Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Anti-Infective Agents

Paclitaxel

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Preoperative

Cycles 1-4 Doxorubicin 60 mg/m2 IV over 15 minutes + Cyclophosphamide 600 mg/m2 IV over 30 minutes of Day 1 every 21 days

followed by:

Cycles 5-8 Paclitaxel 80 mg/m2 IV over 60 minutes (Days 1, 8, and 15) every 28 days in combination with pazopanib (800 mg) PO once daily (2 tablets taken at the same time each day either 1 hour before or 2 hours after a meal) Daily beginning on Day 1 of the first paclitaxel cycle Until 7 days before surgery

Followed by Surgery

Postoperative Pazopanib 800 mg PO once daily (2 tablets taken at the same time each day either 1 hour before or 2 hours after a meal) Daily beginning 4-6 weeks after surgery 6 months from first postoperative dose

4 cycles of doxorubicin + cyclophosphamide followed by 4 cycles of paclitaxel + pazopanib.

doxorubicin + cyclophosphamide

paclitaxel + pazopanib

surgery

6 months of treatment with pazopanib monotherapy

pazopanib monotherapy

GSK Clinical Trials

The purpose of this study is to determine whether the treatment of a doxorubicin in combination with cyclophosphamide followed by a combination of pazopanib in combination with paclitaxel prior to surgery results in a pathological complete response in females with breast cancer.

This is a phase II non-randomized, multi-center study aimed to evaluate the efficacy and safety of the combination of pazopanib and paclitaxel following treatment with cyclophosphamide and doxorubicin for the treatment of neoadjuvant breast cancer.

Patients will receive standard doses of AC every 21 days for 4 cycles. This will be followed by weekly paclitaxel 80 mg/m2 IV on Days 1, 8, and 15 every 28 days for 4 cycles given concurrently with pazopanib 800 mg PO daily starting with the first paclitaxel dose and continuing until 7 days before surgery. Clinical complete response rate will be determined by tumor assessments performed by palpation at two time points: following AC (before paclitaxel/pazopanib begins) and 2-4 weeks following the last dose of paclitaxel (before surgery). Following recovery from preoperative therapy, patients will undergo the clinically-indicated surgery. Pazopanib will resume 4-6 weeks after surgery and continue daily for 6 months of postoperative pazopanib therapy.

Treatment With Pazopanib for Neoadjuvant Breast Cancer

A Phase II Clinical Trial of Four Cycles of Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel Given Concurrently With Pazopanib as Neoadjuvant Therapy Followed by Postoperative Pazopanib for Women With Locally Advanced Breast Cancer

pCR was defined as no histologic evidence of invasive tumor cells in the surgical breast specimen, axillary nodes, or sentinel node identified after neoadjuvant chemotherapy.

pCR was defined as no histologic evidence of invasive tumor cells in the surgical breast specimen.

cCR was determined by tumor assessments performed by palpation. All clinical response assessments were to be performed by physical examination of the breast and the axilla. cCR was defined as the resolution of all target and non-target lesions identified at Baseline and no new lesions or other signs of disease progression. The criteria to be used for the determination of progressive disease were at the investigator's discretion.

IRFI was assessed as the time from study entry until the diagnosis of the first invasive local (evidence of invasive/in situ breast cancer \[except LCIS\] in the ipsilateral breast \[IB\]/skin of the breast), regional (development of tumor in the ipsilateral \[IP\] internal mammary, IP supraclavicular, IP infraclavicular, and/or IP axillary nodes, as well as the soft tissue of the IP axilla, following surgery), or distant (evidence of tumor in all areas, with the exception of those described for local and regional recurrence) breast cancer recurrence during the 24 months after study entry.

