Dose Escalation and Double-blind Study of Veliparib in Combination With Carboplatin and Etoposide in Treatment-naive Extensive Stage Disease Small Cell Lung Cancer
- Conditions
- Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT02289690
- Lead Sponsor
- AbbVie
- Brief Summary
The study seeks to assess the efficacy of veliparib (ABT-888) in combination with carboplatin and etoposide in participants with extensive disease small cell lung cancer (ED SCLC).
- Detailed Description
This is a Phase 1, open-label, dose-escalation/Phase 2 randomized double-blind study of veliparib in combination with carboplatin and etoposide and maintenance veliparib monotherapy.
Participants in Phase 1 will be sequentially assigned to ascending dose levels of veliparib in combination with standard carboplatin/etoposide regimen for up to four 21-day cycles based on the observed toxicities. The study design for Phase 1 will follow a traditional "3 + 3" dose-escalation protocol.
Once the veliparib recommended Phase 2 dose (RPTD) and schedule is determined, enrollment into Phase 2 will begin. Participants from the Phase 1 dose-escalation portion of the study are not eligible for enrollment into the Phase 2 portion. Participants in Phase 2 will be randomized in a 1:1:1 ratio to carboplatin, etoposide, placebo followed by placebo maintenance (Arm C), or carboplatin, etoposide, veliparib followed by either veliparib (Arm A) or placebo (Arm B) maintenance. Randomization for Phase 2 will be stratified by baseline lactate dehydrogenase (LDH) level (\> upper limit of normal \[ULN\] vs. ≤ ULN), and gender.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 221
- Subject with histologically or cytologically confirmed extensive-stage disease SCLC which is newly diagnosed and chemotherapy naive
- Phase 1 ONLY: histologically or cytologically confirmed advanced/metastatic solid tumors for which carboplatin/etoposide treatment is considered appropriate.
- Subject in Phase 2 only: must have measurable disease per RECIST 1.1.
- Subjects with ED SCLC must consent to provide available archived formalin fixed paraffin embedded (FFPE) tissue sample of SCLC lesion (primary or metastatic) for central review and biomarker analysis.
- Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.
- Subject must have adequate hematologic, renal and hepatic function.
-
Phase 1 ONLY: Subject has had any prior anti-cancer therapy other than:
Hormonal, non-myelosuppressive, biologic, targeted, or immune therapy (must be completed ≥ 4 weeks prior to Cycle 1 Day -2).
One line of cytotoxic chemotherapy (must be completed ≥ 4 weeks prior to Cycle 1 Day -2).
Adjuvant/neoadjuvant radiotherapy (must be completed ≥ 12 months prior to Cycle 1 Day -2, with field not involving > 10% of bone marrow reserve).
-
Phase 2 ONLY: Subject has had any prior chemotherapy, radiotherapy, investigational anti-cancer agents or biologic therapy for the disease under study. Single non-target lesion irradiation with intent of symptom palliation is allowed if ≥ 4 weeks prior Cycle 1 Day -2.
-
Subject has current central nervous system (CNS) or leptomeningeal metastases or history of CNS or leptomeningeal metastases.
-
Subject has a history of seizures within 12 months of Cycle 1 Day-2 or diagnosed neurological condition placing subject at the increased risk of seizures.
-
Subject has received anti-cancer Chinese medicine or anti-cancer herbal remedies within 14 days prior to Cycle 1 Day-2.
-
Subject has had major surgery within 6 weeks prior to Cycle 1 Day-2 (subjects must have completely recovered from any previous surgery prior Cycle 1 Day-2).
-
Subject has clinically significant and uncontrolled major medical condition(s) including but not limited to:
- Uncontrolled nausea/vomiting/diarrhea;
- Active uncontrolled infection;
- History of hepatitis B (HBV) with surface antigen (HBsAg) positivity within 3 months prior to the date of informed consent for this study (if no test has been performed within 3 months, it must be done at screening);
- History of hepatitis C (HCV) with HCV ribonucleic acid (RNA) positivity within 3 months prior to the date of informed consent for this study (if no test has been performed within 3 months it must be done at screening);
- Symptomatic congestive heart failure (Yew York Heart Association [NYHA] class ≥ II);
- Unstable angina pectoris or cardiac arrhythmia (except atrial fibrillation);
- Psychiatric illness/social situation that would limit compliance with study requirements;
- Any other medical condition, which in the opinion of the Investigator, places the subject at an unacceptably high risk for toxicities.
