H3E-US-X072: Carboplatin, Bevacizumab and Pemetrexed in Advanced Non Small Cell Lung Cancer

• Sponsor: Christiana Care Health Services (Other)
• Overall Status: Completed
• CT.gov ID: NCT00614822
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 50
• Arm: 1
• Duration (Months): 105.7

Study Details

Study Description

Brief Summary

The purpose of this study is to look for an improvement in progression free survival with the combination of bevacizumab, carboplatin and pemetrexed in patients with newly diagnosed advanced/metastatic non small cell lung cancer. Overall survival and safety will also be assessed.

Condition or Disease	Intervention/Treatment	Phase
Non Small Cell Lung Cancer	Drug: Carboplatin, Pemetrexed and Bevacizumab	Phase 2

Detailed Description

Carboplatin: AUC 5 IV over 30-60 minutes on day 1 Pemetrexed: 500mg/M2 IV over 10 minutes on day 1 Bevacizumab: 15mg/kg IV over 90 minutes on day 1 (if rate is tolerated the 2nd dose may be decreased to 60 minutes and subsequent doses to 30 minutes This regimen will be administered every 6 weeks for up to a maximum of 6 cycles if the patient tolerates the treatment and has stable disease. Bevacizumab will be continues if tolerated for up to 1 year at every 3 week intervals.

Folic acid 1mg by mouth daily, Vitamin B12 1000 ug IM every 9 weeks and Dexamethasone 4mg by mouth twice a day and and antiemetic may be prescribed by the physician investigator to help reduce side effects associated with the Pemetrexed. The Folic acid and Vitamin B12 will continue until 3 weeks after the end of treatment.

Physical exams, vital signs and blood work will be done prior to each chemotherapy cycle. A urine dipstick to check for protein in the urine will be done prior to the first treatment and before cycles 3 and 5. A CAT scan of the chest will be done pretreatment, prior to cycles 3 and 5 and at the end of treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Carboplatin, Bevacizumab and Pemetrexed in Advanced Non-Small Cell Lung Cancer
• Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: Aug 22, 2016
• Actual Study Completion Date: Aug 22, 2016

Arms and Interventions

Arm	Intervention/Treatment
Other: one arm for study Carboplatin, Pemetrexed and Bevacizumab are given day 1 every 3 weeks for 6 cycles and will be continued if patient tolerates treatments and has stable disease. The Bevacizumab will be continued every 3 weeks for 1 year if the patient tolerates treatment and has stable disease.	Drug: Carboplatin, Pemetrexed and Bevacizumab; Carboplatin AUC 5 IV day 1 over 30-60 minutes Pemetrexed 500 mg/M2 IV day 1 over 10 minutes Bevacizumab 15 mg /kg IV day over 90 minutes dose 1, 60 minutes dose 2, 30 minutes subsequent doses. Repeat every 3 weeks for total of 6 cycles; Other Names: Paraplatin Alimta Avastin

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year").]

   From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year").

2. Overall Survival [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year").]

   Overal survival was defined as time between the date of treatment assignment and the date of death

Secondary Outcome Measures

1. Number of Participants With Complete and Partial Tumor Responses [Patients were enrolled over a 24 month period for treatment visits. After end of treatment visits, subjects were seen or contacted every 3 months for survival data. Median follow up was 49 weeks (6 weeks to death.]

   A complete response (CR),was disappearance of all target lesions on CT scan and absence of appearance of any new lesion was required. Partial response (PR) was assessed by at least a 30% decrease in the sum of the longest diameter (LD) of target lesions without appearance of any new lesions. Progressive disease (PD) was defined as at least a 20% increase in the sum of the LD of target lesions or the appearance of one or more new lesions. Patients were assessed to have stable disease if neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD, without appearance of new lesions. Patients who received one or more cycles were evaluable for response.

2. Number of Participants With Adverse Events [Subjects were seen or contacted every 3 months with medain follow up of 49 weeks.]

