Pazopanib in Patients With Relapsed or Refractory Small Cell Lung Cancer

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01253369
• Collaborator: Massachusetts General Hospital (Other), Brigham and Women's Hospital (Other), Beth Israel Deaconess Medical Center (Other), GlaxoSmithKline (Industry)
• Enrollment: 33
• Locations: 3
• Arm: 1
• Duration (Months): 54
• Patients Per Site: 11
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Pazopanib is a drug that inhibits proteins thought to be important for new blood vessel formation. This drug has been used in other cancer research studies and information from those studies suggests that pazopanib may help block proteins that are important for the growth, invasion, and spread of cancer cells.

Condition or Disease	Intervention/Treatment	Phase
Small Cell Lung Cancer; Lung Cancer; SCLC	Drug: Pazopanib	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To determine the progression-free survival rate in participants with relapsed or refractory small cell lung cancer who have received one prior regimen of systemic chemotherapy at 8 weeks

Secondary

• To determine the response rate (as measured by RECIST 1.1 criteria and changes in blood flow/perfusion as measured by perfusion CT)

• To determine median and overall survival

• To characterize the toxicity profile of pazopanib in this patient population.

Exploratory

• To analyze levels of circulating biomarkers from blood and urine samples obtained serially throughout the study and assess the utility of individual or subsets of these proteins to serve as a surrogate marker for treatment effect, treatment efficacy, and for tumor progression

• To measure and investigate the use of monocytes as surrogate markers of angiogenesis inhibition

• To analyze the subject population by identification of intra-tumoral biomarkers (such as c-kit, VEGF receptors, and microvessel density measured in available tumor biopsies) associated with the efficacy, safety and resistance to pazopanib

• To assess the utility of perfusion CT scan in evaluating changes in anti-angiogenic activity as a measure of treatment efficacy

STATISTICAL DESIGN: This study uses a two-stage design to evaluate efficacy of cetuximab based on progression-free rate (PFR) at week 8 defined as complete response (CR), partial response (PR) or stable disease (SD) per RECIST 1.1 criteria. The null and alternative PFR are 30% and 50%. If fewer than 4 patients enrolled in the stage one cohort (n=15 patients) achieve SD or better than accrual would not proceed to stage two (n=15 patients). If 13 or more patients are progression-free of the 30 patients then the null hypothesis will be rejected. The probability that the treatment will be considered promising if the true PFR rate was 30% is 8.4% and 82% if the true PFR rate was 50%.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Pazopanib in Patients With Relapsed or Refractory Small Cell Lung Cancer (SCLC)
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pazopanib Pazopanib was given at a dose of 800 mg orally once per day for 28 day cycles (+/- 3 days). Patients received treatment as long as they were receiving clinical benefit.	Drug: Pazopanib; Other Names: Votrient

Outcome Measures

Primary Outcome Measures

1. 8-Week Progression-Free Rate [For this endpoint, disease was evaluated radiologically at baseline and week 8 on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 3 cycles range (1-20).]

   The 8-week progression free rate (PFR) was defined as achieving complete response (CR), partial response (PR) or stable disease (SD) based on RECIST 1.1 criteria by the time of the first disease assessment (8 weeks). Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD; and SD is neither sufficient decrease to qualify as PR nor sufficient increase to qualify as progressive disease (PD). PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. Response needed confirmation within 4 weeks. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions.

Secondary Outcome Measures

1. Objective Response Rate [Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 3 cycles range (1-20).]

   The objective response rate (ORR) was defined as achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better objective response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of small cell neuroendocrine carcinoma based on either histology or cytology with radiologically-confirmed progressive disease.

• Participants should have received first-line chemotherapy and may have had up to two prior chemotherapy regimens. Radiation therapy may have been part of the permitted prior therapy.

• Participants with brain metastases will be allowed if they have been treated with surgery and/or radiation therapy more than 21 days prior, are asymptomatic, and are stable for at least one week off steroids.

• 18 years of age or older

• ECOG Performance status of 0, 1 or 2

• Ability to swallow and retain oral medication

• Disease must be measurable according to RECIST 1.1

• Adequate organ function as defined in the protocol

Exclusion Criteria:

• Prior malignancy except for participants that have been disease-free for 3 years or with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma

• History or clinical evidence of central nervous system metastases or leptomeningeal carcinomatosis except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for one week prior to first dose of study drug.