-
The subject has a history of another active cancer within the past 3 years except cervical cancer in situ, in situ carcinoma of the bladder, squamous or basal cell carcinoma of the skin or another in situ cancer that is considered cured by the investigator (e.g., in situ prostate cancer, breast DCIS).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase 2: Veliparib + Carboplatin + Etoposide -> Placebo Placebo Participants will receive veliparib 240 mg in combination with carboplatin/etoposide for four to six 21-day cycles followed by placebo monotherapy continuous dosing (21-day cycles) until disease progression or unacceptable toxicity occurs. Phase 2: Placebo + Carboplatin + Etoposide -> Placebo Carboplatin Participants will receive placebo in combination with carboplatin/etoposide for four to six 21-day cycles followed by placebo monotherapy continuous dosing (21-day cycles) until disease progression or unacceptable toxicity occurs. Phase 2: Veliparib + Carboplatin + Etoposide -> Veliparib Etoposide Participants will receive veliparib 240 mg in combination with carboplatin/etoposide for four to six 21-day cycles followed by veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. Phase 2: Placebo + Carboplatin + Etoposide -> Placebo Placebo Participants will receive placebo in combination with carboplatin/etoposide for four to six 21-day cycles followed by placebo monotherapy continuous dosing (21-day cycles) until disease progression or unacceptable toxicity occurs. Phase 1: Veliparib + Carboplatin + Etoposide Veliparib Participants in Phase 1 will be sequentially assigned to ascending dose levels of veliparib in combination with carboplatin/etoposide for up to four 21-day cycles. Participants without evidence of disease progression will continue on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. Phase 1: Veliparib + Carboplatin + Etoposide Carboplatin Participants in Phase 1 will be sequentially assigned to ascending dose levels of veliparib in combination with carboplatin/etoposide for up to four 21-day cycles. Participants without evidence of disease progression will continue on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. Phase 1: Veliparib + Carboplatin + Etoposide Etoposide Participants in Phase 1 will be sequentially assigned to ascending dose levels of veliparib in combination with carboplatin/etoposide for up to four 21-day cycles. Participants without evidence of disease progression will continue on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. Phase 2: Veliparib + Carboplatin + Etoposide -> Veliparib Veliparib Participants will receive veliparib 240 mg in combination with carboplatin/etoposide for four to six 21-day cycles followed by veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. Phase 2: Veliparib + Carboplatin + Etoposide -> Veliparib Carboplatin Participants will receive veliparib 240 mg in combination with carboplatin/etoposide for four to six 21-day cycles followed by veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. Phase 2: Veliparib + Carboplatin + Etoposide -> Placebo Veliparib Participants will receive veliparib 240 mg in combination with carboplatin/etoposide for four to six 21-day cycles followed by placebo monotherapy continuous dosing (21-day cycles) until disease progression or unacceptable toxicity occurs. Phase 2: Veliparib + Carboplatin + Etoposide -> Placebo Carboplatin Participants will receive veliparib 240 mg in combination with carboplatin/etoposide for four to six 21-day cycles followed by placebo monotherapy continuous dosing (21-day cycles) until disease progression or unacceptable toxicity occurs. Phase 2: Veliparib + Carboplatin + Etoposide -> Placebo Etoposide Participants will receive veliparib 240 mg in combination with carboplatin/etoposide for four to six 21-day cycles followed by placebo monotherapy continuous dosing (21-day cycles) until disease progression or unacceptable toxicity occurs. Phase 2: Placebo + Carboplatin + Etoposide -> Placebo Etoposide Participants will receive placebo in combination with carboplatin/etoposide for four to six 21-day cycles followed by placebo monotherapy continuous dosing (21-day cycles) until disease progression or unacceptable toxicity occurs.