   Measured by adverse events such as grade 4 toxicities, hospitalizations for toxicities, fever and neutropenia events, and clinically significant bleeding/thrombotic events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Advanced stage NSCLC (IIIB with malignant pleural effusion; T4 [on basis on satellite lesion] N2, 3; or stage IV) excluding squamous cell histology, with measurable or evaluable disease.

• Prior chemotherapy therapy for early stage disease with one regimen is acceptable if it was completed at least 6 months prior to study entry.

• Palliative radiotherapy to painful bony metastases will be permitted prior to study entry if completed prior to initiation of study treatment, and there are no residual sequelae of therapy such as bone marrow suppression.

• Life expectancy of at least 3 months.

• ECOG Performance status 0-1.

• Age 18 or higher.

• Willingness to use appropriate contraception to avoid pregnancy during the study (female patient or female partner of a male patient)

• Patients must have normal organ and marrow function as defined below:

leukocytes greater than or equal to3,000/µl ANC greater than or equal to 1,500/µl platelets greater than or equal to 100,000/µl total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) ≤ 2.5 x institutional upper limit of normal creatinine within normal institutional limits OR creatinine clearance ≥ 45 mL/min/1.73 m2 for patients with creatinine levels above institutional normal

• Ability to sign informed consent

• Ability to take folic acid, Vitamin B12 and dexamethasone as per protocol

• Ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of Alimta.

Exclusion criteria

Patients meeting any of the following criteria are ineligible for study entry:

• Prior cytotoxic treatment for advanced NSCLC. One prior regimen (up to 4 cycles) of neoadjuvant or adjuvant therapy for early stage disease will be allowed if completed at least 6 months prior to study entry.

• Prior definitive chest irradiation (radiation of rib or spine mets permitted)

• Known brain metastases (unless previously resected and radiated)

• Prior treatment with bevacizumab or pemetrexed

• History of allergic reactions or sensitivity attributed to compounds of similar chemical or biologic composition to bevacizumab or carboplatin

• Current, recent (within 4 weeks of the first infusion of this study), or planned participation in any other experimental drug study.

• Concomitant chemotherapy, radiotherapy or investigational agents.

• Evidence of bleeding diathesis or coagulopathy.

• Use of anti-coagulant agents warfarin (1mg, by mouth, daily for port maintenance permitted), heparin (ASA, NSAID permitted).

• Pregnant (positive pregnancy test) or lactating women.

• 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 procedures, 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 intra- abdominal abscess within 6 months prior to Day

• Serious, non-healing wound, ulcer, or bone fracture.

• Lung carcinoma of squamous cell histology or any histology in close proximity to a major vessel, or with significant cavitation as assessed by treating investigator in consultation with an attending radiologist. -Recent history of hemoptysis (bright red blood of 1/2 teaspoon or more)- within one month of study entry

• Significant co-morbidities including:

Blood pressure of 150/100 mmHg Unstable angina New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix B) History of myocardial infarction within 6 months History of stroke within 6 months Clinically significant peripheral vascular disease

• Psychiatric illness/social situations that would limit compliance with study requirements.

• Another active malignancy except for non-melanoma skin cancers.

• Clinically significant pleural, pericardial, and/or peritoneal effusions unless drained or controlled prior to study entry.

• Undrainable, clinically relevant effusions and presence of third space fluid which cannot be controlled by drainage.

• Hepatic impairment as evidenced by Bilirubin greater than 1.5 times the upper limit of normal Transaminases greater than 3.0 times limit of normal (ULN), except in presence of known hepatic metastasis, wherein may be up to 5 times ULN

• Any CTCAE Version 3.0 Grade 3 or 4 non hematologic toxicity

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Christiana Care Health Services
• Eli Lilly and Company

Investigators

• Principal Investigator: Michael Guarino, MD, Christiana Care Health Services

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Christiana Care Health Services
• ClinicalTrials.gov Identifier: NCT00614822
• Other Study ID Numbers: 24091; Eli Lilly H3E-US-X072
• First Posted: Feb 13, 2008
• Last Update Posted: Mar 20, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Bevacizumab; Carboplatin; Pemetrexed

