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

NCT03575793

Description:

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.

Related Conditions:
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: BTCRC-LUN17-127
  • NCT ID: NCT03575793

Conditions

  • Lung Cancer
  • SCLC

Interventions

DrugSynonymsArms
NivolumabOpdivoPhase I: nivolumab, ipilimumab and plinabulin
PlinabulinPhase I: nivolumab, ipilimumab and plinabulin
IpilimumabYervoyPhase I: nivolumab, ipilimumab and plinabulin

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I: nivolumab, ipilimumab and plinabulinExperimentalOn 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
  • Nivolumab
  • Plinabulin
  • Ipilimumab
Phase II Arm A: nivolumab and ipilimumabExperimentalOn 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 .
  • Nivolumab
  • Plinabulin
Phase II Arm B: nivolumab, ipilimumab, and plinabulinExperimentalOn 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 .
  • Nivolumab
  • Plinabulin
  • Ipilimumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Maximum Tolerated Dose (MTD)
Time Frame:9 Months
Safety Issue:
Description:Establish MTD of plinabulin in combination with nivolumab and ipilimumab for patients with recurrent SCLC

Secondary Outcome Measures

Measure:Assess Adverse Events
Time Frame:36 Months
Safety Issue:
Description:Assess toxicity and tolerability of the combination of nivolumab, ipilimumab and plinabulin using CTCAE v5
Measure:Assess immune-related adverse events (irAEs)
Time Frame:36 Months
Safety Issue:
Description: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.
Measure:Proportion of subjects with a confirmed objective response
Time Frame:36 Months
Safety Issue:
Description: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).
Measure:Clinical Benefit Rate
Time Frame:36 Months
Safety Issue:
Description:Estimate clinical benefit rate (CBR: complete response, partial response, or stable disease).
Measure:6-Month Progression-Free Survival
Time Frame:6 Months
Safety Issue:
Description:Estimate 6-month (±4 weeks) PFS.
Measure:1-year Overall Survival
Time Frame:12 Months
Safety Issue:
Description:Estimate 1-year Overall Survival
Measure:Overall Survival
Time Frame:36 Months
Safety Issue:
Description:Estimate Overall Survival

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Jyoti Malhotra

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