agent chemotherapy. For both treatment arms, 21 days equals 1 cycle of therapy and subjects will be eligible to continue treatment until progressive disease by RECIST v1.1 or unacceptable toxicity. Upon registration, subjects will be randomized in a 1:1 ratio to either treatment with single agent chemotherapy or single agent chemotherapy in combination with nivolumab. Randomization is un-blinded and open-label; therefore there will be no placebo treatment for subjects randomized to single agent chemotherapy
Interventions
DRUGDocetaxel
Docetaxel 75 mg/m2 IV Day 1 of each cycle (21 days = 1 cycle)
DRUGNivolumab
Nivolumab 360 mg IV Day 1 of each cycle (21 days = 1 cycle)
DRUGGemcitabine
Gemcitabine 1000 mg/m2 IV Day 1 and Day 8 of each cycle (21 days = 1 cycle)
DRUGPemetrexed
Pemetrexed 500 mg/m2 IV Day 1 of each cycle (21 days = 1 cycle)
Sponsors
Hoosier Cancer Research Network
Bristol-Myers Squibb
Nasser Hanna, M.D.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-Label
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subject must meet all of the following applicable inclusion criteria to participate in this study: 1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. 2. Age ≥ 18 years at the time of consent. 3. ECOG Performance Status of 0-2 within 28 days prior to randomization. 4. Histological or cytological confirmed squamous or non-squamous non-small cell lung cancer. 5. Measurable disease according to RECIST 1.1 within 28 days prior to randomization. 6. A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to randomization, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic. 7. Subjects must have primary resistance to PD-1 or PDL-1 inhibitors; defined as PD after 3 or fewer treatments with a PD-1 or PDL-1 inhibitor 8. Subjects must have progressed on or after previous platinum-based chemotherapy. Chemotherapy may have previously been given with a PD-1 or PD-L1 inhibitor. Subjects must have also progressed on or after receiving any PD-1 or PD-L1 inhibitor (including nivolumab) as their most recent therapy. 9. Most recent PD-1 or PD-L1 inhibitor infusion must be completed at least 6 weeks of randomization. The subject must have recovered from all reversible acute toxic effects (other than alopecia) to ≤ Grade 1 or baseline. 10. Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to randomization. White blood cell (WBC) ≥ 2 k/mm3 Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3 Hemoglobin (Hgb) ≥ 9 g/dL Platelet \>100k Estimated creatinine clearance OR ≥ 40 cc/min Serum creatinine ≤ 1.5 x upper limit of normal (ULN) Bilirubin 1.5 ≤ (ULN)2 Aspartate aminotransferase (AST) ≤ 1.5 × ULN Alanine aminotransferase (ALT) ≤ 1.5 × ULN International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤ 2 × ULN (Note: use of vitamin K antagonist is not allowed) 11. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to registration. These women must also have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of Nivolumab then every 6 weeks thereafter. NOTE: Women are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are post-menopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL. 12. Women of childbearing potential must be willing to abstain from heterosexual activity or use an effective method of contraception from the time of informed consent until 5 months after treatment discontinuation. Women cannot breast feed from the time of informed consent to 5 months after last dose of study treatment. See below for adequate methods of contraception. 13. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving Nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. See below for methods of contraception. 14. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study
Exclusion criteria
1. Prior treatment with the single agent chemotherapy the site investigator chooses to use for this protocol (pemetrexed, taxotere or gemcitabine). 2. Previous autoimmune complication from PD-1 or PD-L1 requiring discontinuation of therapy or treatment with steroids (ongoing treatment with more than 10 mg of prednisone or steroid equivalent daily, excluding inhaled or topical steroids). 3. Previous discontinuation from PD-1 or PD-L1 due to an adverse event. 4. Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy. 5. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). 6. Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years. 7. Active central nervous system (CNS) metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for \[lowest minimum is 4 weeks or more\] after treatment is complete and within 28 days prior to the first dose of Nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. 8. Treatment with any investigational drug within 30 days prior to registration. 9. Subjects whose tumors express EGFR mutations on exons 19 and 21, ALK rearrangement, or ROS1 rearrangement who still have other FDA approved targeted agents available for treatment. 10. Subjects with an active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids/immunosuppressive medications EXCEPT for syndromes which would not be expected to recur in the absence of an external trigger. (Subjects with vitiligo, autoimmune thyroiditis, or type I diabetes mellitus are permitted to enroll.) 11. As there is potential for hepatic toxicity with Nivolumab, drugs with a predisposition to hepatoxicity should be used with caution in subjects treated with Nivolumab-containing regimen. 12. Subjects should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. 13. Subjects should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). 14. History of allergy to study drug components. 15. Prior solid organ or stem cell transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS), as Defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. | 24 months | Compare PFS rates for subjects on each treatment arm, per RECIST 1.1. Subjects who have not progressed will be right-censored at the date of the last follow up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) for Subjects on Each Treatment Arm, as Defined by RECIST 1.1 and Immune-related Response Criteria (irRECIST) | Every 6 weeks beginning with C3D1 and every odd numbered cycle thereafter, assessed for up to 24 months | Proportion of subjects on each arm with complete response or partial response, per RECIST 1.1 and irRECIST |