Study Results

Participant Flow

Recruitment Details	Between November 2007 and March 2012, 50 patients were enrolled in the phase II trial of carboplatin, pemetrexed and bevacizumab. Patients were enrolled over a 24month period.
Pre-assignment Detail	Carboplatin, Penetrexed and Bevacizumab in Advanced Non-Squamous Non-Small Cell Lung Cancer

Arm/Group Title	One Arm for Study
Arm/Group Description	Carboplatin, Pemetrexed and Bevacizumab are given day 1 every 3 weeks for 6 cycles and will be continued if patient tolerates treatments and has stable disease. The Bevacizumab will be continued every 3 weeks for 1 year if the patient tolerates treatment and has stable disease. Carboplatin, Pemetrexed and Bevacizumab: Carboplatin AUC 5 IV day 1 over 30-60 minutes Pemetrexed 500 mg/M2 IV day 1 over 10 minutes Bevacizumab 15 mg /kg IV day over 90 minutes dose 1, 60 minutes dose 2, 30 minutes subsequent doses. Repeat every 3 weeks for total of 6 cycles
Period Title: Overall Study
STARTED	50
COMPLETED	47
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Carboplatin, Bevacicumab, Premetrexed
Arm/Group Description	Patients (age >18yo) were from 2007 to 2012.. Measurable disease Evaluable disease Stage IV Palliative RT NO brain metastases
Overall Participants	50
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	26 52%
>=65 years	24 48%
Sex: Female, Male (Count of Participants)
Female	24 48%
Male	26 52%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 10%
White	45 90%
More than one race	0 0%
Unknown or Not Reported	0 0%
ECOG Performance (Count of Participants)
ECOG Performance Staus Scale 0	6 12%
ECOG Performance Stsus Scale =1	44 88%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival
Description	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year").
Time Frame	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year").

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carboplatin, Bevacicumab, Premetrexed
Arm/Group Description	Patients (age >18yo) were from 2007 to 2012.. 51 patients with nonsquamous stage IV disease were enrolled over 24 months and followed. The meadian follow up was 49 weeks. Of the 51 patient enrolled, 1 patient was with drawn due to ineligibility. Three other patients were not evaluated for response due to adverse reactions.
Measure Participants	47
Median (95% Confidence Interval) [weeks]	28

2. Primary Outcome

Title	Overall Survival
Description	Overal survival was defined as time between the date of treatment assignment and the date of death
Time Frame	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year").

Outcome Measure Data

Analysis Population Description

Nonsquamous stage IV disease, Male, Female,>18 years of age, white, african american,with ECOG of 0 or 1

Arm/Group Title	One Arm for Study
Arm/Group Description	Carboplatin, Pemetrexed and Bevacizumab are given day 1 every 3 weeks for 6 cycles and will be continued if patient tolerates treatments and has stable disease. The Bevacizumab will be continued every 3 weeks for 1 year if the patient tolerates treatment and has stable disease. Carboplatin, Pemetrexed and Bevacizumab: Carboplatin AUC 5 IV day 1 over 30-60 minutes Pemetrexed 500 mg/M2 IV day 1 over 10 minutes Bevacizumab 15 mg /kg IV day over 90 minutes dose 1, 60 minutes dose 2, 30 minutes subsequent doses. Repeat every 3 weeks for total of 6 cycles
Measure Participants	47
Median (95% Confidence Interval) [weeks]	49

3. Secondary Outcome

Title	Number of Participants With Complete and Partial Tumor Responses
Description	A complete response (CR),was disappearance of all target lesions on CT scan and absence of appearance of any new lesion was required. Partial response (PR) was assessed by at least a 30% decrease in the sum of the longest diameter (LD) of target lesions without appearance of any new lesions. Progressive disease (PD) was defined as at least a 20% increase in the sum of the LD of target lesions or the appearance of one or more new lesions. Patients were assessed to have stable disease if neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD, without appearance of new lesions. Patients who received one or more cycles were evaluable for response.
Time Frame	Patients were enrolled over a 24 month period for treatment visits. After end of treatment visits, subjects were seen or contacted every 3 months for survival data. Median follow up was 49 weeks (6 weeks to death.

