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Nivolumab in Combination With Plinabulin in Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC)

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ClinicalTrials.gov Identifier: NCT02812667
Recruitment Status : Recruiting
First Posted : June 24, 2016
Last Update Posted : August 7, 2018
Sponsor:
Collaborator:
BeyondSpring Pharmaceuticals Inc.
Information provided by (Responsible Party):
Lyudmila Bazhenova, M.D., University of California, San Diego

Brief Summary:

The purpose of the study is to determine whether plinabulin (also known as BPI-2358) has an effect on cancer and body in combination with nivolumab, a standard treatment for metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy.

Plinabulin inhibits tumor growth by targeting both new and existing blood vessels going to the tumor as well as killing tumor cells. Plinabulin is an investigational drug, a drug that is not approved for use outside of research studies by regulatory agencies. Up to 38 patients will be enrolled.


Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Metastatic Drug: Nivolumab + Plinabulin Phase 1

Detailed Description:

Plinabulin is a microtubule destabilizing agent (MDA) that inhibits the polymerization of tubulin monomers with resultant vascular disrupting properties. Plinabulin inhibits tumor growth by targeting both angiogenesis and tumor vasculature as well as directly by inducing apoptosis via the Ras-JNK pathway. It also may activate anti-tumor immunity via inducing maturation of dendritic cells (DC) and triggering release of pro-inflammatory cytokines. Plinabulin could therefore have a synergic anti-tumor effect when combined with immune-checkpoint inhibitors. This hypothesis has been confirmed in a murine model bearing subcutaneous MC38 colon cancers using other MDAs, including ansamitocin P3, which induces DC maturation similar to that of plinabulin. Plinabulin has been tested in a randomized phase 2 trial in combination of docetaxel and showed similar response rate to that of docetaxel alone, but with a significantly longer duration of response.

Nivolumab is an inhibitor of the programmed cell death receptor-1 checkpoint pathway (PD-1) that has superior activity in NSCLC, regardless of tumor histology, comparing to standard of care. In this study, we plan to combine nivolumab with escalating doses of plinabulin to determine the maximum tolerated dose (MTD) and /or recommended Phase 2 dose (RP2D) of the combination. An expansion cohort will be enrolled at RP2D to further assess toxicities and to evaluate preliminary anti-tumor activity.

This is a single-center, phase 1 dose finding trial of plinabulin, combining with FDA approved dose of nivolumab, using a 3+3 design in patients with metastatic NSCLC who progressed after chemotherapy, including a platinum-containing regimen. Patients will receive plinabulin at escalating doses in combination with nivolumab. Doses of plinabulin and nivolumab will be administered as intravenous infusions in 4-week cycles. Patients will receive both medications on Days 1 and 15 and additional dose of plinabulin on Day 8. Plinabulin will be administered 60 minutes after the completion of nivolumab.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 38 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Nivolumab in Combination With Escalating Doses of Plinabulin in Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC)
Actual Study Start Date : August 29, 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Nivolumab + Plinabulin
Nivolumab 240mg IV, day 1 and 15 until disease progression Plinabulin 3.5mg/m2, 20mg/m2, 30 mg/m2 or 40mg/m2 IV, day 1,8 and 15 until disease progression
Drug: Nivolumab + Plinabulin



Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) [ Time Frame: 2 years ]
  2. Frequency and severity of treatment-related adverse events as assessed by CTCAE v4. [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: 2 years ]
  2. Disease control rate (DCR) [ Time Frame: 2 years ]
  3. Progression free survival (PFS) [ Time Frame: 2 years ]
  4. Overall survival (OS) [ Time Frame: 2 years ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects with histologically or cytologically-confirmed metastatic NSCLC whose disease progressed during/after treatment with at least one platinum-containing chemotherapy regimen.
  • At least 1 prior systemic therapy for metastatic disease. Adjuvant chemotherapy or concurrent chemoradiation for early stage disease does not count as prior therapy unless patients progressed within 6 months of completion of chemotherapy
  • Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1
  • Life expectancy ≥ 12 weeks
  • Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST).
  • Adequate hematopoietic, electrolyte, hepatic, and renal laboratory findings.
  • Prior chemotherapy must have been completed at least 4 weeks or at least 5 half-lives (whichever is longer) before study drug administration, and all adverse events have either returned to baseline or stabilized
  • Prior treated brain metastases are allowed. However, prior treated brain metastases must be without MRI evidence of progression for at least 4 weeks and off systemic steroids for at least 2 weeks before study drug administration
  • Prior definitive radiation therapy must have been completed at least 4 weeks before study drug administration. Prior palliative radiotherapy should be completed at least 2 weeks before study drug administration. Whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) and focal radiation to the sites of pain or bronchial obstruction will be considered palliative. No radiopharmaceuticals (strontium, samarium) within 8 weeks before study drug administration
  • Prior major surgery must be completed at least 4 weeks before study drug administration. Prior minor surgery must be completed at least 1 week before study drug administration and subjects should be recovered. Percutaneous biopsies should be completed at least 10 days prior to study drug administration;
  • A negative serum pregnancy test at screening for women of childbearing potential.

Exclusion Criteria:

  • History of grade 3 or above hypersensitivity reactions to other monoclonal antibodies
  • Subjects with a history of a cardiovascular illness.
  • Uncontrolled hypertension, SBP> 160 or DBP>100
  • Symptomatic or untreated brain metastases
  • Presence of leptomeningeal disease
  • Pulmonary conditions, which in the PI's opinion would increase the risk of immunotherapy-related pulmonary toxicity.
  • Has active, non-infectious pneumonitis
  • Presence of a second malignancy, excluding non-melanomatous skin cancer unless in remission for 3 years
  • Subjects with any active, known, or suspected autoimmune disease.
  • History of ileus or other significant gastrointestinal disorder known to predispose to ileus or chronic bowel hypomotility.
  • Prior therapy with microtubule destabilizing agents for NSCLC (ie. Vinorelbine)
  • Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody (or any other antibody targeting T cell co-stimulation pathways);
  • Known history of Human Immunodeficiency Virus;
  • Active infection requiring therapy, positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA)
  • Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events
  • Concurrent medical condition requiring the use of immunosuppressive medications, or systemic steroids.
  • Use of other investigational drugs within 28 days or at least 5 half-lives before study drug administration
  • Pregnant or nursing

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02812667


Contacts
Contact: Lyudmilla Bazhenova, MD 858-822-6189 lbazhenova@ucsd.edu

Locations
United States, California
UC San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Lyudmilla Bazhenova, MD    858-534-1765    lbazhenova@ucsd.edu   
Sponsors and Collaborators
Lyudmila Bazhenova, M.D.
BeyondSpring Pharmaceuticals Inc.
Investigators
Principal Investigator: Lyudmilla Bazhenova, MD University of California, San Diego

Responsible Party: Lyudmila Bazhenova, M.D., Clinical Professor, University of California, San Diego
ClinicalTrials.gov Identifier: NCT02812667     History of Changes
Other Study ID Numbers: 160186
First Posted: June 24, 2016    Key Record Dates
Last Update Posted: August 7, 2018
Last Verified: August 2018

Keywords provided by Lyudmila Bazhenova, M.D., University of California, San Diego:
Metastatic
NSCLC
nivolumab
plinabulin
BPI-2358
opdivo
Non-Small Cell Lung Cancer
cancer

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Nivolumab
Antibodies, Monoclonal
Diketopiperazines
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents