ASH Clinical News ACN_4.1_FULL_ISSUE_DIGITAL | Page 9

to the editor : The December 2017 editorial (“ Solving the Contract Research Agonization Problem ”) sounds funny , but the issue of how CROs act at sites is a real problem . My problem is that I am part of this system .

When I started as a contract research associate ( CRA ) at one of the biggest CROs , my job was to read hundreds of standard operating procedures ( SOPs ) and attend several training meetings via WebEx or recorded trainings . Learning effect = none !

Table 3 : Hematologic Adverse Reactions Reported * in ≥ 20 % of Patients with MCL in Trial LY-004

Hematologic Adverse Reactions

It is not much better at the new CRO . In my first four weeks , I read hundreds of SOP documents from my CRO and , because my position is sponsor-based , hundreds more from the pharmaceutical company . Again , learning effect = none !

The training on topics we have to discuss with the sites is endless , but , in the end , I don ’ t have the appropriate knowledge about the medical disease and the trial protocol . And , because I work on

CALQUENCE ® ( acalabrutinib ) capsules , for oral use

CALQUENCE 100 mg twice daily N = 124

All Grades (%) Grade ≥ 3 (%)

Clinical Impact

Prevention or Management

Moderate CYP3A Inhibitors

Clinical Impact

Prevention or Management

Strong CYP3A Inducers

Clinical Impact

Prevention or Management

Gastric Acid Reducing Agents

Clinical Impact

Prevention or Management

• Co-administration of CALQUENCE with a strong CYP3A inhibitor ( itraconazole ) increased acalabrutinib plasma concentrations [ see Clinical Pharmacology ( 12.3 ) in the full Prescribing Information ].

• Increased acalabrutinib concentrations may result in increased toxicity .

• Avoid co-administration of strong CYP3A inhibitors with CALQUENCE .

• Alternatively , if the inhibitor will be used short-term , interrupt CALQUENCE [ see Dosage and Administration ( 2.2 ) in the full Prescribing Information ].

• Co-administration of CALQUENCE with a moderate CYP3A inhibitor may increase acalabrutinib plasma concentrations [ see Clinical Pharmacology ( 12.3 ) in the full Prescribing Information ].

• Increased acalabrutinib concentrations may result in increased toxicity .

• When CALQUENCE is co-administered with moderate CYP3A inhibitors , reduce acalabrutinib dose to 100 mg once daily .

• Co-administration of CALQUENCE with a strong CYP3A inducer ( rifampin ) decreased acalabrutinib plasma concentrations [ see Clinical Pharmacology ( 12.3 ) in the full Prescribing Information ].

• Decreased acalabrutinib concentrations may reduce CALQUENCE activity .

• Avoid co-administration of strong CYP3A inducers with CALQUENCE .

• If a strong CYP3A inducer cannot be avoided , increase the acalabrutinib dose to 200 mg twice daily .

• Co-administration of CALQUENCE with a proton pump inhibitor , H2-receptor antagonist , or antacid may decrease acalabrutinib plasma concentrations [ see Clinical Pharmacology ( 12.3 ) in the full Prescribing Information ].

• Decreased acalabrutinib concentrations may reduce CALQUENCE activity .

• If treatment with a gastric acid reducing agent is required , consider using a H2-receptor antagonist ( e . g ., ranitidine or famotidine ) or an antacid ( e . g ., calcium carbonate ).

Separate dosing by at least 2 hours [ see Dosage and Antacids

Administration ( 2.2 ) in the full Prescribing Information ].

H2-receptor antagonists

Proton pump inhibitors

Take CALQUENCE 2 hours before taking the H2-receptor antagonist [ see Dosage and Administration ( 2.2 ) in the full Prescribing Information ].

Avoid co-administration . Due to the long-lasting effect of proton pump inhibitors , separation of doses may not eliminate the interaction with CALQUENCE .

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary

Based on findings in animals , CALQUENCE may cause fetal harm when administered to a pregnant woman . There are no available data in pregnant women to inform the drugassociated risk . In animal reproduction studies , administration of acalabrutinib to pregnant rabbits during organogenesis resulted in reduced fetal growth at maternal exposures ( AUC ) approximately 4 times exposures in patients at the recommended dose of 100 mg twice daily ( see Data ). Advise pregnant women of the potential risk to a fetus .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown . All pregnancies have a background risk of birth defect , loss , or other adverse outcomes . In the U . S . general population , the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20 %, respectively . so many different trials in different medical fields , I sometimes look stupid at sites when I am telling a highly professional team how they have to work . I am lucky that most sites are sympathetic and don ’ t blame me – or don ’ t blame me too much . Compared with most CRAs on the market , my background couldn ’ t be better : I worked as a registered nurse in a hematology / oncology inpatient ward for several years in Germany and the U . K .

Data

Animal Data In a combined fertility and embryo-fetal development study in female rats , acalabrutinib was administered orally at doses up to 200 mg / kg / day starting 14 days prior to mating through gestational day [ GD ] 17 . No effects on embryo-fetal development and survival were observed . The AUC at 200 mg / kg / day in pregnant rats was approximately 16-times the AUC in patients at the recommended dose of 100 mg twice daily . The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma .

In an embryo-fetal development study in rabbits , pregnant animals were administered acalabrutinib orally at doses up to 200 mg / kg / day during the period of organogenesis ( from GD 6-18 ). Administration of acalabrutinib at doses ≥ 100 mg / kg / day produced maternal toxicity and 100 mg / kg / day resulted in decreased fetal body weights and delayed skeletal ossification . The AUC at 100 mg / kg / day in pregnant rabbits was approximately 4-times the AUC in patients at 100 mg twice daily .

Lactation Risk Summary

No data are available regarding the presence of acalabrutinib or its active metabolite in human milk , its effects on the breastfed child , or on milk production . Acalabrutinib and its active metabolite were present in the milk of lactating rats . Due to the potential for adverse reactions in a breastfed child from CALQUENCE , advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose .

Pediatric Use The safety and efficacy of CALQUENCE in pediatric patients have not been established .

Geriatric Use Eighty ( 64.5 %) of the 124 MCL patients in clinical trials of CALQUENCE were 65 years of age or older , and 32 patients ( 25.8 %) were 75 years of age or older . No clinically relevant differences in safety or efficacy were observed between patients ≥ 65 years and younger .

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ).

Hemorrhage

Inform patients to report signs or symptoms of severe bleeding . Inform patients that CALQUENCE may need to be interrupted for major surgeries [ see Warnings and Precautions ( 5.1 ) in the full Prescribing Information ].

Infections

Inform patients to report signs or symptoms suggestive of infection [ see Warnings and Precautions ( 5.2 ) in the full Prescribing Information ].

Cytopenias

Inform patients that they will need periodic blood tests to check blood counts during treatment with CALQUENCE [ see Warnings and Precautions ( 5.3 ) in the full Prescribing Information ].

Second Primary Malignancies

Inform patients that other malignancies have been reported in patients who have been treated with CALQUENCE , including skin cancer . Advise patients to use sun protection [ see Warnings and Precautions ( 5.4 ) in the full Prescribing Information ].

Atrial Fibrillation and Flutter

Counsel patients to report any signs of palpitations , lightheadedness , dizziness , fainting , shortness of breath , and chest discomfort [ see Warnings and Precautions ( 5.5 ) in the full Prescribing Information ].

Dosing Instructions

Instruct patients to take CALQUENCE orally twice daily , about 12 hours apart . CALQUENCE may be taken with or without food . Advise patients that CALQUENCE capsules should be swallowed whole with a glass of water , without being opened , broken , or chewed [ see Dosage and Administration ( 2.1 ) in the full Prescribing Information ].

Missed Dose

Advise patients that if they miss a dose of CALQUENCE , they may still take it up to 3 hours after the time they would normally take it . If more than 3 hours have elapsed , they should be instructed to skip that dose and take their next dose of CALQUENCE at the usual time . Warn patients they should not take extra capsules to make up for the dose that they missed [ see Dosage and Administration ( 2.1 ) in the full Prescribing Information ].

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant medications , including over-the-counter medications , vitamins and herbal products [ see Drug Interactions ( 7 ) in the full Prescribing Information ].

Lactation

Advise women not to breastfeed during treatment with CALQUENCE and for at least 2 weeks after the final dose [ see Use in Specific Populations ( 8.2 ) in the full Prescribing Information ].

Distributed by : AstraZeneca Pharmaceuticals LP , Wilmington , DE 19850 Under license of Acerta Pharma B . V .

CALQUENCE is a registered trademark of the AstraZeneca group of companies . © AstraZeneca 2017

10 / 17 US-14202 11 / 17

2 before I started as a study coordinator and later project manager at a German university hospital . I like to learn new tasks and read medical articles in my private time .

At my CRA job now , I try to shorten a site-initiation visit as much as possible , and I don ’ t tell any principal investigator about his or her responsibilities because I am very sure that physicians already are treating patients with their best interests in mind – and that their treatment will comply with the guidelines for good clinical practice put forth by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use .

I don ’ t write many queries because I sit with the study coordinator or research nurse at the end of my monitoring visit and discuss “ my findings .” We can avoid too many queries by making direct changes in the electronic case-report forms together or clarifying some items that I might not understand . What I cannot avoid , though , is asking the staff to sign so many logs and papers . And when a pharmaceutical sponsor attends any visit , I have to conduct the complete and long procedures and visit .

For me , it is difficult to explain to older CRAs that it is better to communicate with sites on another level than what is described in our training . And when I teach new CRAs about my working process , I have to explain myself to my manager .

I believe that the work we do as CRAs is important , but the way we have to do our work is , in my opinion , wrong . Doing my work with joy can sometimes be challenging because of these problems . Also , the problem is not created only by the CROs : Pharmaceutical companies support this “ behavior ” in many ways , and the differing opinions of ethic commissions , local authorities , and other stakeholders create inefficiencies in the system . Again , this is a great article , and there has to be a change in the clinical trial world .

Best regards from Europe ,

— David Pleiss Bergisch Gladbach , Germany

ASH Clinical News 7