A Phase I/II Study of Paclitaxel, Carboplatin and YM155 (Survivin Suppressor) in Subjects With Solid Tumors (Phase I) and Advanced Non-Small Cell Lung Carcinoma (Phase II)

Background:

• Treatment with platinum-based doublet chemotherapy results in a median survival of 7 to 10 months in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).
• Carboplatin-paclitaxel is a commonly used regimen in advanced NSCLC and other solid tumors. In a randomized clinical trial carboplatin, paclitaxel plus bevacizumab resulted in improved efficacy (response rate and survival) compared to carboplatin and paclitaxel alone but only patients with non-squamous histology and who were considered low risk of bleeding were treated. Improvement of survival was not confirmed in another randomized study with a different chemotherapy backbone.
• Novel treatment strategies need to be developed for advanced NSCLC.
• YM155 is a transcriptional inhibitor of survivin, an inhibitor of apoptosis protein. Pre-clinical activity of YM155 has been observed in several solid tumors, including NSCLC models and synergy was observed in combination with chemotherapeutic drugs, including carboplatin and paclitaxel.
• YM155 has been investigated in several phase I and phase II clinical trials and it has been shown to be well tolerated with the most common toxicities reported as being reversible and of grades 1 -2 in severity. In addition, as a monotherapy YM155 alone has shown modest antitumor activity in a phase II trial in advanced NSCLC in patients who had failed one or two prior chemotherapy lines.

Primary Objectives:

• In the Phase I portion of the study the primary objective will be to determine a safe and tolerable phase II dose of YM155 based upon dose limiting toxicities (DLTs) when YM155 is administered over 72 hours by continuous intravenous infusion (CIVI) every 3 weeks in combination with paclitaxel and carboplatin.
• In the Phase II portion of the study the primary objective will be to determine the objective response rate (ORR = partial response (PR)+ complete response (CR)) of YM155 in combination with carboplatin and paclitaxel in the first line treatment of patients with advanced NSCLC.

Secondary Objectives:

• In the Phase I portion of the study the secondary objective will be to determine the preliminary activity of the combination regimen based upon response rate as measured by response evaluation criteria in solid tumors [RECIST].
• In the Phase II portion of the study the secondary objectives will be to determine the median progression free survival (PFS), median overall survival (OS) and safety and tolerability of this combination regimen in this patient population.
• To assess expression of particular genes on the pretreatment tumor and pre/post treatment serum samples to evaluate the treatment effects and correlate them with clinical outcome.

Eligibility:

Phase I

• The phase I portion of the trial will be open to all patients with recurrent or advanced cancer (NSCLC and other solid tumors) for whom standard therapy offers no curative potential and also in patients for whom the carboplatin / paclitaxel regimen is considered standard of care. Patients should have received no more than one previous chemotherapy regimen.

Phase II

• Pathologically confirmed stage IIIB (malignant pleural effusion) or intravenous (IV) or recurrent NSCLC.
• No previous chemotherapy for advanced lung cancer.
• Adequate organ and bone marrow function.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

Design:

• Open label phase I/II trial
• Following a Simon two-stage optimal design

• INCLUSION CRITERIA:

Response should be YES

Phase 1 and 2:

• Has a signed consent/assent been obtained by the patient or parent/legal guardian?
• Is a male or female greater than or equal to 18 years old?
• If patient has brain metastases, is it asymptomatic and does not require steroids or antiepileptic mediations?
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Karnofsky > 60%)?
• Has adequate bone marrow, renal, and hepatic function:

• Absolute neutrophil count (ANC) greater than or equal to 1,500/m^3?
• Hemoglobin greater than or equal to 10.0g/dl?
• Platelets greater than or equal to 100,000/m^3?
• Has adequate renal function defined as serum creatinine < upper limit of normal (ULN) or calculated creatinine clearance > 60 mL/min?
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) less than or equal to 2.5 times ULN?
• Total bilirubin less than or equal to 1.5 times ULN (in patients with evidence of Gilberts disease, elevated bilirubin should not be related to tumor or other liver diseases and should be less than or equal 2 times upper limit of normal)?
• Has negative human immunodeficiency virus (HIV) test?
• If female, has negative pregnancy test?
• Both male and female patients are willing to consent to using effective contraception (hormonal, barrier method or abstinence) prior to study entry, while on treatment and at least 3 months thereafter?

Phase 1 only:

• Has recurrent or advanced cancer for whom standard therapy offers no curative potential and also for patients for whom the carboplatin/paclitaxel regimen is considered standard of care?
• Has received no more than one previous chemotherapy regimen?
• Has evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria?

Phase 2 only:

• Has histological or cytological evidence of non small cell lung cancer?
• Has evidence of metastatic disease or stage IIIB non small cell lung cancer (NSCL) with pleural effusion is required?
• Has no prior chemotherapy for advanced lung cancer?

Note: Patients who received adjuvant or neo-adjuvant chemotherapy more than 12 months prior will be eligible?

• Has measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT) scan?

Exclusion criteria

Response should be NO

• Has any of the following within 6 months prior to study enrollment: myocardial infarction, unstable angina pectoris or uncontrolled angina pectoris, uncontrolled hypertension that is not controllable with antihypertensives, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III or IV congestive heart failure, clinically significant peripheral vascular disease (Grade II or greater).
• Has history of stroke or transient ischemic attack within 6 months?
• Has history of pulmonary embolism, deep venous thrombosis or other thrombo-embolic event within 6 months?
• Has psychiatric or neurologic illness that would limit compliance with study requirements?
• Has severe active infection within 14 days requiring use of intravenous antibiotics before beginning treatment?
• Has received any other investigational agents within 30 days of the start of treatment?
• Has history of an active malignancy unless curatively treated and risk of recurrence of < 5% at five years, with the exception of:

• Adequately treated in situ carcinoma of the cervix
• Non-melanomatous skin cancers (basal or squamous cell)?
• Has history of severe hypersensitivity reaction to compounds of similar chemical or biologic composition to carboplatin, paclitaxel, or medicines of similar composition to YM155?
• Has history of a major surgical procedure, open biopsy, or a significant traumatic injury within 14 days prior to commencing treatment, or the anticipation of the need for a major surgical procedure during the course of the study?
• Has other serious illness, medical condition or significant laboratory abnormality that may cause undue risk for the subject's safety, inhibit protocol participation, or interference with interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study?
• Phase 2 only: Has mixed tumor of any histology including small cell lung cancer?