Clinical Trials /

Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced NSCLC

NCT02504489

Description:

To compare the overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease. Secondary purposes of the study are: - To compare the neutropenia (incidence of Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5 × 10^9/L]) on Day 8 (+/- 1 day) of Cycle 1), DoR, neutrophil count on Day 8 (+/- 1 day) of Cycle 1, incidence of docetaxel dose reduction and/or docetaxel dose withheld in Cycle 2 due to neutropenia in Cycle 1, QoL (EORTC QLQ-C30 [item 30, average overall quality of life over all observable weeks]), ORR, and PFS in patients with NSCLC treated in the DP Arm to patients treated in the D Arm as 2nd- or 3rd-line therapy for advanced or metastatic disease. - To compare the safety and adverse events profile of the DP Arm to D Arm. - To compare dose intensity of docetaxel (percent dose administered compared to dose assigned) between the 2 treatment arms. - To evaluate population pharmacokinetics in patients enrolled in China and rest of world (RoW).

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

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced NSCLC
  • Official Title: Randomized Blinded Phase III Assessment of Second or Third-Line Chemotherapy With Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced Non-Small Cell Lung Cancer and With at Least One Measurable Lung Lesion

Clinical Trial IDs

  • ORG STUDY ID: BPI-2358-103
  • NCT ID: NCT02504489

Conditions

  • Non-Small Cell Lung Cancer

Interventions

DrugSynonymsArms
Docetaxel + Plinabulin (DP)BPI-2358, NPI-2358Docetaxel + Plinabulin (DP)
Docetaxel (D)TaxotereDocetaxel (D)

Purpose

To compare the overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease. Secondary purposes of the study are: - To compare the neutropenia (incidence of Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5 × 10^9/L]) on Day 8 (+/- 1 day) of Cycle 1), DoR, neutrophil count on Day 8 (+/- 1 day) of Cycle 1, incidence of docetaxel dose reduction and/or docetaxel dose withheld in Cycle 2 due to neutropenia in Cycle 1, QoL (EORTC QLQ-C30 [item 30, average overall quality of life over all observable weeks]), ORR, and PFS in patients with NSCLC treated in the DP Arm to patients treated in the D Arm as 2nd- or 3rd-line therapy for advanced or metastatic disease. - To compare the safety and adverse events profile of the DP Arm to D Arm. - To compare dose intensity of docetaxel (percent dose administered compared to dose assigned) between the 2 treatment arms. - To evaluate population pharmacokinetics in patients enrolled in China and rest of world (RoW).

Detailed Description

      Lung cancer is the leading cause of cancer-related mortality worldwide. A report published by
      the WHO in February 2014, estimated there were 1.83 million new cases and 1.59 million deaths
      worldwide in 2012. The American Lung Association reports 399,431 Americans living with lung
      cancer, with an estimated 221,200 new cases predicted to be diagnosed in 2015; of those cases
      158,040 patients will die of their lung cancer which accounts for approximately 29% of all
      cancer deaths in the U.S. Similarly, lung cancer is the most frequent cancer in China and is
      among the 1.96 million estimated annual cancer related deaths. Non-small cell lung cancer
      (NSCLC) accounts for about 85% of lung cancer in China, and approximately half of the
      patients present with advanced disease at the time of diagnosis.

      The prognosis for patients with advanced or metastatic NSCLC, either at initial diagnosis or
      recurrence, remains grim. The mainstay of standard of care has been chemotherapy with agents
      including platinum analogs, taxanes, vinca alkaloids, pemetrexed, vascular endothelial growth
      factor (VEGF) inhibitors. For patients with appropriate disease genotypes, first line therapy
      has also included, epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma
      kinase (ALK) inhibitors.

      In both China and the US, first-line chemotherapy consists of a regimen based on one of two
      platinum-based drugs (etoposide cisplatin and etoposide carboplatin). The platinum analogs
      are commonly combined with paclitaxel, docetaxel, gemcitabine and vinorelbine while other
      drugs such as irinotecan, etoposide and vinblastine are also used.

