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

• ClinicalTrials.gov Identifier: NCT03377023
• Recruitment Status: Active, not recruiting
• First Posted: December 19, 2017
• Last Update Posted: November 25, 2022
• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Information provided by (Responsible Party): H. Lee Moffitt Cancer Center and Research Institute

Tracking Information

• First Submitted Date: December 13, 2017
• First Posted Date: December 19, 2017
• Last Update Posted Date: November 25, 2022
• Actual Study Start Date: February 2, 2018
• Estimated Primary Completion Date: November 28, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 13, 2017)

• Phase 1 - Maximum Tolerated Dose (MTD) [ Time Frame: Up to 12 months ]
  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%.
• Phase 2 - Objective Response Rate (ORR) per Treatment Arm [ Time Frame: Up to 36 months ]
  Objective response is defined as confirmed CR or confirmed PR based on modified RECIST guidelines version 1.1. The ORR will be estimated by calculating the proportion of patients who achieve OR; the 80% Confidence Interval (CI) and 95% CI for the OR rate will be estimated using the exact binomial distribution. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 13, 2017)

• Phase 2: Disease Control Rate (DCR) [ Time Frame: Up to 36 months ]
  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.
• Phase 2: Overall Survival (OS) [ Time Frame: Up to 36 months ]
  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.
• Phase 2: Progression-free Survival (PFS) [ Time Frame: Up to 36 months ]
  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).

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Nivolumab
  Intravenous nivolumab every 2 weeks.
  Other Name: Opdivo®
• Drug: Ipilimumab
  Intravenous ipilimumab every 6 weeks.
  Other Name: Yervoy®
• Drug: Nintedanib
  Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.
  Other Names:

  • Vargatef®
  • Ofev®
  • BIBF1120

Study Arms

• Experimental: Phase 1 - Dose Escalation

  Nivolumab + 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 1-14 (Daily dose =100 mg).

  Nintedanib Level 0:150 mg by mouth (PO) once a day (QD) Days 1-14 (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 1-14 (Daily dose = 300 mg).

  Nintedanib Level 3: 200 mg PO BID Days 1-14 (Daily dose = 400 mg).

  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
  • Drug: Nintedanib
• Active Comparator: Phase 2 - Arm A

  Arm A: Newly diagnosed or treatment-naïve patients, with a target overall response rate (ORR) of 50%.

  Nivolumab + Ipilimumab + Nintedanib at RP2D.

  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
  • Drug: Nintedanib
• Active Comparator: Phase 2 - Arm B

  Arm 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.

  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
  • Drug: Nintedanib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 20, 2021): 68
• Original Estimated Enrollment (submitted: December 13, 2017): 98
• Estimated Study Completion Date: November 2024
• Estimated Primary Completion Date: November 28, 2023 (Final data collection date for primary outcome measure)

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 5 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03377023
• Other Study ID Numbers: MCC-19406
• Has Data Monitoring Committee: No

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: Not Provided
• Current Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jhanelle E. Gray, M.D.; H. Lee Moffitt Cancer Center and Research Institute

• PRS Account: H. Lee Moffitt Cancer Center and Research Institute
• Verification Date: November 2022