The number of participants with cardiac toxicity was defined as those who had cardiac events of Grades (G) 3 and 4 leftventricular dysfunction (LVD) (CTCAE Version 3.0) and/or who had definite or probable cardiac death. Grade refers to the severity of the AE: G 1, mild AE; G 2, moderate AE; G 3, severe AE; G 4, life-threatening/disabling AE; G 5, death related to the AE. A G3 LVD event is defined as symptomatic congestive heart failure (CHF) responsive to intervention. A G4 event is defined as poorly controlled refractory CHF; ventricular assist device or heart transplant indicated.

The number of participants with normal thyroid function at Baseline who had an elevation in TSH during the study were recorded. TSH elevation was derived based on local laboratory ranges.

The number of participants with recurrence events during the 24 months after study entry are reported. A recurrence event is defined as invasive local (evidence of invasive/in situ breast cancer \[except LCIS\] in the ipsilateral breast \[IB\]/skin of the breast), regional (development of tumor in the ipsilateral \[IP\] internal mammary, IP supraclavicular, IP infraclavicular, and/or IP axillary nodes, as well as the soft tissue of the IP axilla, following surgery), or distant (evidence of tumor in all areas, with the exception of those described for local and regional recurrence) breast cancer recurrence during the 24 months after study entry.

NSABP Foundation Inc

GlaxoSmithKline

Participants were treated with intravenous (IV) doxorubicin (60 milligrams per meters squared \[mg/m\^2\]) and cyclophosphamide (AC) (600 mg/m\^2) every 21 days for 4 cycles. This was followed by weekly paclitaxel (WP) 80 mg/m\^2 IV on Days 1, 8, and 15 every 28 days for 4 cycles given concurrently with oral pazopanib 800 mg (2 tablets taken at the same time each day, either 1 hour before or 2 hours after a meal) taken daily and continuing until 7 days before surgery. Pazopanib was resumed at the same oral dose 4-6 weeks after surgery and was continued daily for 6 months.

AC, Followed by Weekly Paclitaxel and Concurrent Pazopanib

Baseline Characteristic data are reported for members of the Treated Population, comprised of all participants who entered the study and received at least one dose of any study medication.

Age, Continuous

Sex: Female, Male

White - White/Caucasian/European Heritage (W/C/EH)

African American/African Heritage

White - Arabic/North African Heritage

Asian - South East Asian Heritage

American Indian (AI) or Alaskan Native (AN)

Asian - Central/South Asian Heritage

Asian - East Asian Heritage

AI or AN + White - W/C/EH

Race/Ethnicity, Customized

Estrogen receptor (ER) status positive

ER status negative

Progesterone receptor (PgR) status positive

PgR status negative

HER-2/NEU status positive

HER-2/NEU status negative

HER-2/NEU status equivocal (uncertain)

Baseline Characteristic (BC) data are reported for members of the Treated Population. Receptor status is used to determine a course of treatment. Participants with hormone-receptor positive tumors could have been treated with hormonal therapy. Human epidermal growth factor receptor-2 (HER-2) is also known as NEU. Each participant was to be assessed for each tumor hormone receptor.

Number of participants with a positive or negative status for the indicated hormone receptors

Positive

Negative

BC data are reported for members of the Treated Population. Estrogen causes certain breast cancers (called ER+ cancers) to grow; these cancer cells have ERs on their surfaces. ER+ and PR+ indicate ER and PR positivity; a minus sign indicates that cells are negative for receptors. A participant's hormone status determines treatment modalities.

Number of participants with the indicted hormonal status (ER+ and PR+ / ER- and PR-)

GSK Response Center

Evaluable Population: all participants who entered the study and received at least one dose of pazopanib.

Number of Participants With Pathologic Complete Response (pCR) in the Breast and Nodes

Number of Participants With Pathologic Complete Response (pCR) in the Breast

Number of Participants With Clinical Complete Response (cCR) in the Breast and Nodes at the Completion of the Doxorubicin and Cyclophosphamide (AC) Period

Number of Participants With Clinical CR (cCR) in the Breast and Nodes at the Completion of the AC and Weekly Paclitaxel (WP) + Pazopanib Preoperative Periods

Overall Study Arm

Evaulable Population. Participants with recurrence before study entry were excluded from analysis.

Invasive Recurrence-free Interval (IRFI)

Treated Population: all participants who entered the study and received at least one dose of any study medication

Number of Participants With Cardiac Toxicity (Per Common Terminology Criteria for Adverse Events Version 3) at the Completion of the AC Period

Number of Participants With Cardiac Toxicity (Per CTCAE Version 3) at the Completion of the AC and Weekly Paclitaxel (WP) + Pazopanib Preoperative Periods

Treated Population: Only those members of the Treated Population who started the postoperative pazopanib period were assessed.

Number of Participants With Cardiac Toxicity (Per CTCAE Version 3.0) During the Postoperative Pazopanib Period

Elevated TSH at Least Once during the Study, n=101

AC Period, n=91

(WP) + Pazopanib Preoperative Periods, n=89

Surgery Period, n=78

Postoperative Pazopanib Period, n=36

Follow-up Period, n=33

Treated Population. Data are presented for only those participants who remained in the study during the indicated period and had their blood drawn for assessment.

Participants With Normal Thyroid Stimulating Hormone (TSH) Levels at Baseline Who Had an Elevated TSH Level at Least Once During the Study and During the Individual Study Periods

Rash

Pneumonitis

Number of Participants With the Indicated Radiotherapy-related Complications

Evaulable Population, excluding participants with recurrence before study entry

Number of Participants With Recurrence Events

Participants (par.) were treated with intravenous (IV) doxorubicin (60 milligrams per meters squared \[mg/m\^2\]) and cyclophosphamide (AC) (600 mg/m\^2) every 21 days for 4 cycles. This was followed by weekly paclitaxel (WP) 80 mg/m\^2 IV on Days 1, 8, and 15 every 28 days for 4 cycles given concurrently with oral pazopanib 800 mg (2 tablets taken at the same time each day, either 1 hour before or 2 hours after a meal) taken daily and continuing until 7 days before surgery. Pazopanib was resumed at the same oral dose 4-6 weeks after surgery and was continued daily for 6 months.

Doxorubicin and Cyclophosphamide (AC)

Weekly Paclitaxel

Pazopanib Presurgery Treatment (PPT)

Pazopanib Postsurgery Treatment

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Androgens

Pazopanib (GW786034)

A growing body of literature supports the role of angiogenesis in the development and spread of a variety of human cancers including prostate cancer.

* Vascular endothelial growth factor (VEGF) expression is low in normal prostate tissue, but markedly increased in tumor tissues, and has a positive association with tumor stage and grade
* Plasma VEGF levels are significantly elevated in patients with hormone refractory prostate cancer (HRPC) compared to those patients with localized disease and have been associated with disease progression in other cancer patient population.
* The Cancer and Leukemic Group-B demonstrated that VEGF levels correlate with survival.

Pazopanib is a potent multi-target receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptors.

VEGF expression is low in all normal prostate tissue, but markedly increased in tumor tissue, and has a positive association with MVD (micro vessel density) tumor stage, grade, and disease-specific survival in patients with prostate cancer. VEGF is known to be under the influence of HIF-1α, which is also up-regulated in the majority of prostate cancer tissue. It has been shown that complete androgen blockade down-regulates VEGF expression via the HIF-1α pathway with concomitant up-regulation of thrombospondin and induction of endothelial cell apoptosis. The VEGF pathway appears to be the dominant vascular formation pathway in prostate cancer with bFGF having a lesser role.

Pazopanib , a hydrochloride salt, is a small molecule inhibitor of several tyrosine kinases, ie: VEGF 1, 2, 3, c-KIT and platelet-derived growth factor receptors. The broad blockade of the VEGF receptors should interfere with the VEGF/VEGF-receptor pathway, and have an impact on cell growth.