| Clinical Benefit Rate (CBR) for Subjects on Each Treatment Arm, as Defined by RECIST 1.1 and irRECIST | From D1 of treatment until documented disease progression/recurrence, assessed for up to 24 months | Proportion of subjects on each arm with complete response, partial response or stable disease for at least 3 months, per RECIST 1.1 and irRECIST |
| Progression Free Survival (PFS), as Defined by irRECIST | 24 months | Compare PFS rates for subjects on each treatment arm, per irRECIST. From date of randomization until the criteria for disease progression is met or death as a result of any cause, assessed up to 24 months |
| Number of Participants With Grade 3 or Grade 4 Adverse Events | 6 months | Assess toxicity of Nivolumab plus single agent chemotherapy compared with single agent chemotherapy alone. Number of grade 3 and 4 toxicities as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A Single Agent Chemotherapy of choice plus nivolumab:
Taxotere Pemetrexed Gemcitabine
Docetaxel: Docetaxel 75 mg/m2 IV Day 1 of each cycle (21 days = 1 cycle)
Nivolumab: Nivolumab 360 mg IV Day 1 of each cycle (21 days = 1 cycle)
Gemcitabine: Gemcitabine 1000 mg/m2 IV Day 1 and Day 8 of each cycle (21 days = 1 cycle)
Pemetrexed: Pemetrexed 500 mg/m2 IV Day 1 of each cycle (21 days = 1 cycle) | 1 |
| Arm B Single Agent Chemotherapy of choice Taxotere Pemetrexed Gemcitabine
Docetaxel: Docetaxel 75 mg/m2 IV Day 1 of each cycle (21 days = 1 cycle)
Gemcitabine: Gemcitabine 1000 mg/m2 IV Day 1 and Day 8 of each cycle (21 days = 1 cycle)
Pemetrexed: Pemetrexed 500 mg/m2 IV Day 1 of each cycle (21 days = 1 cycle) | 2 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease Progression | 1 | 2 |
Baseline characteristics
| Characteristic | Arm A | Total | Arm B |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Histology Adenocarcinoma | 1 Participants | 3 Participants | 2 Participants |
| Histology Large Cell Carcinoma | 0 Participants | 0 Participants | 0 Participants |
| Histology Mixed Histology | 0 Participants | 0 Participants | 0 Participants |
| Histology Non-small Cell Carcinoma | 0 Participants | 0 Participants | 0 Participants |
| Histology Sqamous | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 1 participants | 3 participants | 2 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 1 / 2 |
| other Total, other adverse events | 1 / 1 | 2 / 2 |
| serious Total, serious adverse events | 0 / 1 | 1 / 2 |
Outcome results
Primary
Progression Free Survival (PFS), as Defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Compare PFS rates for subjects on each treatment arm, per RECIST 1.1. Subjects who have not progressed will be right-censored at the date of the last follow up.
Time frame: 24 months
Population: Data for this objective was neither collected or analyzed due to the early termination of the study.
Secondary
Clinical Benefit Rate (CBR) for Subjects on Each Treatment Arm, as Defined by RECIST 1.1 and irRECIST
Proportion of subjects on each arm with complete response, partial response or stable disease for at least 3 months, per RECIST 1.1 and irRECIST
Time frame: From D1 of treatment until documented disease progression/recurrence, assessed for up to 24 months
Population: Data for this objective was neither collected or analyzed due to the early termination of the study.
Secondary
Number of Participants With Grade 3 or Grade 4 Adverse Events
Assess toxicity of Nivolumab plus single agent chemotherapy compared with single agent chemotherapy alone. Number of grade 3 and 4 toxicities as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A | Number of Participants With Grade 3 or Grade 4 Adverse Events | GR4 Thromboembolic Event | 0 participants |
| Arm A | Number of Participants With Grade 3 or Grade 4 Adverse Events | GR3 Adverse Events | 0 participants |
| Arm B | Number of Participants With Grade 3 or Grade 4 Adverse Events | GR4 Thromboembolic Event | 1 participants |
| Arm B | Number of Participants With Grade 3 or Grade 4 Adverse Events | GR3 Adverse Events | 0 participants |
Secondary
Overall Response Rate (ORR) for Subjects on Each Treatment Arm, as Defined by RECIST 1.1 and Immune-related Response Criteria (irRECIST)
Proportion of subjects on each arm with complete response or partial response, per RECIST 1.1 and irRECIST
Time frame: Every 6 weeks beginning with C3D1 and every odd numbered cycle thereafter, assessed for up to 24 months
Population: Data for this objective was neither collected or analyzed due to the early termination of the study.
Secondary
Progression Free Survival (PFS), as Defined by irRECIST
Compare PFS rates for subjects on each treatment arm, per irRECIST. From date of randomization until the criteria for disease progression is met or death as a result of any cause, assessed up to 24 months
Time frame: 24 months
Population: Data for this objective was neither collected or analyzed due to the early termination of the study.