Phase I/II Study to Evaluate the Efficacy and Safety of a Combination Chemotherapy

The primary objective of phase I study is to define the maximum tolerated dose (MTD) of weekly bortezomib in combination with Carboplatin and Bevacizumab

The primary objective of phase II study is to estimate the efficacy (response rate and progression free survival) and safety of combination therapy with Carboplatin, bortezomib and bevacizumab as first line therapy in patients with advanced NSCLC.

The secondary objectives of this study are to estimate the time to progression, duration of response, and overall survival

Patient population Stage IIIB with pleural effusion or stage IV Non-Small Cell Lung Cancer. No prior chemotherapy. Specific inclusion and exclusion criteria are detailed in section 3.2. Number of patients Phase I: 9-18 patients Phase II: 19-55 patients A maximum of 55 patients (range 31-55). Study design and methodology The study will have two phases.

The phase I will use traditional dose escalation model (3-6 patient per dose level) to determine the maximum tolerated dose (MTD).

In the phase II portion, the optimal two-stage design for phase II clinical trials described by Simon et al. will be utilized (33).

Treatments administered

In phase I, three dose levels of weekly bortezomib will be studied in conjunction with fixed dose carboplatin and bevacizumab on a 21 day cycle to define the maximum tolerated dose (MTD).

A maximum of six cycles will be administered. Patients with complete response, partial response or stable disease after six cycles will be allowed to continue on single agent bevacizumab every 3 weeks as maintenance therapy until disease progression.

If no dose limiting toxicity (DLT) is observed in 3 patients during the first cycle, the next dose level will be accrued. If 1 DLT is observed, 3 additional patients will be accrued to the dose level. If no additional DLTs are observed, the next dose level will be accrued. However, if 2 or more DLTs are observed in a given dose level, MTD will be defined. MTD will be defined as the dose below which ≥2 DLTs were observed.

NUMBER OF EVALUABLE PATIENTS WITH UNACCEPTABLE TOXICITIES NEXT DOSE LEVEL 0/3 Accrue 3 new patients for next highest dose level. 1/3 Accrue additional 3 patients at current dose level. 1/3 + 0/3 Accrue 3 new patients for next dose level. 1/3 + 1/3 Accrue 3 new patients to previous dose level (if only 3 patients were enrolled to that cohort. If 6 patients had been enrolled already, then declare that Previous dose as MTD).

1/3 + 2/3 Stop: Previous dose = MTD 2/3 Stop: Previous dose = MTD

The following three levels will be studied:

Level I (q21d cycle): D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1.3 mg/m2 D8 : bortezomib 1.3 mg/m2

Level II(q21d cycle): D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1.6 mg/m2 D8 : bortezomib 1.6 mg/m2

Level III(q21d cycle):D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1.8 mg/m2 D8 : bortezomib 1.8 mg/m2

If 2 or more DLT are observed in Level 1, level -1 will be accrued.

Level -1: (q21d cycle): D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1 mg/m2 D8: bortezomib 1 mg/m2

In phase II, either level III or the MTD dose level will be used in the same q21day cycle to evaluate the efficacy and safety of the regimen in first line treatment of advanced NSCLC.

Efficacy data collected

The following evaluations will be conducted to assess the efficacy of the combination:

• response rate by RECIST criteria
• disease free and overall survival, TTP and duration of response Safety data collected

The following evaluations will be conducted to assess the safety of the combination chemotherapy:

• toxicity based on NCI-CTCAE version 3.0 Statistical procedures

In phase I portion, 9-18 patients will be enrolled. The patients treated at recommended dose level for phase II will also be eligible for response evaluation as part of phase II.

The primary objective of the phase II study is to estimate the efficacy and safety of the combination therapy with carboplatin, bortezomib and bevacizumab as the first line therapy in patients with advanced NSCLC. The primary endpoints are response rate and progression-free survival (PFS).

In phase II portion, the optimal two-stage design for phase II clinical trials described by Simon et al. will be utilized.

Overall survival, progression free survival and time to progression will be estimated using Kaplan-Meier methods. Time to progression, progression free survival and survival will be calculated from the date of study entry.

• Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10.
• Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50.

Inclusion Criteria:

• Histologically confirmed SCLC (adeno- and large cell, anaplastic carcinoma and broncho-alveolar-carcinoma). Patients with squamous-cell histology are eligible with extra thoracic or peripheral lung lesions only.
• Sputum cytology alone not acceptable evidence of cell type. Cytologic specimens obtained by brushing, washings, or needle aspiration of defined lesions will be acceptable. Mixed tumors will be categorized by the predominant cell type unless a small cell anaplastic elements are present, in which case the patient is ineligible.
• Stage III B because of pleural effusion or Stage IV disease
• Measurable disease.
• Age: 18 years or older
• No history of thrombotic, hemorrhagic, or coagulopathy disorders
• INR<1.5 and a PTT no greater than normal limits of normal within 1 week prior to registration. NB: subjects with lung cancer placed on anticoagulant therapy for a thrombotic event are not eligible for this study.
• No gross hemoptysis (defined as bright red blood of ½ teaspoon or more)
• No CNS or brain metastasis

• Laboratory Criteria (completed <2 weeks before enrollment):

  • Hematologic: WBC > 3500/mm3 or ANC > 1500/mm3 and platelet count > 100 000/ mm3;
  • Hepatic: Total bilirubin < 1.5 mg/dl
  • Renal: Creatinine < 1.5 mg/dl. or calculated
  • Creatinine clearance > 45 ml/min (NB: Urine protein:creatinine ratio in exclusion criteria)
• ECOG performance status < 2
• Be free of active infection.
• Be available for active follow up.
• No prior chemotherapy for metastatic disease.
• Be disease free for > 5 years if they had a prior second malignancy other than treated basal cell carcinoma or squamous cell skin cancer, or carcinoma in situ of the cervix.
• Female subject post-menopausal; surgically sterilized or willing to use an acceptable method of birth control for the duration of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study.

Exclusion Criteria:

• CNS or brain metastasis
• Patient has = or greater Grade 2 peripheral neuropathy within 14 days before enrollment.
• Known previous sensitivity reactions with boron, or mannitol,
• Patients with known HIV positivity
• Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
• Blood pressure of >150/100 mmHG
• History of myocardial infarction or stroke within 6 months
• Clinically significant peripheral vascular disease
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study.
• Minor surgical procedure such as fine needle aspirations or core biopsies within 7 days prior to day 0
• Urine protein: Creatinine ratio > 1.0 at screening
• History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 6 months prior to Day 0
• Serious, non-healing wound, ulcer, or bone fracture
• Lung carcinoma or any histology in close proximity to a major vessel or cavitation
• Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
• Patient has received other investigational drugs with 14 days before enrollment or is expected to participate in an experiment drug study during this study treatment.
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

• Millennium Pharmaceuticals, Inc.
• Genentech