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Phase I/II Study of Nivolumab and Ipilimumab Combined With Nintedanib in Non Small Cell Lung Cancer

NCT03377023

Description:

The main purpose of this study is to see if the combination of nivolumab, ipilimumab and nintedanib is effective in people with non- small cell lung cancer. Researchers also want to find out if the combination of nivolumab, ipilimumab and nintedanib is safe and tolerable.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I/II Study of Nivolumab and Ipilimumab Combined With Nintedanib in Non Small Cell Lung Cancer
  • Official Title: Phase I/II Study of Nivolumab and Ipilimumab Combined With Nintedanib in Non Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: MCC-19406
  • NCT ID: NCT03377023

Conditions

  • Non Small Cell Lung Cancer
  • Lung Cancer, Nonsmall Cell
  • Non Small Cell Lung Cancer Metastatic

Interventions

DrugSynonymsArms
NivolumabOpdivo®Phase 1 - Dose Escalation
IpilimumabYervoy®Phase 1 - Dose Escalation
NintedanibVargatef®, Ofev®, BIBF1120Phase 1 - Dose Escalation

Purpose

The main purpose of this study is to see if the combination of nivolumab, ipilimumab and nintedanib is effective in people with non- small cell lung cancer. Researchers also want to find out if the combination of nivolumab, ipilimumab and nintedanib is safe and tolerable.

Trial Arms

NameTypeDescriptionInterventions
Phase 1 - Dose EscalationExperimentalNivolumab + Ipilimumab + Nintedanib dose escalation. Nivolumab: 3 mg/kg IV Q2 weeks. Ipilimumab: 1 mg/kg Q6 weeks. Nintedanib Level -1: 100 mg by mouth (PO) once a day (QD) Days 1-28 (Daily dose =100 mg). Nintedanib Level 0:150 mg by mouth (PO) once a day (QD) Days 1-28 (Daily dose =150 mg) Nintedanib Level 1: 100 mg PO twice daily (BID) Days 2-28 (Daily dose = 200 mg). Nintedanib Level 2: 150 mg PO BID Days 2-28 (Daily dose = 300 mg). Nintedanib Level 3: 200 mg PO BID Days 2-28 (Daily dose = 400 mg).
  • Nivolumab
  • Ipilimumab
  • Nintedanib
Phase 2 - Arm AActive ComparatorArm A: Newly diagnosed or treatment-naïve patients, with a target overall response rate (ORR) of 50%. Nivolumab + Ipilimumab + Nintedanib at RP2D.
  • Nivolumab
  • Ipilimumab
  • Nintedanib
Phase 2 - Arm BActive ComparatorArm B: Patients who have been previously exposed to immunotherapy, such as anti-PD-1, anti-PD-L1 or anti-CTLA-4, with a target ORR of 20%. Nivolumab + Ipilimumab + Nintedanib at RP2D.
  • Nivolumab
  • Ipilimumab
  • Nintedanib

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologic or cytological diagnosis of advanced/metastatic
             Non-Small Cell Lung Cancer (NSCLC) with no curative treatment options. For those with
             mixed histology, there must be a predominant histology.

          -  18 years of age or older on day of signing informed consent.

          -  Life expectancy of at least 3-6 months.

          -  Eastern Cooperative Oncology Group (ECOG) performance status score 0 and 1

          -  For phase I trial portion, treatment naïve or patients previously treated with
             chemotherapy, immunotherapy or targeted therapy for NSCLC are allowed. Patient who
             underwent curative intent chemotherapy and/radiation in the neoadjuvant or adjuvant
             setting are allowed to enroll if tumor recurrence occurred greater than 6 months from
             completion of that therapy (and will be considered treatment naïve in the Stage IV
             setting). Patients with NSCLC tumor known to harbor a genomic aberration for which FDA
             approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M
             mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to
             enroll if they have received prior treatment with the FDA approved targeted therapy.

          -  For phase II trial portion, Patients will be enrolled as two parallel cohorts:

               -  A.) Arm A (treatment naïve): Patients who are newly diagnosed and treatment
                  naïve. Patient who underwent curative intent chemotherapy and/radiation in the
                  neoadjuvant or adjuvant setting are allowed to enroll if tumor recurrence
                  occurred greater than 6 months from completion of therapy. Patients with NSCLC
                  tumor known to harbor a genomic aberration for which FDA approved treatment is
                  available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK
                  rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if
                  they have received prior treatment with the FDA approved targeted therapy.

