alliance study a021202 – prospective randomized phase ii ... 2016/study progres… · 16/12/2015...

A021202 November 2015

Template Version Date: September 24, 2013

Alliance Study A021202 – Prospective Randomized Phase II Trial of Pazopanib (NSC #737754, IND #75648) Versus Placebo in Patients with Progressive Carcinoid Tumors

Committee: Health Outcomes Committee Study Statistician: Donna Niedzwiecki, PhD Study Chair: Emily K. Bergsland, M.D. 1.0 OBJECTIVES Primary

• For patients with progressive carcinoid tumors, progression-free survival (PFS defined by central review according to RECIST 1.1) will be compared between patients randomized to treatment with pazopanib versus placebo

Primary Endpoint • PFS will be measured from date of patient entry until documented progression of disease as

determined by central review or death from any cause Secondary

• Overall Survival will be compared between treatment arms. • Objective Response Rate, duration of response, and time to treatment failure will be compared

between treatment arms. • Progression Free Survival as assessed by central radiology review and local radiology review will

be compared overall and within treatment arms. • PFS at 6 months and 12 months will be estimated within each treatment arm • Safety and Tolerability of treatment with pazopanib/placebo will be evaluated within each

treatment arm. • Biochemical response (for chromogranin A, defined as a decrease of 50% or more in plasma

chromogranin A levels from baseline and for 5-HIAA, defined as a decrease of 50% or more in urinary 5-HIAA levels from baseline) will be compared between treatment arms among patients with elevated baseline levels of CGA and 5-HIAA.

• PFS and other indicators of efficacy will be estimated in patients who crossover to pazopanib from placebo.

Secondary Endpoints • The objective response rate (ORR) will be defined as the percentage of patients with a confirmed

CR or PR per RECIST 1.1 criteria • Overall survival (OS) will be measured from randomization until death from any cause. • Duration of response (DR) will be defined, for the subset of patients with a confirmed CR or PR,

as the time from first documented evidence of CR or PR until first documented disease progression or death from any cause.

• Time to treatment failure (TTF) will be measured from randomization until termination of protocol therapy

2.0 CURRENT SCHEMA*

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mailto:[email protected]



3.0 ELIGIBILITY CRITERIA

• Low- or intermediate-grade neuroendocrine carcinoma • Locally unresectable or metastatic carcinoid tumors • Patients must have histologic documentation or clinical evidence of a carcinoid tumor of primary

site (including foregut, midgut, hindgut or other non-pancreatic site). • Radiological evidence for progressive disease (measureable or non-measurable) within 12

months prior to randomization. • No known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase

the risk of pulmonary hemorrhage • Patients must have measurable disease per RACIST 1.1 by CT scan or MRI. Lesions must be

accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 1 cm with CT or MRI (or ≥ 1.5 cm for lymph nodes).

• No prior treatment with an inhibitor of VEGF or VEGFR • Prior treatment must be completed at least 4 weeks prior to registration • Concurrent use of somatostatin analogs is allowed • Prior treatment with embolization or ablative therapies is allowed • Patients should have completed any major surgery ≥ 4 weeks prior to registration and must have

completed any minor surgery ≥ 2 weeks prior to registration. • No concurrent condition resulting in immune compromise • No clinical evidence of brain metastases or carcinomatous meningitis • No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within

28 days prior to registration • No clinically significant GI abnormalities that may increase the risk for GI bleeding < 28 days prior

to registration • No history of serious non-healing wound, ulcer, or bone fracture within 28 days prior to registration • Patients with a history of hypertension must have blood pressure that is adequately

controlled (< 140/90 mmHg). • No symptomatic congestive heart failure • No arterial thrombotic events within 6 months of registration, including transient ischemic attack

(TIA), cerebrovascular accident (CVA), peripheral arterial thrombus, unstable angina or angina requiring surgical or medical intervention in 6 months prior to registration, or myocardial infarction (MI).