• Clinically significant gastrointestinal abnormalities

• Presence of uncontrolled infection

• Prolongation of corrected QT interval (QTc) > 480msecs

• History of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting; myocardial infarction; unstable angina; symptomatic peripheral vascular disease; Class III or IV congestive heart failure

• Poorly controlled hypertension

• History of cerebrovascular accident including transient ischemic attack, pulmonary embolism or insufficiently treated deep venous thrombosis within the past 6 months

• Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture or ulcer

• Evidence of active bleeding or bleeding diathesis

• Hemoptysis in excess of 2.5mL within 6 weeks of first dose of study drug

• Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures

• Use of any prohibited medication within the timeframes listed in the protocol

• Use of an investigational agent, including an investigational anti-cancer agent, within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug

• Prior use of an investigational or licensed drug that targets VEGF or VEGF receptors

• Is now undergoing and/or has undergone in the 14 days immediately prior to first dose of study drug, any cancer therapy

• Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is progressing in severity

• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Massachusetts General Hospital
• Brigham and Women's Hospital
• Beth Israel Deaconess Medical Center
• GlaxoSmithKline

Investigators

• Principal Investigator: David Jackman, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: David M. Jackman, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT01253369
• Other Study ID Numbers: 10-125; 113115
• First Posted: Dec 3, 2010
• Last Update Posted: Apr 23, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by David M. Jackman, MD, Principal Investigator, Dana-Farber Cancer Institute: pazopanib
• Additional relevant MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma

Study Results

Participant Flow

Recruitment Details	Patients enrolled from November 2010 through April 2012.

Arm/Group Title	Pazopanib
Arm/Group Description	Pazopanib was given at a dose of 800 mg orally once per day for 28 day cycles (+/- 3 days). Patients received treatment as long as they were receiving clinical benefit.
Period Title: Overall Study
STARTED	33
Evaluable	30
COMPLETED	0
NOT COMPLETED	33

Baseline Characteristics

Arm/Group Title	Pazopanib
Arm/Group Description	Pazopanib was given at a dose of 800 mg orally once per day for 28 day cycles (+/- 3 days). Patients received treatment as long as they were receiving clinical benefit.
Overall Participants	33
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	15 45.5%
Male	18 54.5%
Region of Enrollment (participants) [Number]
United States	33 100%
Response to 1st Line Therapy (participants) [Number]
Chemo-Refractory	18 54.5%
Chemo-Sensitive	15 45.5%

Outcome Measures

1. Primary Outcome

Title	8-Week Progression-Free Rate
Description	The 8-week progression free rate (PFR) was defined as achieving complete response (CR), partial response (PR) or stable disease (SD) based on RECIST 1.1 criteria by the time of the first disease assessment (8 weeks). Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD; and SD is neither sufficient decrease to qualify as PR nor sufficient increase to qualify as progressive disease (PD). PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. Response needed confirmation within 4 weeks. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions.
Time Frame	For this endpoint, disease was evaluated radiologically at baseline and week 8 on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 3 cycles range (1-20).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of evaluable patients. Patients who had measurable disease at baseline, received at least 1 cycle of therapy and had their disease re-evaluated were considered evaluable for response.

Arm/Group Title	Pazopanib
Arm/Group Description	Pazopanib was given at a dose of 800 mg orally once per day for 28 day cycles (+/- 3 days). Patients received treatment as long as they were receiving clinical benefit.
Measure Participants	30
Number (80% Confidence Interval) [proportion of patients]	0.567

2. Secondary Outcome

Title	Objective Response Rate
Description	The objective response rate (ORR) was defined as achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better objective response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time Frame	Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 3 cycles range (1-20).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of evaluable patients. Patients who had measurable disease at baseline, received at least 1 cycle of therapy and had their disease re-evaluated were considered evaluable for response.