      For those patients intolerant to platinum-containing regimen, platinum-free double-agent
      chemotherapy regimens are used as an alternative. For those patients with ECOG score as 2 or
      the elderly patients, single-agent or double-agent regimens are recommended. The chemotherapy
      of cisplatin plus vinorelbine may recombine human endostatin. China has approved that
      single-agent gefitinib may be used in first-line treatment of locally advanced or metastatic
      NSCLC patients with sensitive mutation of epidermal growth factor receptor tyrosine kinase
      gene.

      Second-line Chemotherapy: In both China and the US, the drugs used for second-line treatment
      include docetaxel, pemetrexed and the targeted drug EGFR-TKI.

      Several drugs [docetaxel, pemetrexed, erlotinib, gefitinib (outside U.S and in China), and
      ramucirumab combined with docetaxel] have been approved as single agents or combination for
      second line therapy for locally advanced or metastatic NSCLC, but with limited efficacy, that
      is, limited clinical significant improvement or overall survival.

      Docetaxel, a taxane, binds to and stabilizes tubulin, thereby inhibiting microtubule
      disassembly resulting in cell cycle arrest at the G2/M phase and cell death. In patients with
      NSCLC previously treated with a platinum-based chemotherapy, second line therapy with
      docetaxel afforded a median overall survival (OS) in the range from 5.7 to 7.5 months. The
      most common adverse reactions included infections, neutropenia, anemia, febrile neutropenia,
      hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia,
      nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis,
      alopecia, skin reactions, and myalgia. Since the approval of docetaxel in 1999 as the second
      line treatment for advanced or metastatic NSCLC, other drugs, namely pemetrexed, erlotinib,
      have been approved in the same indication. However, despite the availability of newer
      treatment, patient survival did not demonstrably improve over docetaxel. The OS from these
      trials remained in the range of 5.6-8.3 months.

      With the advent of molecular profiling, it became possible to select patients based on
      disease genomic characteristics and match disease genotype with appropriate treatment. EGFR
      TKIs were found to be particularly effective in patients with EGFR mutation, and similarly
      crizotinib was highly effective in patients with ALK translocation. However, NSCLC patients
      with EGFR mutation or ALK translocation are the minority. For the 80-90% of patients in the
      U.S. without EGFR mutation, chemotherapy with docetaxel is the standard of care for the
      second line of treatment. As recently reported from the TAILOR trial, docetaxel demonstrated
      a statistically significant survival improvement compared to erlotinib. The median overall
      survival was 8.2 months (95% CI 5.8-10.9) with docetaxel versus 5.4 months (4.5-6.8) with
      erlotinib (adjusted hazard ratio [HR] 0.73, 95% CI 0.53-1.00; p=0.05).

      As discussed below, a retrospective analysis of the plinabulin phase II study suggests that
      plinabulin prolongs progression and survival in NSCLC patients with measurable lung tumors.
      Tumor size is a well known prognostic factor for survival in NSCLC; patients with large
      tumors have a shorter survival than patients with smaller tumors. Among patients with
      recurrent or metastatic disease, especially those wildtype for EGFR or ALK, the presence of
      large lesions carries particularly grim prognosis, and treatment of these tumors represents
      an unmet medical need.

      Large tumors carry a rich tumor vasculature which may make them more susceptible to drugs
      such as plinabulin. Plinabulin inhibits angiogenesis, disrupts existing tumor vasculature as
      well as induces cancer cell apoptosis.

      This study investigates the efficacy and safety of plinabulin and docetaxel combination in
      patients with wild type NSCLC and large tumors requiring 2nd line therapy for advanced or
      metastatic disease after failing a platinum-containing regimen. The primary endpoint is
      overall survival (OS) with docetaxel alone as active comparator.
    

Trial Arms

NameTypeDescriptionInterventions
Docetaxel (D)Active ComparatorA treatment cycle is 21 days. Treatment will be repeated until disease progression is detected by imaging studies or unacceptable toxicities are encountered. On Day 1, all patients will receive docetaxel 75 mg/m2 by intravenous (IV) infusion over 1 hour. Oral dexamethasone (16 mg, given as 8 mg twice daily) will be given on the day prior to, the day of (Day 1), and the day following docetaxel infusion (Day 2). Antiemetic prophylaxis will be administered according to institutional guideline for docetaxel. Institutional guideline/practice should be followed in the event of infusion/hypersensitivity reaction. Diphenhydramine and dexamethasone infusion may be administered in the event of infusion reaction.
  • Docetaxel (D)
Docetaxel + Plinabulin (DP)ExperimentalThe treatment regimen for Docetaxel (D) will be followed for this arm. In addition, on Days 1 and 8 of the 21 day cycle, patients will receive Plinabulin (P) administered via IV infusion over 60 minutes. On Day 1, the infusion begins 2 hours from the starting time of docetaxel infusion, i.e, approximately 60 minutes from the end of docetaxel infusion. On Day 8, patients must be given an anti-emetic prophylactically before the plinabulin infusion. If emesis persists after Day 8, with a grade >1, plinabulin will be reduced to 20 mg/m2. Patients from the DP Arm who stop treatment with docetaxel due to toxicity or another medically acceptable reason, may continue treatment with plinabulin alone as previously described.
  • Docetaxel + Plinabulin (DP)
  • Docetaxel (D)

Eligibility Criteria

        INCLUSION CRITERIA:

          1. ECOG performance status ≤ 2.

          2. Histopathologically or cytologically confirmed NSCLC.

          3. Disease progression during or after treatment with one or two treatment regimen(s)
             Treatment regimens can be chemotherapy, targeted therapy, biological therapy, or
             immunotherapy for advanced (Stage IIIB) or metastatic disease (Stage IV). Modification
             of a regimen to manage toxicity with a different drug does not constitute a new
             regimen. Maintenance therapy following platinum-based chemotherapy is not considered
             as a separate regimen. Adjuvant or neoadjuvant chemotherapy and/or chemo-radiation for
             early stage disease do not count as prior systemic therapy. Prior radiation therapy is
             not exclusionary. Prior immunotherapy with a PD-1/PD-L1 inhibitor is not exclusionary.
             Prior treatment for advanced or metastatic disease must have included a platinum-based
             regimen. (Treatment of early stage disease [Stage IIIA or earlier] with a
             platinum-containing therapy does not count).

          4. At least 1 lung lesion ≥10 mm by CT or MRI per RECIST 1.1 criteria. Radiographic tumor
             assessment is to be performed within 28 days prior to randomization.

          5. patients with nonsquamous NSCLC must have been tested for EGFR exon 19 deletion and
             Exon 21 L858R substitution mutation. Only patients without EGFR sensitizing mutations
             are eligible, and they must have progressed on platinum-based chemotherapy. Patients
             with known ALK-rearrangements should be treated with an appropriate tyrosine kinase
             inhibitor (TKI) before entering the study. The TKI regimen would count as a line of
             treatment

          6. Patients with active brain metastasis or leptomeningeal involvement with brain
             metastases who are asymptomatic, and whose lesions by imaging are at least stable and
             without interim development of new lesions for at least 4 weeks may be enrolled.
             Patients who require continued therapy with steroid medication for management for
             their brain metastases are eligible; dosing must be stable for at least 4 weeks prior
             to randomization.

          7. All AE's of prior systemic therapy, surgery, or radiotherapy, must have resolved to
             CTCAE v 4.03 Grade ≤2, except for neurological AE's that must have resolved to Grade
             ≤1.

          8. The following laboratory results ≤14 days prior to study drug admin:

             Hgb ≥9 g/dL independent of transfusion or growth factor support; absolute neutrophil
             count 1.5x10^9/L independent of growth factor support; platelet count ≥100x10^9/L
             independent of transfusion or growth factor support; Serum total bilirubin ≤ ULN,
             unless the patient has a diagnosis of Gilbert's disease then serum bilirubin 3.0 times
             ULN;

          9. AST & ALT ≤2.5 x ULN(≤1.5 x ULN if alkaline phosphatase is > 2.5 x ULN), and serum
             creatinine ≤1.5 x ULN.

         10. Life expectancy >12 weeks.

         11. Female patients of childbearing potential have a negative pregnancy test at baseline.

         12. Signed informed consent.

        EXCLUSION CRITERIA: Patients with any of the following:

          1. Administration of chemo, biological, immunotherapy, radiotherapy or investigational
             agent (therapeutic or diagnostic) ≤3 weeks prior to receipt of study medication. Major
             surgery, other than diagnostic surgery, ≤4 weeks before first study drug admin.

          2. Significant cardiac history:

             History of myocardial infarction or ischemic heart disease ≤1 year before 1st study
             drug administration; uncontrolled arrhythmia; history of congenital QT prolongation;
             ECG findings consistent with acute ischemic heart disease; NYHA Class III-IV cardiac
             disease; & uncontrolled hypertension: BP consistently >150 mm Hg systolic & 100 mm Hg
             diastolic in spite of antihypertensive medication

          3. Patients who have received prior treatment with docetaxel.

          4. Prior transient ischemic attack or cerebrovascular accident with in the past
             year(within an 18-day window). Neurologic toxicities ≥Grade 2 within 3 weeks of
             randomization.

          5. History of hemorrhagic diarrhea, inflammatory bowel disease or active uncontrolled
             peptic ulcer disease. (Concomitant therapy with ranitidine or its equivalent and/or
             omeprazole or its equivalent is acceptable.) History of ileus or other significant
             gastrointestinal disorder known to predispose to ileus or chronic bowel hypomotility.

          6. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.

          7. Known infection with human immunodeficiency virus (HIV) or active hepatitis A, B, or
             C.

          8. Known prior hypersensitivity reaction to any product containing polysorbate 80,
             Polyoxyethylene 15 hydroxystearate/Macrogol 15 Hydroxystearate (Solutol HS 15).

          9. Female subject who is pregnant or lactating

         10. Second malignancy unless in remission for >5 years. (Non-melanoma skin cancer or
             carcinoma in situ of the cervix treated with curative intent is not exclusionary.)

         11. Medical conditions that would impose excessive patient risk. Examples: uncontrolled
             diabetes, infection requiring parenteral anti infective treatment, liver failure,
             altered mental status or psychiatric condition that would interfere with the
             understanding of the informed consent.

         12. Unwilling or unable to comply with protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival
Time Frame:Approximately 2 years after study initiation
Safety Issue:
Description:Overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy

Secondary Outcome Measures

Measure:Grade 4 neutropenia
Time Frame:During 1st 21-day cycle
Safety Issue:
Description:Incidence of Grade 4 neutropenia on Day 8 of Cycle 1
Measure:Neutrophil count
Time Frame:During 1st 21-day cycle
Safety Issue:
Description:Neutrophil count on Day 8 of Cycle 1
Measure:docetaxel dose reduction and/or docetaxel dose withheld
Time Frame:During 2nd 21-day cycle
Safety Issue:
Description:incidence of docetaxel dose reduction and/or docetaxel dose withheld in Cycle 2 due to neutropenia in Cycle 1
Measure:Quality of Life (EORTC QLQ-C30)
Time Frame:Approximately 2 years after study initiation.
Safety Issue:
Description:Average Quality of Life score over all observed weeks (scale 0 - 30, higher value represents better outcome)
Measure:ORR
Time Frame:Approximately 2 years after study initiation.
Safety Issue:
Description:Overall response rate
Measure:PFS
Time Frame:Approximately 2 years after study initiation.
Safety Issue:
Description:Progress-free survival
Measure:DoR
Time Frame:Approximately 2 years after study initiation.
Safety Issue:
Description:Duration of response

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:BeyondSpring Pharmaceuticals Inc.

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