Patient case: 52-year-old male with Lung cancer. Genetic variant: EML4-ALK Fusion transcript. Other conditions: Hypertension, Osteoarthritis.

Clinical trial: Assessment of Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced NSCLC With at Least One Measurable Lung Lesion

Summary: The primary purpose of the study is to compare the overall survival of NSCLC patients receiving second- or third-line chemotherapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D Arm) for advanced or metastatic disease.
  Secondary purposes of the study are:
  1. To compare the neutropenia (frequency, severity and clinical sequelae), duration of response, quality of life, response rate and progression free survival in patients with NSCLC treated with DP to patients treated with D as second- or third-line chemotherapy for advanced or metastatic disease; and
  2. To compare the safety and adverse event profiles of DP to D respectively, as well as dose delays, dose modifications, and/or dose discontinuation of docetaxel due to safety concerns in the two treatment arms.
  3. To evaluate population pharmacokinetics in patients enrolled in China and western countries (US and Australia).

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 od 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 large 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.

Eligibility: 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 regiments can be chemotherapy or immunotherapy for advanced (Stage IIIB) or metastatic disease (Stage IV). Modification of 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 chemotherapy and/or chemoradiation for early stage disease do not count as prior chemotherapy. Prior radiation and/or PD-1/PD-L1 immunotherapy is not exclusionary. Prior treatment for advanced or metastatic disease must have included a platinum-based regimen.
  4. At least 1 lesion > 3 cm in longest diameter in lung parenchyma.
  5. patients with nonsquamous NSCLC must have been tested for EGFR exon 19 deletion and Exon 21 L858R substitution mutation. Patients without EGFR sensitizing mutations are eligible and must have progressed on platinum-containing chemo.
  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 enrollment
  7. All AE's of prior chemo., 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 1.5x109/L independent of growth factor support; platelet count 100x109/L independent of transfusion or growth factor support; Serum total bilirubin 1.5 times the upper limit normal (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. 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, paclitaxel or other taxane preparation for advanced or metastatic disease.
  4. Prior transient ischemic attack or cerebrovascular accident. Neurologic toxicities > Grade 2.
  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: 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.

Relevance to patient case: not relevant