Nivolumab, Ipilimumab, and Plinabulin in Treating Patients with Recurrent Extensive Stage Small Cell Lung Cancer
- Must have signed and dated written informed consent form in accordance with regulatory and institutional guidelines
- Histological or cytological confirmed extensive-stage SCLC with availability of representative baseline tumor tissue (10 slides; archived or on-study biopsy). If patient already has FoundationOne testing results, baseline tumor tissue is not required to meet eligibility
- Patients who progressed after at least 1 platinum-based chemotherapy regimen. Patients with platinum resistance (defined as recurrence or progression of disease within 90 days of completion of the platinum-based regimen) are eligible
- Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 obtained by imaging within 28 days prior to study registration
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days before registration and minimum life expectancy of at least 12 weeks
- Treatment to be initiated at least 2 weeks since last dose of prior systemic anticancer therapy (chemotherapy, radiation, and/or surgery)
- Recovery to grade 1 of any clinically significant toxicity (excluding alopecia) prior to initiation of study drugs
- Female patients of childbearing potential have a negative pregnancy test at baseline. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression * Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test) documented within 14 days of study registration and within the 24-hour period prior to the first dose of study drug * Sexually active women of childbearing potential enrolled in the study must agree to use 2 forms of accepted methods of contraception during the course of the study and for 23 weeks after their last dose of study drug. Effective birth control includes (a) intrauterine device plus 1 barrier method; (b) on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or (d) a vasectomized partner * For male patients who are sexually active and who are partners of premenopausal women: agreement to use 2 forms of contraception during the treatment period and for 31 weeks after the last dose of study drug
- Absolute neutrophil count >= 1,000/uL
- Platelet count >= 100,000/uL
- Hemoglobin >= 9.0 g/dL
- Total bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for subjects with Gilbert’s disease
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN (=< 5 x ULN if evidence of hepatic involvement by malignant disease)
- Creatinine =< 1.5 x ULN or estimated glomerular filtration rate (eGFR) >= 40 mL/min/1.73 m^2
- Lipase and amylase =< 1.5 x ULN. Subjects with lipase > 1.5 x ULN may enroll if there are neither clinical nor radiographic signs of a pancreatitis
- Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or pneumonitis requiring treatment with steroids
- Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 23 weeks (female) or 31 weeks (male) after the last dose of study drug
- Must not have received PD-1, PD-L1 or CTLA-4 targeted therapy previously
- Treatment with any investigational agent within 28 days prior to registration for protocol therapy
- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with neurological symptoms must undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to exclude brain metastasis. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images obtained after treatment to the brain metastases at least 4 weeks apart and show no evidence of intracranial progression)
- Known history of human immunodeficiency virus (HIV) or active hepatitis B (by surface antigen expression or polymerase chain reaction [PCR]) or active hepatitis C (by PCR) infection
- Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Vitiligo, alopecia, hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment, celiac disease controlled by diet alone or conditions not expected to recur in the absence of an external trigger are permitted
- A condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to administration of study drugs
- History of psychiatric illness or social situations that would limit compliance with study requirements. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient’s participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
- Prior malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 2 years prior to study entry
- Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) class III–IV within 6 months prior to their first dose of study drugs
- Evidence of ongoing inadequately controlled hypertension (defined as baseline systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg)
- Any active grade 3 or higher viral, bacterial, or fungal infection within 2 weeks of the first dose of the study drugs. Routine antimicrobial prophylaxis is permitted
I. To establish the maximum tolerated dose (MTD) of plinabulin in combination with nivolumab and ipilimumab for patients with recurrent small cell lung cancer (SCLC). (Phase I)
II. To determine if the addition of plinabulin to double checkpoint inhibition (PD-1 and CTLA-4) for recurrent SCLC will improve progression-free survival (PFS) (the time from treatment assignment to the date of the first documented tumor progression, or death due to any cause, whichever occurred first). (Phase II)
I. To assess toxicity and tolerability of the combination of nivolumab, ipilimumab and plinabulin.
II. To compare the frequency of immune-related adverse events (irAEs) between the nivolumab/ipilimumab arm versus (vs) the nivolumab/ipilimumab/plinabulin arm.
III. To determine the proportion of patients with a confirmed objective response in the 2 arms of the phase II part (defined as the number of patients with a best overall response of complete response [CR] or partial response [PR] divided by the number of assigned patients).
IV. To estimate clinical benefit rate (CBR: complete response, partial response, or stable disease).
V. To estimate 6-month (+/- 4 weeks) PFS.
VI. To estimate overall survival (OS) and 1-year OS.
I. To compare biomarkers of inflammation (high sensitivity C-reactive protein [hsCRP], erythrocyte sedimentation rate [ESR], serum amyloid A [SAA]) between the nivolumab/ipilimumab arm vs the nivolumab/ipilimumab/plinabulin arm.
II. To correlate tumor mutational burden with PFS and objective response rate (ORR).
OUTLINE: This is a phase I, dose-escalation study of plinabulin followed by a phase II study.
PHASE I: Patients receive nivolumab intravenously (IV) over 30 minutes, ipilimumab IV over 30 minutes, and plinabulin IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes and plinabulin IV over 60 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
PHASE II: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive nivolumab IV over 30 minutes, ipilimumab IV over 30 minutes, and plinabulin IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes and plinabulin IV over 60 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3 months for 1 year.
Trial Phase Phase I/II
Trial Type Treatment
Rutgers Cancer Institute of New Jersey
- Primary ID 031805
- Secondary IDs NCI-2019-00209
- Clinicaltrials.gov ID NCT03575793