- Primary Outcome Measures
Name Time Method Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL.
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL.
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.
Phase 1: Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. The area under the plasma concentration-time curve from 0 to the last measurable concentration (24 hours) of etoposide was estimated using using non-compartmental methods.
Phase 1: Terminal Phase Elimination Half-life (t1/2) of Etoposide With and Without Veliparib Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. The terminal half-life of etoposide was estimated using using non-compartmental methods. Values reported represent the harmonic mean ± pseudo-standard deviation.
Phase 1: Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL. Dose normalized Cmax is calculated as Cmax / etoposide dose in mg/m².
Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. The area under the plasma concentration-time curve from 0 to the last measurable concentration (24 hours) of etoposide was estimated using using non-compartmental methods. Dose normalized AUC(0-t) is calculated as AUC(0-t) / etoposide dose in mg/m².
Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) Cycle 1 Day -2 to pre-dose on Cycle 2 Day 1 (23 days) A DLT was defined as any of the following drug-related toxicities, graded according to the Common Toxicity Criteria for Adverse Events (CTCAE), V.4.0:
1. Events associated with treatment delay \>14 days in initiating Cycle 2 therapy:
Grade 4 thrombocytopenia, neutropenia, or febrile neutropenia, or Grade 3 febrile neutropenia with fever for \> 7 days
2. Grade ≥ 3 non-hematologic toxicity with ≥ 2 grade increase from baseline and attributed to veliparib treatment, excluding nausea or vomiting for ≤ 48 hours or inadequately treated, electrolyte abnormalities resolving in ≤ 24 hours, hypersensitivity reactions or alopecia
3. Grade 2 non-hematologic toxicity of ≥ 2 grade increase from baseline, attributed to veliparib treatment requiring delay of \>14 days in initiation of Cycle 2
4. Any toxicity of ≥ 2-grade increase from baseline, attributed to veliparib and requiring a dose modification in Cycle 1 or omission of carboplatin, \>1 daily etoposide dose, or \>30% veliparib doses in Cycle 1Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration. Dose normalized AUC(0-12) is calculated as AUC(0-12) / veliparib dose in mg.
Phase 1: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods.
Phase 2: Progression-free Survival From randomization up to the date the 126th PFS event was reached; Median time on follow-up was 7.3, 7.1, and 8.9 months in each treatment group respectively. Progression-free survival (PFS) is defined as the time from the date of randomization to the date of earliest radiographic disease progression or death provided no radiographic disease progression occurred.
If a participant did not have an event of disease progression and had not died on or prior to the cutoff for PFS analysis, the participant's data was censored at the date of their last disease assessment or randomization date provided participant did not have any post-baseline disease assessment.
Disease assessments were performed using computed tomography according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
Progressive Disease (PD) was defined as at least a 20% increase in the size of target lesions and an absolute increase of at least 5 mm taking as reference the smallest lesion size recorded since the treatment started (baseline or after), or the appearance of one or more new lesions.Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods.
Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration.
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Etoposide With and Without Veliparib Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.
Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods. Dose normalized AUC(0-∞) is calculated as AUC(0-∞) / etoposide dose in mg/m².
Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL.
Dose normalized Cmax is calculated as Cmax / veliparib dose in mg.Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods. Dose normalized AUC(0-8) is calculated as AUC(0-8) / veliparib dose in mg.
- Secondary Outcome Measures
Name Time Method Phase 2: Overall Survival From randomization until the end of study; median time on follow-up was 10.0, 8.6, and 11.7 months in each treatment group respectively. Overall survival (OS) is defined as the time from the date of randomization to the date of death. If a participant did not die on or prior to the cut-off for OS analysis, the participant's data were censored at the date of their last known alive date, which is defined as the last date of the last survival follow-up visit, the start date of the last AE, the start date or end date of the last dose of any study drugs, the last lab and vital sign collection date, or the last disease assessment date, whichever occurred last.