• Patients on therapeutic anticoagulation with low molecular weight heparins are allowed • No ongoing cardiac dysrhythmias, atrial fibrillation, or prolongation of corrected QTc interval

to > 480 msec. • No evidence of active bleeding, bleeding diathesis, or hemoptysis within 8 weeks prior to

registration. • No currently unstable angina and/or uncontrolled cardiac arrhythrmias • No symptomatic peripheral vascular disease • Ejection fraction on Echo or MUGA > 50% • Women must not be pregnant or nursing: Women of child bearing potential must have a negative

serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within



72 hours prior to registration • Age ≥ 18; • ECOG Performance Status: 0 – 1 • Required Initial Laboratory Values

Granulocyte ≥ 1,500/mcL Platelets ≤100,000/mcL International normalized ratio (INR)* ≤1.2 X ULN QTc ≤480 msecs TSH WNL Bilirubin ≤ 1.5 x ULN AST (SGOT) & ALT (SGPT) ≤ 2.5 x ULN Serum Creatinine ≤ 1.5 x ULN Urine Protein to Creatinine Ratio < 1, or, 24-hour urine protein < 1g

4.0 TREATMENT SCHEDULE

• Protocol treatment is to begin within 14 days of registration. • Pazopanib/placebo • Patients will take pazopanib/placebo 800 mg orally every day until disease progression or

unacceptable toxicity. • Disease progression/crossover to open label treatment • At the time of documented radiographic progression as determined by central review, patients

may be unblinded (see Section 11.2). Patients who were receiving placebo may elect to crossover to treatment with pazopanib 800 mg orally every day. Patients must be re-registered to the crossover portion of the study per Section 5.5.

• Patients should initiate open-label treatment within 28 days of the most CT scan documenting progression.

• Patients who discontinue protocol treatment for reasons other than progressive disease by central review (e.g. toxicity or progression by local read only) will not be eligible for crossover.

• General rules for dose modifications: • Pazopanib/placebo will not be re-escalated once reduced • If dose reduction below 400 mg/day is required or pazopanib/placebo is held > 3 weeks,

pazopanib/placebo will be discontinued. • If more than one of these apply, use the most stringent (i.e., the greatest dose reduction.)

Dose level table: Dose Level pazopanib/plac

ebo 0 800 mg daily -1 600 mg daily -2 400 mg daily

• Cardiac Toxicity • For QTc interval > 500 msecs, Once QTc returns to ≤ 500 msecs, electrolyte abnormalities have

been corrected, and any symptoms have resolved, resume pazopanib/placebo with one dose level reduction for all subsequent cycles. Remove patient from study if repeat ECG shows QTc interval >500 msec.

• Thrombosis • For grade 2 or 3 venous thrombosis requiring anticoagulation, interrupt pazopanib/placebo. If the

planned duration of full dose anticoagulation is ≤ 2 weeks, omit pazopanib/placebo until anticoagulation is completed. If the planned duration of full dose anticoagulation is > 2 weeks, pazopanib/placebo may be restarted during anticoagulation if all of the following are met:

• The patient must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin or be on a stable dose of LMWH prior to restarting pazopanib/placebo.

• The patient must not have any pathological condition that carries a high risk of bleeding. • The patient must not have had any hemorrhagic events while on study.



• Persistent Grade 2 Hypertension (Systolic 140-159, Diastolic 90-99) • Recommend maximal medical management. If BP is still not controlled after maximal medical

management (see guidelines under Section 12.8), proceed with 1 dose level reduction.. • For persistent Grade 3 hypertension (Systolic ≥ 160 Diastolic ≥ 100): • Hold pazopanib/placebo until systolic BP ≤ 159 and diastolic BP ≤ 99. Once BP is controlled to

this level, resume pazopanib/placebo at1 dose level reduction. HOWEVER, if the patient requires hospitalization for management of symptomatic systolic BP > 180 or diastolic BP > 110, permanently discontinue

• Hemorrhage • For grade 2 CNS or pulmonary hemorrhage, discontinue pazopanib/placebo. For other grade 2

bleeding, hold pazopanib/placebo until resolved to ≤ grade 1; reduce dose to next lower dose level, and continue treatment. If grade 2 or greater hemorrhage/bleeding recurs following dose reduction, discontinue pazopanib/placebo.

• For any grade bowel obstruction requiring medical intervention, interrupt pazopanib/placebo until obstruction resolves completely, then resume pazopanib/placebo at the previous dose. For obstruction requiring surgery interrupt pazopanib/placebo until full recovery from surgery, then resume pazopanib/placebo at the previous dose. If pazopanib/placebo is interrupted for > 21 days for bowel obstruction, discontinue pazopanib/placebo.