Outcome Measure Data

Analysis Population Description

Number of Participants with Complete and Partial Tumor Responses

Arm/Group Title	One Arm for Study
Arm/Group Description	Carboplatin, Pemetrexed and Bevacizumab are given day 1 every 3 weeks for 6 cycles and will be continued if patient tolerates treatments and has stable disease. The Bevacizumab will be continued every 3 weeks for 1 year if the patient tolerates treatment and has stable disease. Carboplatin, Pemetrexed and Bevacizumab: Carboplatin AUC 5 IV day 1 over 30-60 minutes Pemetrexed 500 mg/M2 IV day 1 over 10 minutes Bevacizumab 15 mg /kg IV day over 90 minutes dose 1, 60 minutes dose 2, 30 minutes subsequent doses. Repeat every 3 weeks for total of 6 cycles
Measure Participants	47
Complete Response	1 2%
Partial Response	27 54%

4. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Measured by adverse events such as grade 4 toxicities, hospitalizations for toxicities, fever and neutropenia events, and clinically significant bleeding/thrombotic events.
Time Frame	Subjects were seen or contacted every 3 months with medain follow up of 49 weeks.

Outcome Measure Data

Analysis Population Description

four patients discontinued treatment because of treatment related adverse events.

Arm/Group Title	One Arm for Study
Arm/Group Description	Carboplatin, Pemetrexed and Bevacizumab are given day 1 every 3 weeks for 6 cycles and will be continued if patient tolerates treatments and has stable disease. The Bevacizumab will be continued every 3 weeks for 1 year if the patient tolerates treatment and has stable disease. Carboplatin, Pemetrexed and Bevacizumab: Carboplatin AUC 5 IV day 1 over 30-60 minutes Pemetrexed 500 mg/M2 IV day 1 over 10 minutes Bevacizumab 15 mg /kg IV day over 90 minutes dose 1, 60 minutes dose 2, 30 minutes subsequent doses. Repeat every 3 weeks for total of 6 cycles
Measure Participants	47
Thrombocytopenia	1 2%
Respiratory distress	1 2%
Grade 3 diarrhea	1 2%
fatigue	1 2%

Adverse Events

Arm/Group Title	One Arm for Study
Arm/Group Description	Carboplatin, Pemetrexed and Bevacizumab are given day 1 every 3 weeks for 6 cycles and will be continued if patient tolerates treatments and has stable disease. The Bevacizumab will be continued every 3 weeks for 1 year if the patient tolerates treatment and has stable disease. Carboplatin, Pemetrexed and Bevacizumab: Carboplatin AUC 5 IV day 1 over 30-60 minutes Pemetrexed 500 mg/M2 IV day 1 over 10 minutes Bevacizumab 15 mg /kg IV day over 90 minutes dose 1, 60 minutes dose 2, 30 minutes subsequent doses. Repeat every 3 weeks for total of 6 cycles
All Cause Mortality
	One Arm for Study
	Affected / at Risk (%)	# Events
Total	0/50 (0%)
Serious Adverse Events
	One Arm for Study
	Affected / at Risk (%)	# Events
Total	4/50 (8%)
Blood and lymphatic system disorders
Thrombocytopenia	1/50 (2%)	1
Gastrointestinal disorders
grade 3 Diarrhea	1/50 (2%)	1
General disorders
Fatigue	1/50 (2%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory Disease	1/50 (2%)	1
Other (Not Including Serious) Adverse Events
	One Arm for Study
	Affected / at Risk (%)	# Events
Total	3/50 (6%)
Blood and lymphatic system disorders
Neutropenia	3/50 (6%)	3

Limitations/Caveats

include the absence of randomization, lack of independent radiology review and small sample size

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.