Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

A Phase I/II Study of Nivolumab, Ipilimumab and Plinabulin in Patients With Recurrent Small Cell Lung Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03575793
Recruitment Status : Recruiting
First Posted : July 3, 2018
Last Update Posted : April 17, 2020
Sponsor:
Information provided by (Responsible Party):
Jyoti Malhotra, Big Ten Cancer Research Consortium

Tracking Information
First Submitted Date  ICMJE June 20, 2018
First Posted Date  ICMJE July 3, 2018
Last Update Posted Date April 17, 2020
Actual Study Start Date  ICMJE September 6, 2018
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 29, 2018)
  • Phase I: Maximum Tolerated Dose (MTD) [ Time Frame: 9 Months ]
    Establish MTD of plinabulin in combination with nivolumab and ipilimumab for patients with recurrent SCLC
  • Phase II: Progression-Free Survival (PFS) [ Time Frame: 36 Months ]
    Determine if the addition of plinabulin to double checkpoint inhibition (PD-1 and CTLA-4) for recurrent SCLC will improve PFS (the time from treatment assignment to the date of the first documented tumor progression, or death due to any cause, whichever occurred first).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 29, 2018)
  • Assess Adverse Events [ Time Frame: 36 Months ]
    Assess toxicity and tolerability of the combination of nivolumab, ipilimumab and plinabulin using CTCAE v5
  • Assess immune-related adverse events (irAEs) [ Time Frame: 36 Months ]
    Compare the frequency of immune-related adverse events (irAEs) between the nivolumab/ipilimumab arm vs the nivolumab/ipilimumab/plinabulin arm. irAE's are defined as any treatment-related AE that is inflammatory in nature, consistent with the mechanism of action of immunotherapy and generally medically manageable with topical and/or systemic immunosuppressants.
  • Proportion of subjects with a confirmed objective response [ Time Frame: 36 Months ]
    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 PR divided by the number of assigned patients).
  • Clinical Benefit Rate [ Time Frame: 36 Months ]
    Estimate clinical benefit rate (CBR: complete response, partial response, or stable disease).
  • 6-Month Progression-Free Survival [ Time Frame: 6 Months ]
    Estimate 6-month (±4 weeks) PFS.
  • 1-year Overall Survival [ Time Frame: 12 Months ]
    Estimate 1-year Overall Survival
  • Overall Survival [ Time Frame: 36 Months ]
    Estimate Overall Survival
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase I/II Study of Nivolumab, Ipilimumab and Plinabulin in Patients With Recurrent Small Cell Lung Cancer
Official Title  ICMJE A Phase I/II Study of Nivolumab, Ipilimumab and Plinabulin in Patients With Recurrent Small Cell Lung Cancer: Big Ten Cancer Research Consortium. BTCRC-LUN17-127
Brief Summary An open-label Phase I/II study, with a dose escalation part (Phase I) and a 2-arm randomized part (Phase II), in patients with recurrent SCLC.
Detailed Description

This is an open-label Phase I/II study, with a dose escalation part (Phase I) and a 2-arm randomized part (Phase II), in patients with recurrent SCLC.

In the Phase I part, patients will receive plinabulin at escalating doses in combination with nivolumab and ipilimumab. Doses of study drug will be administered as intravenous (IV) infusions in 21 day cycles. Patients will receive all study drugs on Day 1 of each cycle. After 4 treatment cycles, ipilimumab is stopped and patients continue treatment with nivolumab and plinabulin every 2 weeks (maintenance period) or until disease progression, development of unacceptable toxicity or one of the protocol-defined reasons for treatment discontinuation occurs.

At least 3 patients will be enrolled in each cohort, starting at 20 mg/m2 of plinabulin. The dose of plinabulin will be escalated in sequential patient cohorts after the safety data from the first cycle is reviewed. Thereafter the dose of plinabulin will be escalated to 30 mg/m2, provided that dose-limiting toxicities (DLTs) are not observed per the specified criteria, until the RP2D is determined.