Arm/Group Title	Pazopanib
Arm/Group Description	Pazopanib was given at a dose of 800 mg orally once per day for 28 day cycles (+/- 3 days). Patients received treatment as long as they were receiving clinical benefit.
Measure Participants	30
Number (80% Confidence Interval) [proportion of patients]	0.033

Adverse Events

Time Frame	Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment.
Adverse Event Reporting Description	Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv4. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv4.
Arm/Group Title	Pazopanib
Arm/Group Description	Pazopanib was given at a dose of 800 mg orally once per day for 28 day cycles (+/- 3 days). Patients received treatment as long as they were receiving clinical benefit.
All Cause Mortality
	Pazopanib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Pazopanib
	Affected / at Risk (%)	# Events
Total	12/33 (36.4%)
Cardiac disorders
Cardiac disorders - Other, specify	4/33 (12.1%)
Heart failure	1/33 (3%)
Ventricular arrhythmia	5/33 (15.2%)
Gastrointestinal disorders
Nausea	2/33 (6.1%)
General disorders
Fatigue	2/33 (6.1%)
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	3/33 (9.1%)
Investigations
Alanine aminotransferase increased	1/33 (3%)
Alkaline phosphatase increased	1/33 (3%)
Aspartate aminotransferase increased	1/33 (3%)
Lipase increased	2/33 (6.1%)
Metabolism and nutrition disorders
Hypophosphatemia	1/33 (3%)
Musculoskeletal and connective tissue disorders
Bone pain	2/33 (6.1%)
Nervous system disorders
Memory impairment	1/33 (3%)
Renal and urinary disorders
Proteinuria	2/33 (6.1%)
Vascular disorders
Hypertension	1/33 (3%)
Thromboembolic event	1/33 (3%)
Other (Not Including Serious) Adverse Events
	Pazopanib
	Affected / at Risk (%)	# Events
Total	26/33 (78.8%)
Blood and lymphatic system disorders
Anemia	3/33 (9.1%)
Blood and lymphatic system disorders - Other, specify	5/33 (15.2%)
Cardiac disorders
Cardiac disorders - Other, specify	6/33 (18.2%)
Supraventricular tachycardia	2/33 (6.1%)
Endocrine disorders
Endocrine disorders - Other, specify	1/33 (3%)
Hypothyroidism	3/33 (9.1%)
Eye disorders
Watering eyes	1/33 (3%)
Gastrointestinal disorders
Abdominal pain	4/33 (12.1%)
Constipation	2/33 (6.1%)
Diarrhea	15/33 (45.5%)
Dyspepsia	1/33 (3%)
Flatulence	2/33 (6.1%)
Mucositis oral	2/33 (6.1%)
Nausea	10/33 (30.3%)
Pancreatitis	2/33 (6.1%)
Vomiting	8/33 (24.2%)
General disorders
Edema face	1/33 (3%)
Fatigue	13/33 (39.4%)
Hepatobiliary disorders
Hepatobiliary disorders - Other, specify	8/33 (24.2%)
Injury, poisoning and procedural complications
Bruising	2/33 (6.1%)
Investigations
Alanine aminotransferase increased	6/33 (18.2%)
Alkaline phosphatase increased	2/33 (6.1%)
Aspartate aminotransferase increased	5/33 (15.2%)
Blood bilirubin increased	2/33 (6.1%)
Investigations - Other, specify	2/33 (6.1%)
Neutrophil count decreased	4/33 (12.1%)
Platelet count decreased	3/33 (9.1%)
Serum amylase increased	2/33 (6.1%)
Weight loss	5/33 (15.2%)
White blood cell decreased	2/33 (6.1%)
Metabolism and nutrition disorders
Anorexia	6/33 (18.2%)
Dehydration	1/33 (3%)
Hypocalcemia	1/33 (3%)
Hypokalemia	1/33 (3%)
Hypomagnesemia	1/33 (3%)
Hyponatremia	1/33 (3%)
Hypophosphatemia	1/33 (3%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/33 (3%)
Muscle weakness upper limb	2/33 (6.1%)
Pain in extremity	1/33 (3%)
Nervous system disorders
Ataxia	1/33 (3%)
Depressed level of consciousness	2/33 (6.1%)
Dizziness	1/33 (3%)
Dysgeusia	5/33 (15.2%)
Nervous system disorders - Other, specify	5/33 (15.2%)
Psychiatric disorders
Insomnia	1/33 (3%)
Renal and urinary disorders
Proteinuria	1/33 (3%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/33 (3%)
Sinus disorder	2/33 (6.1%)
Skin and subcutaneous tissue disorders
Dry skin	3/33 (9.1%)
Pruritus	1/33 (3%)
Rash acneiform	2/33 (6.1%)
Rash maculo-papular	1/33 (3%)
Skin and subcutaneous tissue disorders - Other, specify	2/33 (6.1%)
Vascular disorders
Hypertension	8/33 (24.2%)

Limitations/Caveats

[Not Specified]

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.