               -  B.) Arm B (Immunotherapy pre-treated group): Patients who have received prior
                  immunotherapy. Patients who are primary refractory to immunotherapy (i.e.,
                  Patients who were previously treated with immunotherapy and did not at least
                  achieve stable disease on first imaging assessment on immunotherapy) or have
                  relapsed disease (i.e., Patients that were treated with immunotherapy, achieved
                  at least stable disease on first imaging assessment and subsequently developed
                  disease progression or relapse). Patients with NSCLC tumor known to harbor a
                  genomic aberration for which FDA approved treatment is available (i.e,
                  non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS
                  rearrangement, BRAF V600E mutation) are allowed to enroll if they have received
                  prior treatment with the FDA approved targeted therapy

          -  At least one measurable lesion according to Response Evaluation Criteria in Solid
             Tumors (RECIST) v1.1 criteria.

          -  QTcB must be <470 ms for males and <480 ms for females.

          -  Adequate normal organ and marrow function as defined below:

               -  Absolute neutrophil count (ANC) >1.5 x 10^9/L (> 1500 per mm^3)

               -  Hemoglobin ≥ 9.0 g/dL

               -  Platelet count ≥ 100 x 10^9/L (>100,000 per mm^3)

               -  Total bilirubin ≤ 1.5 X normal institutional limits. For patients with liver
                  metastasis: total bilirubin must be within normal limits.

               -  Proteinuria less than Common Terminology Criteria for Adverse Events (CTCAE)
                  grade 2 or greater

               -  (Except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL

               -  AST (SGOT)/ALT(SGPT) ≤1.5 X institutional upper limit of norma (ULN)l or ≤ 2.5 X
                  ULN for patients with liver metastases. This will not apply to patients with
                  confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is
                  predominantly unconjugated in the absence of hemolysis or hepatic pathology), who
                  will be allowed only in consultation with their physician.

               -  Serum creatinine CL ≤ 1.5 X ULN or creatinine clearance > 45 mL/min by the
                  Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection
                  for determination of creatinine clearance.

          -  Have archival tissue where available.

          -  In addition, patients enrolled on the clinical trial must be willing and able to
             provide tissue from a newly obtained core or excisional biopsy of a tumor lesion.
             Patients for whom newly obtained samples cannot be provided may submit an archived
             specimen only upon agreement from the Sponsor.

          -  Female participants of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours before receiving the first dose of study medication. If the
             urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
             be required.

          -  Ability to understand and willingness to provide written informed consent signed and
             dated prior to admission to the study in accordance with International Conference on
             Harmonisation-Good Clinical Practice (ICH-GCP) guidelines and to the local
             legislation.

        Exclusion Criteria:

          -  Concurrent use of other anticancer agents including chemotherapy, targeted therapy,
             radiotherapy or immunotherapy not otherwise specified in the protocol.

          -  Concurrent use of other investigational drugs or treatment in another clinical trial
             with a non- FDA-approved medication within the past 4 weeks before start of therapy.

          -  Chemo-, or immunotherapy or therapy with monoclonal antibodies or small tyrosine
             kinase inhibitors within the past 2 weeks prior to treatment with the trial drug.

          -  Radiotherapy (except for brain and extremities or stereotactic treatment) within the
             past 2 weeks prior to treatment with the trial drug.

          -  In immunotherapy pretreated patients, any history of dose-limiting toxicity with prior
             immunotherapy agents, including grade 3/4 immune-related adverse events (irAEs);
             irreversible irAEs; Grade ≥3 irAEs that did not respond to steroid rescue; or
             neurologic irAE with significant clinical sequelae.

          -  Prior treatment with nintedanib (BIBF1120).

          -  Known hypersensitivity to nintedanib, nivolumab, ipilimumab, peanut or soy or any
             other trial drug, or their excipients.

          -  Any toxicity (>CTCAE version 4 grade 3) from previous anti-cancer therapy that has not
             resolved to a Grade 1. Persistence of clinically relevant therapy related toxicity
             from previous chemo and/or radiotherapy. Patients with irreversible toxicity that is
             not reasonably expected to be exacerbated by the investigational product may be
             included (e.g., hearing loss, peripherally neuropathy, alopecia).

          -  History of leptomeningeal carcinomatosis.

          -  Radiotherapy to a target lesion within the past 3 months prior to baseline imaging
             unless that area has demonstrated progression.

          -  Active brain metastases (e.g., stable for <2 weeks, symptomatic, no adequate previous
             treatment, requiring treatment with anti-convulsants); dexamethasone therapy will be
             allowed if administered as stable or decreasing dose for at least 3 weeks before
             randomization otherwise no steroids to exceed prednisone 10 mg/day prior to starting
             trial treatment. Symptomatic or uncontrolled central nervous system (CNS) metastasis.