In the Phase II part, approximately 40 patients will be randomized in a 1:1 ratio to receive either nivolumab + ipilimumab (Arm NI) or the triple combination of plinabulin (at RP2D) + nivolumab + ipilimumab (Arm PNI). Patients will continue treatment until disease progression, development of unacceptable toxicity or one of the protocol-defined reasons for treatment discontinuation occurs.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lung Cancer
  • SCLC
Intervention  ICMJE
  • Drug: Nivolumab
    A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1,PCD-1,) with immune checkpoint inhibitory and antineoplastic activities.
    Other Name: Opdivo
  • Drug: Plinabulin
    Plinabulin (BPI-2358) is a synthetic, low molecular weight, new chemical entity originally developed by Nereus Pharmaceuticals, Inc., and now by BeyondSpring Pharmaceuticals, Inc. It belongs to the diketopiperazine class of compounds with a chemical name 2, 5-piperazinedione, 3-[[5-(1,1-dimethylethyl)-1H-imidazol-4-yl[methylene]-6-(phenylmethylene)-, (3Z,6Z) (trivial name t-butyl-dehydrophenylahistin).
  • Drug: Ipilimumab
    Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.
    Other Name: Yervoy
Study Arms  ICMJE
  • Experimental: Phase I: nivolumab, ipilimumab and plinabulin

    On Day 1 in a 21-day cycle, all patients will receive nivolumab (1 mg/kg, IV), ipilimumab (3 mg/kg, IV) and plinabulin (escalating cohorts, IV).

    After 4 treatment cycles, ipilimumab will be discontinued and patients will continue treatment with nivolumab 240 mg and plinabulin every 2 weeks (maintenance period) until one of the end of treatment criteria occur.

    Plinabulin escalation is as follows:

    Level -1 : 13.5mg/m^2

    Level 1 (start) : 20mg/m^2

    Level 2 : 30mg/m^2

    Interventions:
    • Drug: Nivolumab
    • Drug: Plinabulin
    • Drug: Ipilimumab
  • Experimental: Phase II Arm A: nivolumab and ipilimumab

    On Day 1 in a 21-day cycle, all patients will receive nivolumab (1 mg/kg, IV), ipilimumab (3 mg/kg, IV).

    After 4 treatment cycles, ipilimumab will be discontinued and patients will continue treatment with nivolumab 240 mg (maintenance period) until one of the end of treatment criteria occur .

    Interventions:
    • Drug: Nivolumab
    • Drug: Plinabulin
  • Experimental: Phase II Arm B: nivolumab, ipilimumab, and plinabulin

    On Day 1 in a 21-day cycle, all patients will receive nivolumab (1 mg/kg, IV), ipilimumab (3 mg/kg, IV) and plinabulin (MTD from Phase I).

    After 4 treatment cycles, ipilimumab will be discontinued and patients will continue treatment with nivolumab 240 mg and plinabulin every 2 weeks (maintenance period) until one of the end of treatment criteria occur .

    Interventions:
    • Drug: Nivolumab
    • Drug: Plinabulin
    • Drug: Ipilimumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 29, 2018)
55
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2022
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Must have signed and dated written informed consent form in accordance with regulatory and institutional guidelines.
  • Males and females aged >18 years at time of consent.
  • 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 RECIST v1.1 (Section 8) 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 as in criterion 9b above during the treatment period and for 31 weeks after the last dose of study drug.
  • Absolute neutrophil count ≥1,000/µL
  • Platelet count ≥100,000/µL
  • 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/1.73m2
  • 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.

Exclusion Criteria:

  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jyoti Malhotra, MD 732-235-7521 Jm1940@cinj.rutgers.edu
Contact: Ahran Lee 317-634-5842 ext 14 alee@hoosiercancer.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03575793
Other Study ID Numbers  ICMJE BTCRC-LUN17-127
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jyoti Malhotra, Big Ten Cancer Research Consortium
Study Sponsor  ICMJE Jyoti Malhotra
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jyoti Malhotra, MD Rutgers Cancer Institute of New Jersey
PRS Account Big Ten Cancer Research Consortium
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP