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Phase I/II Study to Evaluate the Efficacy and Safety of Combination Chemotherapy With Carboplatin, Bortezomib and Bevacizumab as First Line Therapy in Patients With Advanced Non-small Cell Lung Cancer


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Lung Cancer

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Trial Information

Phase I/II Study to Evaluate the Efficacy and Safety of Combination Chemotherapy With Carboplatin, Bortezomib and Bevacizumab as First Line Therapy in Patients With Advanced Non-small Cell Lung Cancer


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.


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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Time Frame:

1-year

Safety Issue:

No

Principal Investigator

William Walsh, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of MassachusettsMedical School

Authority:

United States: Institutional Review Board

Study ID:

UM200601

NCT ID:

NCT00424840

Start Date:

June 2006

Completion Date:

May 2013

Related Keywords:

  • Lung Cancer
  • lung cancer, Carboplatin, bortezomib, Bevacizumab
  • Lung Neoplasms

Name

Location

University of Massachusetts Medical SchoolWorcester, Massachusetts  01605