Pazopanib in Molecularly Selected Patients With Advanced NSCLC

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02193152
• Collaborator: Novartis (Industry)
• Enrollment: 16
• Location: 1
• Arm: 1
• Actual Duration (Months): 55.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate how participants with advanced non-small cell lung cancer (NSCLC) that have certain abnormalities in the pazopanib target genes respond to pazopanib treatment.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small Cell Lung; Non-Small Cell Lung Cancer; Nonsmall Cell Lung Cancer	Drug: Pazopanib	Phase 2

Detailed Description

There has been a limited benefit from anti-angiogenesis drugs in patients with NSCLC. Bevacizumab provides a modest survival improvement when added to chemotherapy and VEGFR tyrosine kinase inhibitors have been associated with minimal efficacy as single agents and increased toxicity when combined with chemotherapy. We postulate that the response rates and survival may be improved with a better selection of patients based on abnormalities of the targets for the drugs. According to the preliminary data from the cancer genome atlas (TCGA), the targets of pazopanib are altered in 28% of patients with adenocarcinoma and 24% of patients with squamous cell lung cancer. Since, despite the molecular selection prior to treatment, only a small percentage of patients will benefit from the treatment, we plan to further investigate those patients with whole exome sequencing in both the pre-treatment samples to identify the predictors for response and at the time of progression, with repeated biopsy, in an attempt to identify the predictors for secondary resistance. By identifying more reliable predictors for response to pazopanib, our study may help to establish its role in the treatment of NSCLC.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Pazopanib in Molecularly Selected Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)
• Actual Study Start Date: Apr 27, 2015
• Actual Primary Completion Date: Dec 24, 2019
• Actual Study Completion Date: Dec 24, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment: Pazopanib Pazopanib 800 mg daily should be taken orally without food at least one hour before or two hours after a meal. One cycle of pazopanib is 28 days.	Drug: Pazopanib; Other Names: GW786034 Votrient®

Outcome Measures

Primary Outcome Measures

1. Response Rate [Until the end of treatment (median length of treatment=85.5 days (full range 25-334 days)]

   Participants should be re-evaluated for response 8 weeks after initiation of pazopanib and then every 8 weeks thereafter. In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks following initial documentation of objective response. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Response rate is the percentage of participants with a complete or partial response Complete response=Disappearance of all target and non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Partial response=At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters

2. Progression-free Survival (PFS) [Until progressive disease or death (median follow-up 174 days, full range 41 days-545 days)]

   Progression-free survival is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. There is no limit on following for progression-free survival besides death of the participant. Progressive disease=At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Secondary Outcome Measures

1. Outcomes Associated With Specific Mutations [Until time of death (an expected average of 8 months)]

   Participants are followed until death. All participants will undergo next generation sequencing prior to enrollment into the study. Initial predictors are the mutations in VEGFR or PDGFR, but sequencing will be used to evaluate for other predictors as well.

2. Mutational Predictors for Extreme Responders [Until end of treatment (an expected average of 8 months)]

   -Whole exome and transcriptome sequencing will be performed in 10 participants, including 4 to 6 responders and 4 to 6 non-responders in order to identify the predictors for benefit.

3. Mechanisms of Secondary Resistance. [Until the time of progressive disease (an expected average of 8 months)]

   -Participants will also undergo next generation sequencing at the time of progression in an attempt to identify the mechanisms for secondary resistance.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed diagnosis of advanced (metastatic or unresectable) non-small cell lung cancer (NSCLC) with mutations, rearrangement and fusion involving RET oncogene, or abnormalities in the pazopanib target genes defined as VEGFR1-3, PDGFRA, PDGFRB, or TP53 with abnormalities including deletion, insertion, early stop codon, and/or nonsynonymous mutations with functional consequences. CLIA certified lab testing for pazopanib target genes using cell free DNA from peripheral blood and/or assays performed on tumor tissues are acceptable.

• Evaluable disease by imaging or physical exam OR measurable disease defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.

• Failed at least one standard chemotherapeutic treatment for NSCLC.

• At least 18 years of age.

• ECOG performance status ≤ 2

• Normal bone marrow and organ function as defined below:

• Absolute neutrophil count ≥ 1,500/mcl

• Platelets ≥ 100,000/mcl

• Hemoglobin ≥ 9.0 g/dL

• PT or INR ≤ 1.2 x IULN

• aPTT ≤ 1.2 x IULN

• Total bilirubin ≤ 1.5 x IULN

• AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN

• Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 30 mL/min/1.73 m2 for patients with creatinine levels above 1.5 mg/dL

• UPC < 1 or, if UPC ≥ 1, 24-hour urine protein < 1 g; use of urine dipstick for renal function assessment is not acceptable.

• Patients receiving anticoagulation therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation.

• Ability to swallow and retain oral tablets.

• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informed consent document.

Exclusion Criteria:

• Treatment with any of the following anti-cancer therapies:

• Radiation therapy, surgery, or tumor embolization within 14 days prior to the first dose of pazopanib OR

• Chemotherapy, immunotherapy, investigational therapy or hormonal therapy within 14 days prior to the first dose of pazopanib

• Prior treatment with any VEGFR tyrosine kinase inhibitor.

• Administration of any non-oncologic investigational drug within 30 days or 5 half-lives (whichever is longer) prior to the first dose of pazopanib.

• Use of a strong CYP3A4 inhibitor less than 14 days prior to initiation of study treatment

• A history of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix.

• Symptomatic brain metastases. Patients with known brain metastases are allowed if they are asymptomatic.

• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib or other agents used in the study.

• Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is progressing in severity (except alopecia). Any IO related adverse events must be ≤ grade 1 to be eligible.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled seizure disorder, chronic underlying liver disease unrelated to cancer, or psychiatric illness/social situations that would limit compliance with study requirements.

• Corrected QT interval (QTc) > 480 msecs.

• History of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina pectoris, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure as defined by the New York Heart Association (see Appendix B).

• Poorly controlled hypertension (defined as systolic blood pressure of ≥ 140 mmHg or diastolic blood pressure of ≥ 90 mmHg). Note: initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Following antihypertensive medication initiation or adjustment, blood pressure must be reassessed three times at approximately 2-minute intervals. At least 24 hours must have elapsed between antihypertensive medication initiation or adjustment and blood pressure measurement. These three values should be averaged to obtain the mean diastolic and systolic blood pressures, which must be < 140/90 mmHg in order for a patient to be eligible for the study.

• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding, including (but not limited to) active peptic ulcer disease, known intraluminal metastatic lesions with risk of bleeding, inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other GI conditions with increased risk of perforation, history of abdominal fistula or intra-abdominal abscess within 28 days prior to beginning study treatment.

• Clinically significant gastrointestinal abnormalities that may affect absorption of pazopanib, including (but not limited to) malabsorption syndrome or major resection of the stomach or small bowel.

• History of cerebrovascular accident including transient ischemic attack, pulmonary embolism (including asymptomatic or previously treated PE), or untreated deep venous thrombosis within the past 6 months. Patients with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible.

• Major surgery or trauma within 28 days prior to first dose of pazopanib and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery).

• Evidence of active bleeding or bleeding diathesis.

• Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage. Note: lesions infiltrating major pulmonary vessels (contiguous tumor and vessels) are excluded; however, the presence of a tumor that is touching but not infiltrating (abutting) the vessels is acceptable (CT with contrast is strongly recommended to evaluate such lesions). Large protruding endobronchial lesions in the mail or lobar bronchi are excluded; however, endobronchial lesions in the segmented bronchi are allowed. Lesions extensively infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in the wall of thee bronchi are allowed.

• Recent hemoptysis (≥ ½ teaspoon of red blood within 8 weeks before first dose of pazopanib).

• Pregnant and/or breastfeeding. Patient must have a negative serum pregnancy test within 14 days of study entry.