• Other Non-Hematologic Grade 3 or 4 Toxicity • considered at least possibly related to treatment, interrupt pazopanib/placebo treatment until

toxicity improves to ≤ grade 1, then resume treatment with one dose level reduction. • For recurrent other non-hematologic grade 3 toxicity, discontinue pazopanib/placebo. • Other non-hematologic grade 4 toxicity not described above, discontinue pazopanib/placebo • Discontinue pazopanib/placebo if any of the following occurs:

For grade 3 or 4 hyper-or hypothyroidism For any grade of Hemolytic Uremic Syndrome (See CTCAE Blood and Lymphatic System Disorders) For wound dehiscence requiring medical or surgical intervention For any grade perforation of any organ, GI leak, or any fistula, discontinue pazopanib/placebo. For any grade 3 or 4 hemorrhage For Reversible Posterior Leukoencephalopathy Syndrome (RPLS) (see CTCAE v.4: Nervous System Disorders) If patients require a delay of greater than 3 weeks for management of hypertension For arterial thromboembolic events (any grade) including cerebrovascular ischemia, cardiac ischemia/infarction, peripheral or visceral arterial ischemia For grade 4 venous thromboembolic events, For recurrent/worsening venous thromboembolic events after resumption of pazopanib/placebo, discontinue pazopanib/placebo. Permanently discontinue pazopanib/placebo. Recommend optimal management with intensive IV support in ICU The treatment schedule is described in detail in the Study Schema (Section 2.0 of this report).

5.0 STUDY DESIGN

5.1 Study Phase/Type of Design/Stratification Factors This is a randomized Phase II study in patients with progressive carcinoid tumors. Progression-free survival (PFS defined by central review according to RECIST 1.1) will be compared between patients randomized to treatment with pazopanib versus placebo. Patients will be randomized according to stratification factors: Site of Primary (Small Bowl; Other) and Concurrent Somatostatin Analogue use (Yes; No).

5.2 Primary Endpoint PFS will be measured from date of patient entry until documented progression of disease as determined by central review or death from any cause. If a patient does not have a documented



date of progression or death, then PFS will be censored at the date of last adequate assessment. PFS will be estimated within treatment arm using the Kaplan-Meier method. Secondary Endpoints The objective response rate (ORR), Overall survival (OS), Duration of response (DR), and Time to treatment failure (TTF) will be measured as secondary endpoints. 5.3 Target Accrual Patients will be randomized with equal probability to treatment with pazopanib or placebo. With 150 patients enrolled over 25 months (6 patients per month) and a follow-up period of 12 months, 85% power is achieved to detect the difference between a median PFS of 14 months with pazopanib and 9 months for placebo (log rank test, 1-sided α =0.1; hazard ratio 0.6429). Accounting for 10% drop out, we estimate that we will need to enroll approximately 165 patients in order to meet the targeted sample size (N=150). The target accrual for this study is 165 patients using a 1:1 randomization. The target accrual rate is 6 patients per month.

6.0 CURRENT ACCRUAL

Study Activation Date 06/21/2013 Target Accrual (n) 165 Current Accrual (n) 171 Expected Accrual Rate 6/month Accrual Rate – Since activation 5.90/month Accrual Rate – Past 12 months 7.5/month Accrual Rate – Past 6 months 7.65/month

*Based on Freeze date 10/15/2015



7.0 CURRENT STUDY STATUS The study has reached its target accrual and is temporarily suspended to enrollment. An amendment to expand the study sample size is currently under consideration. Institutions will be notified by broadcast email when the study is re-opened to accrual. A suspension notice is posted on the Alliance website at www.allianceforclinicaltrialsinoncology.org. 8.0 PATIENT CHARACTERISTICS

Table 8a. Demographics (All randomized patients)

1

(N=97) 2

(N=74) Total

(N=171) Age N 97 74 171 Mean (SD) 61.6 (11.2) 62.8 (10.9) 62.1 (11.1) Median 62.0 63.0 63.0 Q1, Q3 54.0, 69.0 56.0, 72.0 55.0, 69.0 Range (33.0-89.0) (37.0-85.0) (33.0-89.0) Race

http://www.allianceforclinicaltrialsinoncology.org/



1

(N=97) 2

(N=74) Total

(N=171) White 77 (79.4%) 62 (83.8%) 139 (81.3%)

Black or African American 13 (13.4%) 9 (12.2%) 22 (12.9%) Native Hawaiian or Other Pacific Islander 1 (1.0%) 0 (0.0%) 1 (0.6%) Asian 1 (1.0%) 1 (1.4%) 2 (1.2%) American Indian or Alaska Native 2 (2.1%) 0 (0.0%) 2 (1.2%) Not reported: patient refused or not available 3 (3.1%) 1 (1.4%) 4 (2.3%)

Unknown: Patient unsure 0 (0.0%) 1 (1.4%) 1 (0.6%) Gender Female 63 (64.9%) 33 (44.6%) 96 (56.1%) Male 34 (35.1%) 41 (55.4%) 75 (43.9%)