Phase 1: Number of Participants With Adverse Events From first dose of any study drug to 30 days after the last dose; the median duration of treatment with veliparib across all groups in Phase 1 was 127.5 days. The intensity of each adverse event (AE) was assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0, and according to the following: Grade 1 (Mild): AE is transient and easily tolerated by the participant; Grade 2 (Moderate): AE causes the participant discomfort and interrupts the participant's usual activities; Grade 3/4 (Severe): The adverse event causes considerable interference with the participant's usual activities and may be incapacitating or life-threatening; Grade 5: Death.
Serious adverse events were those that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in congenital anomaly, or persistent or significant disability/incapacity.Phase 2: Objective Response Rate Tumor assessments were performed every 6 weeks for the first 30 weeks and every 9 weeks thereafter until disease progression; median time on follow-up was 7.3, 7.1, and 8.9 months in each group respectively. Objective response rate (ORR) is defined as the percentage of participants with objective response (confirmed) as assessed by the investigator using RECIST version 1.1. Objective response includes both complete response (CR) and partial response (PR). Response must be confirmed at a subsequent tumor assessment at least 28 days apart. Participants with no post-baseline confirmed response were counted as non-responders.
CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. No new lesions.
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and no new lesions.
Trial Locations
- Locations (62)
Vitkovicka nemocnice a. s. /ID# 149839
🇨🇿Ostrava, Czechia
Chonnam National University Hwasun Hospital /ID# 153188
🇰🇷Jeonnam, Korea, Republic of
Georgia Regents University /ID# 148567
🇺🇸Augusta, Georgia, United States
Gabrail Cancer Center Research /ID# 129216
🇺🇸Canton, Ohio, United States
Mayo Clinic - Scottsdale /ID# 129127
🇺🇸Scottsdale, Arizona, United States
Border Medical /ID# 157894
🇦🇺Wodonga, Victoria, Australia
Cliniques Universitaires Saint Luc /ID# 151024
🇧🇪Woluwe-Saint-Lambert, Bruxelles-Capitale, Belgium
Jasz-Nagykun-Szolnok Megyei /ID# 155090
🇭🇺Szolnok, Hungary
Oncocenter Oncologie Clinica S /ID# 151694
🇷🇴Timisoara, Timis, Romania
University of Texas MD Anderson Cancer Center /ID# 129213
🇺🇸Houston, Texas, United States
Univ of Colorado Cancer Center /ID# 129220
🇺🇸Aurora, Colorado, United States
Emory University Hospital /ID# 141682
🇺🇸Atlanta, Georgia, United States
Allegheny General Hospital /ID# 147328
🇺🇸Pittsburgh, Pennsylvania, United States
Northwestern University Feinberg School of Medicine /ID# 137088
🇺🇸Chicago, Illinois, United States
Herbert Herman Cancer Center /ID# 167020
🇺🇸Lansing, Michigan, United States
The Townsville Hospital /ID# 155499
🇦🇺Douglas, Queensland, Australia
Peninsula & South Eastern Haem /ID# 155497
🇦🇺Frankston, Victoria, Australia