          -  Current or prior use of immunosuppressive medication 7 days before the first dose of
             nivolumab or ipilimumab, with the exceptions of intranasal and inhaled corticosteroids
             or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day
             of prednisone, or an equivalent corticosteroid. A brief course (≤28 days) of
             corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of
             non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by
             contact allergen) is permitted. Topical corticosteroids are permitted.

          -  Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients
             with vitiligo, Grave's disease, type I diabetes mellitus or residual hypothyroidism
             due to autoimmune condition only requiring hormone replacement, or psoriasis not
             requiring systemic treatment (within the past 2 years) are not excluded.

          -  Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of
             major blood vessels.

          -  Has known history of, or any evidence of active, non-infectious pneumonitis.

          -  Therapeutic anticoagulation with drugs requiring INR monitoring (except low-dose
             heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous
             devise) or antiplatelet therapy (except for low-dose therapy with acetylsalicylic acid
             < 325 mg per day.

          -  Major injuries and/or surgery within the past 4 weeks prior to start of study
             treatment with incomplete wound healing and/or planned surgery during the on-treatment
             study period.

          -  History of clinically significant hemorrhagic or thromboembolic event in the past 6
             months.

          -  Known inherited predisposition to bleeding or thrombosis.

          -  Significant cardiovascular diseases (i.e., uncontrolled hypertension, unstable angina,
             history of infarction within the past 3 months prior to start of study treatment,
             congestive heart failure > New York Heart Association (NYHA) II, serious cardiac
             arrhythmia).

          -  Coagulation parameters: International normalized ratio (INR) > 2, prothrombin time
             (PT) and partial thromboplastin time (PTT) > 50% of deviation of institutional ULN.

          -  History of another primary malignancy within the past 2 years except for:

               -  Basal cell skin cancer

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               -  Adequately treated carcinoma in situ without evidence of disease (e.g., cervical
                  cancer in situ)

          -  Active serious infections in particular if requiring systemic antibiotic or
             antimicrobial therapy

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected)

          -  History of known active primary immunodeficiency

          -  History of allogeneic organ transplant

          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days of receiving study treatment.

          -  Gastrointestinal disorders or abnormalities that would interfere with absorption of
             the study drug

          -  Serious illness or concomitant non-oncological disease such as neurologic,
             psychiatric, infectious disease or active ulcers (gastrointestinal tract, skin) or
             laboratory abnormality that may increase the risk associated with study participation
             or study drug administration and in the judgment of the investigator would make the
             patient inappropriate for entry into the study

          -  Patients who are sexually active and unwilling to use a medically acceptable method of
             contraception (e.g., such as implants, injectables, combined oral contraceptives, some
             intrauterine devices or vasectomized partner for participating females, condoms for
             participating males) for the duration specified during the trial and after end of
             active therapy

          -  Pregnancy or breastfeeding female patients must have a negative pregnancy test (β-HCG
             test in urine or serum) prior to commencing study treatment

          -  Psychological, familial, sociological, or geographical factors potentially hampering
             compliance with the study protocol and follow-up schedule

          -  Active alcohol or drug abuse

          -  Significant weight loss (> 20% of Body Weight) within past 6 months prior to inclusion
             into the trial

          -  History of active tuberculosis
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1 - Maximum Tolerated Dose (MTD)
Time Frame:Up to 12 months
Safety Issue:
Description:Dose escalation to determine the MTD and Recommended Phase 2 Dose (RP2D) of concurrent administration of nivolumab, ipilimumab, and nintedanib. The maximum tolerated dose (MTD) is defined as the dose with the dose limiting toxicity (DLT) rate of 30%.

Secondary Outcome Measures

Measure:Phase 2: Disease Control Rate (DCR)
Time Frame:Up to 36 months
Safety Issue:
Description:Disease control is defined as CR, PR, or SD based on RECIST guidelines version 1.1 with modifications. The disease control rate (DCR) will be estimated by the proportion of patients who achieve DC, and its 80% CI and 95% CI will be estimated using the exact binomial distribution. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Measure:Phase 2: Overall Survival (OS)
Time Frame:Up to 36 months
Safety Issue:
Description:Overall survival will be determined as the time from the start of treatment with nivolumab plus ipilimumab plus nintedanib until death due to any cause. For patients who are alive at the time of data cut-off, OS will be censored on the last date when patients are known to be alive. The Kaplan-Meier method will be used to estimate the OS curve and the OS rate at time points of interest.
Measure:Phase 2: Progression-free Survival (PFS)
Time Frame:Up to 36 months
Safety Issue:
Description:Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:H. Lee Moffitt Cancer Center and Research Institute

Trial Keywords

  • Nivolumab
  • Ipilimumab
  • Nintedanib
  • Immunotherapy
  • Advanced stage non-small cell lung cancer
  • Locally advanced non-small cell lung cancer

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