Table 8b. Stratification Factors (All randomized patients)

1

(N=97) 2

(N=74) Total

(N=171) CURRENT OCTREOTIDE Yes 84 (86.6%) 64 (86.5%) 148 (86.5%) No 13 (13.4%) 10 (13.5%) 23 (13.5%) Name of Site Other sites 35 (36.1%) 24 (32.4%) 59 (34.5%) Small bowel 62 (63.9%) 50 (67.6%) 112 (65.5%)

9.0 ADVERSE EVENTS

9.1 Adverse Event Summary 142 patients are evaluable for adverse events (AE) analyses (Arm 1: 82 patients and Arm 2: 60 patients). Arm 1: The most common severe grade 3 adverse events possibly, probably, or definitely related

to study intervention included: hypertension 13(16%), alanine aminotransferase increased 5(6%), aspartate aminotransferase increased 5(6%), fatigue 5(6%), Blood bilirubin increased 2(2%), dehydration 3(4%), diarrhea 2(2%), hyperglycemia 2(2%) and Metabolism, nutrition disord - Oth spec 2(2%). The grade 4 events probably or definitely related to study medication included: alanine aminotransferase increased 1(1%) and hypertension 1(1%). There was one grade 5 adverse event possibly related to study intervention: sepsis 1(1%) .This patient passed away on 6/25/14 due to pneumonia/sepsis and completed 3 cycles of initial treatment and One other patient had grade 5 Sudden death NOS 1(1%) but was not related to treatment. This ppatient completed initial blided therapy for 2 cycles.

Arm 2: The most common severe grade 3 adverse events possibly, probably, or definitely related

to study intervention included: fatigue 4(7%), hypertension 4(7%), aspartate aminotransferase increased 3(5%), blood bilirubin increased 3(5%), diarrhea 4(7%),



vomiting 3(5%), alanine aminotransferase increased 2(3%) and nausea 2(3%). There were no grade 4 or grade 5 events related to study medication.

Table 9a. Summary of Grade 3+ Adverse Events Regardless of Attribution

Number of Evaluable Patients: Arm 1=82 Arm 2=60

Patients with a maximum: Arm n (%)

Total

Grade 3 Event 1 44 (53.7%)

2 27 (45.0%)

Grade 4 Event 1 3 (3.7%)

2 1 (1.7%)


2 0 (0.0%)

Hematologic Adverse Events


2 1 (1.7%)


2 0 (0.0%)


2 0 (0.0%)

Non-Hematologic Adverse Events

Grade 3 Event 1 44 (53.7%)

2 26 (43.3%)


2 1 (1.7%)


2 0 (0.0%)

Note: Summaries are based on available patient data

Table 9b. Listing of Grade 3+ Adverse Events Max Grade Per Patient Per Event

Regardless of Attribution Number of Evaluable Patients:

Arm 1=82 Arm 2=60 Grade of AdverseEvent

Arm 3-Severe 4-LifeThr 5-Lethal n (%) n (%) n (%)

Hematologic Adverse Events







Blood/Bone Marrow Leukocytosis 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Lymphocyte count decreased 1 2 ( 2%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%)

Non-Hematologic Adverse Events Cardiac disorders

Cardiac disorders - Other, specify 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 1 ( 2%) 0 ( 0%)

Ear and labyrinth disorders Hearing impaired 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%)

Eye disorders Retinal detachment 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Gastrointestinal disorders Abdominal pain 1 3 ( 4%) 0 ( 0%) 0 ( 0%) 2 3 ( 5%) 0 ( 0%) 0 ( 0%) Ascites 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Dental caries 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Diarrhea 1 3 ( 4%) 0 ( 0%) 0 ( 0%) 2 4 ( 7%) 0 ( 0%) 0 ( 0%) Gastrointestinal disorders - Oth spec

1 1 ( 1%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Mucositis oral 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Nausea 1 2 ( 2%) 0 ( 0%) 0 ( 0%) 2 3 ( 5%) 0 ( 0%) 0 ( 0%) Small intestinal obstruction 1 2 ( 2%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Vomiting 1 2 ( 2%) 0 ( 0%) 0 ( 0%)







2 4 ( 7%) 0 ( 0%) 0 ( 0%) Gen disord and admin site cond

Edema limbs 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Fatigue 1 7 ( 9%) 0 ( 0%) 0 ( 0%) 2 5 ( 8%) 0 ( 0%) 0 ( 0%) Pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Sudden death NOS 1 0 ( 0%) 0 ( 0%) 1 ( 1%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Hepatobiliary disorders Gallbladder obstruction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%)