Southern Medical Day Care Ctr /ID# 155498
🇦🇺Wollongong, New South Wales, Australia
CHU de Liege /ID# 151025
🇧🇪Liège, Liege, Belgium
C.H.U.de Mons Borinage /ID# 151023
🇧🇪Mons, Belgium
UZ Antwerp /ID# 151026
🇧🇪Edegem, Belgium
CHU UCL Namur /ID# 151022
🇧🇪Namur, Belgium
Juravinski Cancer Clinic /ID# 152543
🇨🇦Hamilton, Ontario, Canada
University of Calgary /ID# 152544
🇨🇦Calgary, Alberta, Canada
Cross Cancer Institute /ID# 132883
🇨🇦Edmonton, Alberta, Canada
Hopital du Sacre Coeur Montreal /ID# 154436
🇨🇦Montreal, Quebec, Canada
Nemocnice Na Plesi s.r.o. /ID# 149825
🇨🇿Nová Ves pod Pleší, Pribram, Czechia
Nemocnice Novy Jicin /ID# 149838
🇨🇿Nový Jičín 1, Czechia
Multiscan s.r.o. /ID# 150887
🇨🇿Pardubice, Czechia
CHU Dupuytren /ID# 153622
🇫🇷Limoges CEDEX 1, Franche-Comte, France
Centre Hospitalier Le Mans /ID# 158103
🇫🇷Le Mans CEDEX 9, Sarthe, France
Orszagos Koranyi Pulmonologiai Intezet /ID# 151351
🇭🇺Budapest XII, Budapest, Hungary
Centre Hosp Intercommunal de Creteil /ID# 157970
🇫🇷Creteil, Val-de-Marne, France
Petz Aladar Megyei Oktato Korh /ID# 155352
🇭🇺Gyor, Hungary
Markusovszky Egyetemi Oktatókórház /ID# 158806
🇭🇺Szombathely, Vas, Hungary
Debreceni Egyetem Klinikai Központ /ID# 151354
🇭🇺Debrecen, Hungary
Matrahaza Gyogyintezet /ID# 151355
🇭🇺Kékesteto, Hungary
Veszprem Megyei Tudogyogyintez /ID# 158807
🇭🇺Farkasgyepu, Hungary
Fejer Megyei Szent Gyorgy Korh /ID# 151352
🇭🇺Szekesfehervar, Hungary
Chungbuk National Univ Hosp /ID# 153186
🇰🇷Cheongju, Korea, Republic of
Dong-A University Hospital /ID# 153187
🇰🇷Busan, Busan Gwang Yeogsi, Korea, Republic of
Universitair Medisch Centrum Groningen /ID# 131252
🇳🇱Groningen, Netherlands
Ziekenhuis St. Jansdal /ID# 151974
🇳🇱Harderwijk, Netherlands
Asan Medical Center /ID# 153185
🇰🇷Seoul, Korea, Republic of
Erasmus Medisch Centrum /ID# 131251
🇳🇱Rotterdam, Netherlands
Isala /ID# 151975
🇳🇱Zwolle, Netherlands
Atrium-Orbis Zuyderland Medisch Centrum /ID# 149830
🇳🇱Heerlen, Netherlands
S.C. Centrul de Oncologie Sf. Nectarie S.R.L. /ID# 161137
🇷🇴Craiova, Dolj, Romania
S.C. Radiotherapy Center Cluj /ID# 165137
🇷🇴Cluj, Romania
NN Blokhin Russian Cancer /ID# 152329
🇷🇺Moscow, Moskva, Russian Federation
Univercity Headache Clynic,LTD /ID# 161708
🇷🇺Moscow, Russian Federation
Belgorod Oncology Dispensary /ID# 152330
🇷🇺Belgorod, Russian Federation
Sverdlovsk Regional Oncology Center Dispensary /ID# 152328
🇷🇺Ekaterinburg, Sverdlovskaya Oblast, Russian Federation
Murmansk RCH P.A. Bayandina /ID# 152331
🇷🇺Murmansk, Russian Federation
Ogarev Mordovia State Univ /ID# 152327
🇷🇺Saransk, Russian Federation
Road Hospital Open Joint Stock Company Russian Railways /ID# 152731
🇷🇺St. Petersburg, Russian Federation
Hospital Stanta Creu i Sant Pau /ID# 151254
🇪🇸Barcelona, Spain
Hosp Univ Quiron Dexues /ID# 130302
🇪🇸Barcelona, Spain
Hosp Univ Puerta de Hierro Maj /ID# 151253
🇪🇸Majadahonda, Spain
Hosp Univ Madrid Sanchinarro /ID# 130301
🇪🇸Madrid, Spain
Hospital Universitario Gregori /ID# 164982
🇪🇸Madrid, Spain
Hosp Univ 12 de Octubre /ID# 151252
🇪🇸Madrid, Spain