According to the NCCN guidelines , first line therapy for metastatic prostate cancer is considered total androgen blockade, either utilizing orchiectomy and/or LH/RH agonists plus Casodex.

Second line therapy would depend on the patient's response to first line therapy, urgency of a response, and the location of metastatic disease.

Pazopanib has been explored in several settings. It has recently been looked at with Bicalutamide in hormone refractory prostate cancer. The second study was with earlier disease, i.e. D-0 relapse androgen-sensitive patients. The University of Chicago has a study looking at the sub-population of prostate cancer patients that have a "chemical relapse" in which patients are given one shot of Lupron, and if the PSA is adequately suppressed, the patients are randomized between pazopanib and placebo.

Pazopanib as Second Line Therapy in Patients With Metastatic Prostate Cancer Refractory to Total Androgen Blockade

A Study of Pazopanib as Second Line Therapy in Patients With Metastatic Prostate Cancer Who Have Received Prior Therapy With an LHRH Agonist.

Response rate defined as 50% decrease in the Prostate Specific Antigen (PSA) level at week 12 compared to baseline

Safety was evaluated by documentation of Adverse Events (AEs), by assessment of clinical laboratory findings, and by physicial examination, including measurement of vital signs and weight in all eleven subjects.

Illinois CancerCare, P.C.

Principal Investigator

Pazopanib 800mg Daily by Mouth

Pazopanib

Pazopanib (GW786034) : Pazopanib 800 mg daily x 12 weeks

Advanced Prostate Cancer, Treatment, Pazopanib

Age, Categorical

Age Continuous

United States

Region of Enrollment

Because of slow enrollment, the study was terminated. The study planned enrollment of 34 subjects, 11 were enrolled.

James Knost, M.D.

Five subjects completed the 12 week treatment requirement.

Response Rate at 12 Weeks

Adverse events for all participants, all grades

Participants With Adverse Events 800mg Pazopanib

The adverse events for all participants enrolled were evaluated by documentation of Adverse Events (AEs)Grades 1-5 using NCI-CTCAE v 3.0

Number Adverse Events, Grades 1-5 Using NCI-CTCAE v 3.0

Overall Study

Rare Diseases

Carcinoma

Carcinoma, Renal Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Kidney Neoplasms

Urologic Neoplasms

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Pharmaceutical Solutions

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Part 1 is a dose escalation phase in which subjects will receive pazopanib orally and the MK 3475 intravenously. Subjects will be evaluated for a minimum of 8 weeks before the next dose level cohort is enrolled.

Part 2 is a randomized phase in which subjects will be enrolled in each treatment arm:

Pazopanib monotherapy Pazopanib+MK-3475 MK-3475 monotherapy

Pazopanib is an orally administered 200 mg tablet available in the dose range of 400 to 800 mg

Pazopanib

MK 3475 is an intravenously administered 100 mg/ 4mL solution available in the potential dose range of 1 to 10 mg/kg.

MK-3475

Novartis Pharmaceuticals

This is an open-label, 2 part study of pazopanib and/or MK 3475 in treatment naïve subjects with advanced RCC. Part 1 consists of a Phase I dose escalation of pazopanib + MK 3475 followed by an expansion cohort to determine the maximum tolerated regimen and the recommended Phase II dose. Part 2 is a randomized 3-arm Phase II study to evaluate the clinical efficacy and safety of pazopanib + MK 3475 as compared to single-agent pazopanib and single-agent MK 3475. The objectives of this Phase I/II study are to test the safety and tolerability of pazopanib in combination with MK 3475, and study the clinical efficacy of pazopanib in combination with MK 3475 in subjects with advanced RCC as compared with single-agent pazopanib and single-agent MK 3475.

Following the Urgent Safety Measure (USM) released on February 09, 2017, the phase II (Part 2) portion of this study will not commence.

