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

NCT03377023 | Active Not Recruiting Phase 1 Results FDA Drug

• 1 other identifier: MCC-19406
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Phase 1 - Maximum Tolerated Dose (MTD)

  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 1 began with 100 mg nintedanib, 3 mg/kg IV nivolumab + 1 mg/kg ipilimumab. Dosing of nintedanib increased by 50 mg in each level until dose limiting toxicity.

  Up to 12 months

• Phase 2 - Objective Response Rate (ORR) Per Treatment Arm

  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.

  Up to 36 months

Secondary Outcomes (3)

• Phase 2: Disease Control Rate (DCR)

  Up to 36 months

• Phase 2: Overall Survival (OS)

  Up to 36 months

• Phase 2: Progression-free Survival (PFS)

  Up to 36 months

Study Arms (3)

Phase 1 Nintedanib Dose Escalation 100-200 mg QD to BID

EXPERIMENTAL

Nivolumab + Ipilimumab + Nintedanib dose escalation. Participants were given the following: 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).

Drug: Nivolumab; Drug: Ipilimumab; Drug: Nintedanib

Phase 2 - Arm A Nintedanib 100-200 mg BID Treatment-naïve

ACTIVE COMPARATOR

Arm A: Treatment-naïve defined as newly diagnosed or treatment-naïve patients, with a target overall response rate (ORR) of 50%. Participants were given the following: Nivolumab + Ipilimumab + Nintedanib at RP2D. Nivolumab: Intravenous nivolumab every 2 weeks. Ipilimumab: Intravenous ipilimumab every 6 weeks. Nintedanib: Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.

Drug: Nivolumab; Drug: Ipilimumab; Drug: Nintedanib

Phase 2 - Arm B Nintedanib 100-200 mg BID Treatment Non-naïve

ACTIVE COMPARATOR

Arm B: Treatment Non-naïve defined as 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%. Participants were given the following: Nivolumab + Ipilimumab + Nintedanib at RP2D. Nivolumab: Intravenous nivolumab every 2 weeks. Ipilimumab: Intravenous ipilimumab every 6 weeks. Nintedanib: Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.

Drug: Nivolumab; Drug: Ipilimumab; Drug: Nintedanib

Interventions

Nivolumab DRUG

Intravenous nivolumab every 2 weeks.

Also known as: Opdivo®

Phase 1 Nintedanib Dose Escalation 100-200 mg QD to BID; Phase 2 - Arm A Nintedanib 100-200 mg BID Treatment-naïve; Phase 2 - Arm B Nintedanib 100-200 mg BID Treatment Non-naïve

Ipilimumab DRUG

Intravenous ipilimumab every 6 weeks.

Also known as: Yervoy®

Phase 1 Nintedanib Dose Escalation 100-200 mg QD to BID; Phase 2 - Arm A Nintedanib 100-200 mg BID Treatment-naïve; Phase 2 - Arm B Nintedanib 100-200 mg BID Treatment Non-naïve

Nintedanib DRUG

Nintedanib 100-200 mg capsules by mouth twice daily for two-week cycles.

Also known as: Vargatef®, Ofev®, BIBF1120

Phase 1 Nintedanib Dose Escalation 100-200 mg QD to BID; Phase 2 - Arm A Nintedanib 100-200 mg BID Treatment-naïve; Phase 2 - Arm B Nintedanib 100-200 mg BID Treatment Non-naïve

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• H. Lee Moffitt Cancer Center and Research Institute: lead

Study Sites (1)

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

Related Links

• Moffitt Cancer Center Clinical Trials website

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Nivolumab; Ipilimumab; nintedanib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Jhanelle E. Gray
• Organization: Moffitt Cancer Center

jhanelle.gray@moffitt.org

813-745-7282

Study Officials

• Jhanelle E. Gray, M.D.

  H. Lee Moffitt Cancer Center and Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 13, 2017
• First Posted: December 19, 2017
• Study Start: February 2, 2018
• Primary Completion: November 28, 2023
• Study Completion: August 1, 2026
• Last Updated: April 2, 2026
• Results First Posted: March 25, 2025

Record last verified: 2026-03

Locations

US (1)