Infections and infestations Infections and infestations - Oth spec

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 1 ( 2%) 0 ( 0%) 0 ( 0%) Sepsis 1 0 ( 0%) 0 ( 0%) 1 ( 1%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Sinusitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Urinary tract infection 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%)

Investigations Alanine aminotransferase increased

1 5 ( 6%) 1 ( 1%) 0 ( 0%)

2 3 ( 5%) 0 ( 0%) 0 ( 0%) Alkaline phosphatase increased 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Aspartate aminotransferase increased

1 5 ( 6%) 0 ( 0%) 0 ( 0%)

2 5 ( 8%) 0 ( 0%) 0 ( 0%) Blood bilirubin increased 1 3 ( 4%) 0 ( 0%) 0 ( 0%) 2 3 ( 5%) 0 ( 0%) 0 ( 0%)







Investigations - Other, specify 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Weight loss 1 2 ( 2%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Metabol and nutrition disord Anorexia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Dehydration 1 4 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Hyperglycemia 1 5 ( 6%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Hyponatremia 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Hypophosphatemia 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 2 ( 3%) 0 ( 0%) 0 ( 0%) Metabolism, nutrition disord - Oth spec

1 2 ( 2%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Musculosk and conn tiss disord

Back pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Bone pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Flank pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Generalized muscle weakness 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%) Myalgia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%)

Nervous system disorders Concentration impairment 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%)

Renal and urinary disorders







Renal and urinary disorders - Oth spec

1 1 ( 1%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Renal calculi 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 2%) 0 ( 0%) 0 ( 0%)

Respirat, thor, mediast disord Hypoxia 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Surgical and medical proced Surgical and medical proced - Oth spec

1 0 ( 0%) 1 ( 1%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Vascular disorders

Hypertension 1 21 ( 26%) 1 ( 1%) 0 ( 0%) 2 11 ( 19%) 0 ( 0%) 0 ( 0%) Hypotension 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

10.0 IMBEDDED CORRELATIVES

10.1 Imaging: This is mandatory companion study. Objectives • To determine the turn-around time for timely adjudicated central review • To characterize the nature of discordance between local and central radiology review in

assessment of progression • To characterize the type and rate of progression in carcinoid (at study entry, on-study,

and at progression) • Schedule of imaging submission

Baseline (28 days prior to patient registration) Time of Restaging (every 3 cycles after Cycle 1 Day 1)

10.2 Quality of Life (A021202-HO1) Objectives • To assess for differences in QOL-related domains between the two treatment groups

(pazopanib versus placebo) • To determine if the more brief measures of QOL-related domains provide comparable

information to that which is provided by the longer assessments (EORTC, NET21) • To provide validation data for the EORTC NET21 module in terms of responsiveness

over time and differences across arms. • Schedule of QOL submission



• Total 145 (84%) patients consented for the quality of life sub-study. 10.3 Blood Specimens

• Multiplex angiome profiling in patients treated with pazopanib (vs. placebo) may help to identify predictive and prognostic biomarkers.

• Schedule of blood specimen submission

• Total 158 (92%) patients has given permission to keep sample(s) for use in future

research to learn about, prevent, or treat cancer.



10.4 Pharmacogenomics • To determine whether biomarker associations discovered in other diseases treated with

pazopanib have a consistent effect in carcinoid • To investigate the association between the genotypes of rs1126647 and baseline IL-8

levels • To investigate the association between the IL-8 SNP (rs1126647) and progression-free

survival (PFS) • To investigate the potential for a SNP by drug, and SNP by IL8 level interactions with

respect to PFS • To identify specific SNPs and/or copy number variations that are associated with the

response to and toxicity associated with pazopanib therapy

* Patients for whom the end of treatment occurs within 28 days of documented progression do not need to have samples submitted twice at this time point. 1 To be banked for potential correlative science studies described in Section 10.3 and 10.4. 2 Sample may be drawn at any time, although baseline (prior to treatment) is preferred.

During Blinded Therapy

Prior to Treatment

Prior to Day 1 of Cycle 2

At Progression*

Prior to Day 1 of Cycle 2

At Progression*

At the End of Protocol Therapy*

Ship to:

Whole Blood1,2

(lavender top)

1 x 10mL OSU

alliance study a021202 – prospective randomized phase ii ... 2016/study progres… · 16/12/2015...

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