Safety and Efficacy Study of Pazopanib and MK 3475 in Advanced Renal Cell Carcinoma (RCC; KEYNOTE-018)

A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and MK 3475 in Patients With Advanced Renal Cell Carcinoma

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

MTR is defined as the highest dose of pazopanib in combination with the highest dose of MK 3475 at which no more than 1 of 6 subjects experiences a DLT after a minimum of 8 weeks of treatment. DLT is defined as a drug-related AE starting in the first 8 weeks of treatment

Laboratory assessments include haematology, clinical chemistry, urine, coagulation and thyroid function test

Vital sign measurements will include heart rate, temperature and blood pressure

Cardiac assessments will include Electrocardiogram (ECG) and Echocardiograms (ECHOs)

Subjects will be monitored for anti-MK 3475 antibodies throughout the study

PFS is defined as the interval between the date of randomization and the earlier date of disease progression (using RECIST v1.1) or death due to any cause.

For analysis of plasma pazopanib and serum MK 3475 concentrations, blood samples will be collected from all subjects

Area under the plasma concentration-time curve from time 0 to 24 hrs (AUC\[0-24\], maximum observed concentration (Cmax), tmax, and concentration at 24 hours (C24) of pazopanib; Pre-dose (trough) concentration at the end of the dosing interval (Ctau), and apparent clearance following oral dosing CL/F of pazopanib will be determined if data permit.

Overall response rate is defined as the percentage of subjects, who achieved either a confirmed complete response (CR) or partial response (PR) by RECIST v1.1 and modified RECIST

Clinical benefit rate is defined as a confirmed response of CR or PR or at least 6-months stable disease by RECIST v1.1 and modified RECIST.

Time to response is defined for all subjects with a confirmed CR or PR as per RECIST v1.1as the time from randomization until the first documented evidence of CR or PR (whichever status is recorded first)

Duration of response is defined for all subjects with confirmed CR or PR as the time from the first documented evidence of CR or PR until time of first documented disease progression or death due to any causes, whichever is first by RECIST v1.1 and modified RECIST

PFSR18 will be calculated based on Kaplan-Meier estimates of Progression-free survival (PFS) at 18 months by RECIST v1.1 and modified RECIST

Overall survival at 18 months will be summarized based on the Kaplan-Meier method.

Overall survival will be summarized using Kaplan-Meier survival curves

Cardiac assessments will include ECG and ECHOs

For analysis of plasma pazopanib and serum MK 3475 concentrations, blood samples will be collected from all subjects. AUC\[0-24\], Cmax, tmax, and C24 of pazopanib alone and in combination with MK 3475; Cmax, Ctau, and apparent clearance following oral dosing CL/F of pazopanib will be determined if data permit.

Merck Sharp & Dohme LLC

Sarcoma

Soft Tissue Sarcoma

Epirubicin

once daily oral administration of pazopanib for Days 1-21 days in combination with epirubicin given as a bolus intravenous administration on Day 3

once daily oral administration of pazopanib for Days 1-8 of a 3-week cycle in combination with epirubicin (bolus intravenous administration) on Day 3

epirubicin (bolus intravenous administration) on Day 1 with once-daily oral administration of pazopanib for Days 14-21 of a 3-week cycle

once-daily oral administration of pazopanib (according to schedule selected from either Arm A, B, or C) (3 week cycle) in combination with doxorubicin (bolus intravenous administration) on Day 1 or 3, depending on the schedule selected from either Arm A, B, or C

Arm D - doxorubicin given as a intravenous bolus injection on Day 1 or Day 3 depending on schedule selected from Arm A, B or C - starting dose 60 mg/m2 and increase to 75mg/m2

Arm A - daily administration of pazopanib on Days 1 through 21 starting at 200mg with a maximum dose of 800mg; Arm B daily administration of pazopanib on Days 1 through 8 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm C daily dose of pazopanib on Days 14 through 21 of a 3-week cycle starting at 200mg escalating to a maximum dose of 800mg; Arm D once daily administration of pazopanib (according to schedule selected from Arm A, B, or C) starting at 400mg escalating to a maximum dose of 800mg