• Known HIV-positivity. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine
• Novartis

Investigators

• Principal Investigator: Daniel Morgensztern, M.D., Washington University School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 1, 2018

More Information

Additional Information:

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT02193152
• Other Study ID Numbers: 201408009
• First Posted: Jul 17, 2014
• Last Update Posted: Jul 14, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Washington University School of Medicine: Advanced Non-Small Cell Lung Cancer; NSCLC; Pazopanib
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung

Study Results

Participant Flow

Arm/Group Title	Treatment: Pazopanib
Arm/Group Description	Pazopanib 800 mg daily should be taken orally without food at least one hour before or two hours after a meal. One cycle of pazopanib is 28 days.
Period Title: Overall Study
STARTED	16
COMPLETED	16
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment: Pazopanib
Arm/Group Description	Pazopanib 800 mg daily should be taken orally without food at least one hour before or two hours after a meal. One cycle of pazopanib is 28 days.
Overall Participants	16
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66.5
Sex: Female, Male (Count of Participants)
Female	11 68.8%
Male	5 31.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	16 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 6.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 18.8%
White	12 75%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	16 100%

Outcome Measures

1. Primary Outcome

Title	Response Rate
Description	Participants should be re-evaluated for response 8 weeks after initiation of pazopanib and then every 8 weeks thereafter. In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks following initial documentation of objective response. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Response rate is the percentage of participants with a complete or partial response Complete response=Disappearance of all target and non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Partial response=At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters
Time Frame	Until the end of treatment (median length of treatment=85.5 days (full range 25-334 days)

Outcome Measure Data

Analysis Population Description

4 participants were not evaluable for this outcome measure because they were removed from treatment prior to the re-evaluation response at 8 weeks

Arm/Group Title	Treatment: Pazopanib
Arm/Group Description	Pazopanib 800 mg daily should be taken orally without food at least one hour before or two hours after a meal. One cycle of pazopanib is 28 days.
Measure Participants	12
Count of Participants [Participants]	2 12.5%

2. Primary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. There is no limit on following for progression-free survival besides death of the participant. Progressive disease=At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
Time Frame	Until progressive disease or death (median follow-up 174 days, full range 41 days-545 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment: Pazopanib
Arm/Group Description	Pazopanib 800 mg daily should be taken orally without food at least one hour before or two hours after a meal. One cycle of pazopanib is 28 days.
Measure Participants	16
Median (Full Range) [weeks]	13.25

3. Secondary Outcome

Title	Outcomes Associated With Specific Mutations
Description	Participants are followed until death. All participants will undergo next generation sequencing prior to enrollment into the study. Initial predictors are the mutations in VEGFR or PDGFR, but sequencing will be used to evaluate for other predictors as well.
Time Frame	Until time of death (an expected average of 8 months)

Outcome Measure Data

Analysis Population Description

The data was not collected for this outcome measure.

Arm/Group Title	Treatment: Pazopanib
Arm/Group Description	Pazopanib 800 mg daily should be taken orally without food at least one hour before or two hours after a meal. One cycle of pazopanib is 28 days.
Measure Participants	0

4. Secondary Outcome

Title	Mutational Predictors for Extreme Responders
Description	-Whole exome and transcriptome sequencing will be performed in 10 participants, including 4 to 6 responders and 4 to 6 non-responders in order to identify the predictors for benefit.
Time Frame	Until end of treatment (an expected average of 8 months)

Outcome Measure Data

Analysis Population Description

The data was not collected for this outcome measure.

Arm/Group Title	Treatment: Pazopanib
Arm/Group Description	Pazopanib 800 mg daily should be taken orally without food at least one hour before or two hours after a meal. One cycle of pazopanib is 28 days.
Measure Participants	0

5. Secondary Outcome

Title	Mechanisms of Secondary Resistance.
Description	-Participants will also undergo next generation sequencing at the time of progression in an attempt to identify the mechanisms for secondary resistance.
Time Frame	Until the time of progressive disease (an expected average of 8 months)

Outcome Measure Data

Analysis Population Description

The data was not collected for this outcome measure.

Arm/Group Title	Treatment: Pazopanib
Arm/Group Description	Pazopanib 800 mg daily should be taken orally without food at least one hour before or two hours after a meal. One cycle of pazopanib is 28 days.
Measure Participants	0