Arm A and Arm B - epirubicin given as a bolus intravenous injection on Day 3 starting dose 60mg/m2 increase to 90mg/m2 if tolerated; Arm C - epirubicin given as a bolus intravenous injection on Day 1 starting dose 60mg/m2 increase to 90mg/m2 if tolerated

This is an open-label, four-arm, Phase I, dose escalation study to evaluate the safety and tolerability and to determine the optimal tolerated regimen (OTR) of pazopanib in combination with epirubicin or doxorubicin in patients with advanced solid tumors. Patients will be enrolled in cohorts of 3 to receive escalating doses of pazopanib and epirubicin or doxorubicin. Dose escalation schemas for each study arm are described in the protocol. For each arm, the OTR will be defined as the highest dose combination of the agents where no more than one out of six patients experiences a dose-limiting toxicity. Twelve additional patients in each arm will be studied with the OTR to evaluate toxicity and pharmacokinetics. This will allow an assessment of potential drug-drug interactions. Antitumor activity will be assessed using RECIST criteria.

A Phase I, Open-label, Study of Pazopanib in Combination With Epirubicin or Doxorubicin for Advanced Solid Tumors

A Phase I, Open-label, Study of the Safety, Pharmacokinetics, and Pharmacodynamics Dose Escalation of Pazopanib in Combination With Epirubicin or Doxorubicin for Advanced Solid Tumors

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Treatment With Pazopanib for Neoadjuvant Breast Cancer	NCT00849472	Neoplasms, Brea...	doxorubicin + c... paclitaxel + pa... surgery pazopanib monot...	18 Years -	GlaxoSmithKline
Pazopanib as Second Line Therapy in Patients With Metastatic Prostate Cancer Refractory to Total Androgen Blockade	NCT00945477	Prostate Cancer	Pazopanib (GW78...	18 Years - 85 Years	Illinois CancerCare, P.C.
Safety and Efficacy Study of Pazopanib and MK 3475 in Advanced Renal Cell Carcinoma (RCC; KEYNOTE-018)	NCT02014636	Carcinoma, Rena...	Pazopanib MK-3475	18 Years -	Novartis
Safety and Efficacy Study of Pazopanib and MK 3475 in Advanced Renal Cell Carcinoma (RCC; KEYNOTE-018)	NCT02014636	Carcinoma, Rena...	Pazopanib MK-3475	18 Years -	Novartis
A Phase I, Open-label, Study of Pazopanib in Combination With Epirubicin or Doxorubicin for Advanced Solid Tumors	NCT00722293	Neoplasms, Brea...	Doxorubicin Pazopanib (GW78... Epirubicin	18 Years -	GlaxoSmithKline
A Phase I, Open-label, Study of Pazopanib in Combination With Gemcitabine and Gemcitabine Plus Cisplatin for Advanced Solid Tumors	NCT00678977	Lung Cancer, No...	Pazopanib (GW78... Gemcitabine Cisplatin	18 Years -	GlaxoSmithKline
A Two-way Crossover Study Of The Effect Of Food On The Pharmacokinetics Of Pazopanib In Cancer Patients	NCT00363194	Carcinoma, Rena...	Pazopanib (GW78...	21 Years -	GlaxoSmithKline
A Phase I, Open-label, Study of Pazopanib in Combination With Epirubicin or Doxorubicin for Advanced Solid Tumors	NCT00722293	Neoplasms, Brea...	Doxorubicin Pazopanib (GW78... Epirubicin	18 Years -	GlaxoSmithKline
Monotherapy Pazopanib in Subjects With Advanced Non-Small Cell Lung Cancer	NCT00549328	Lung Cancer, No...	Pazopanib (GW78...	18 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for pazopanib (gw786034)