Adverse Events

Time Frame	Adverse events were collected from study start through 30 days after completion of treatment (median treatment length 85.5 days (full range=25 days-334 days)).
Arm/Group Title	Treatment: Pazopanib
Arm/Group Description	Pazopanib 800 mg daily should be taken orally without food at least one hour before or two hours after a meal. One cycle of pazopanib is 28 days.
All Cause Mortality
	Treatment: Pazopanib
	Affected / at Risk (%)	# Events
Total	14/16 (87.5%)
Serious Adverse Events
	Treatment: Pazopanib
	Affected / at Risk (%)	# Events
Total	8/16 (50%)
General disorders
Fatigue	1/16 (6.3%)
Fever	1/16 (6.3%)
Infections and infestations
Lung infection	3/16 (18.8%)
Upper respiratory infection	1/16 (6.3%)
Investigations
Alanine aminotransferase increased	1/16 (6.3%)
Aspartate aminotransferase increased	1/16 (6.3%)
Blood bilirubin increased	1/16 (6.3%)
Death	1/16 (6.3%)
Metabolism and nutrition disorders
Hyponatremia	2/16 (12.5%)
Nervous system disorders
Syncope	1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/16 (6.3%)
Other (Not Including Serious) Adverse Events
	Treatment: Pazopanib
	Affected / at Risk (%)	# Events
Total	16/16 (100%)
Blood and lymphatic system disorders
Anemia	1/16 (6.3%)
Cardiac disorders
Tachycardia	1/16 (6.3%)
Endocrine disorders
Hypothryoidism	3/16 (18.8%)
Eye disorders
Visual changes	1/16 (6.3%)
Gastrointestinal disorders
Abdominal pain	4/16 (25%)
Constipation	11/16 (68.8%)
Diarrhea	5/16 (31.3%)
Dyspepsia	7/16 (43.8%)
Gingival pain	1/16 (6.3%)
Mucositis oral	5/16 (31.3%)
Nausea	11/16 (68.8%)
Vomiting	5/16 (31.3%)
General disorders
Chills	6/16 (37.5%)
Dry mouth	1/16 (6.3%)
Edema limbs	7/16 (43.8%)
Edema face	2/16 (12.5%)
Fatigue	14/16 (87.5%)
Leg pain	1/16 (6.3%)
Non-cardiac chest pain	2/16 (12.5%)
Foot pain	1/16 (6.3%)
Left side pain	1/16 (6.3%)
Fever	2/16 (12.5%)
Flu like symptoms	2/16 (12.5%)
Hip pain	1/16 (6.3%)
Shoulder pain	1/16 (6.3%)
Infections and infestations
Papulopustular rash	1/16 (6.3%)
Lung infection	1/16 (6.3%)
Infection	3/16 (18.8%)
Investigations
Platelet count decreased	1/16 (6.3%)
Alkaline phosphatase increased	2/16 (12.5%)
Creatinine increased	1/16 (6.3%)
Weight loss	2/16 (12.5%)
Metabolism and nutrition disorders
Anorexia	10/16 (62.5%)
Hypercalcemia	1/16 (6.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	7/16 (43.8%)
Back pain	5/16 (31.3%)
Myalgia	6/16 (37.5%)
Neck pain	1/16 (6.3%)
Left shoulder pain	1/16 (6.3%)
Nervous system disorders
Dizziness	10/16 (62.5%)
Headache	9/16 (56.3%)
Peripheral sensory neuropathy	12/16 (75%)
Memory impairment	1/16 (6.3%)
Peripheral motor neuropathy	5/16 (31.3%)
Dysgeusia	3/16 (18.8%)
Psychiatric disorders
Anxiety	5/16 (31.3%)
Depression	5/16 (31.3%)
Insomnia	12/16 (75%)
Confusion	3/16 (18.8%)
Renal and urinary disorders
Polyuria	1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	12/16 (75%)
Dyspnea	11/16 (68.8%)
Productive cough	1/16 (6.3%)
Bronchopulmonary hemorrhage	1/16 (6.3%)
Hiccups	1/16 (6.3%)
Voice alteration	2/16 (12.5%)
Skin and subcutaneous tissue disorders
Alopecia	6/16 (37.5%)
Bruising	1/16 (6.3%)
Dry skin	4/16 (25%)
Hyperhidrosis	3/16 (18.8%)
Nail changes	1/16 (6.3%)
Rash acneiform	4/16 (25%)
Palmar-plantar erythrodysethesia	2/16 (12.5%)
Vascular disorders
Hot flashes	6/16 (37.5%)
Hypertension	9/16 (56.3%)
Thromboembolic event	1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.