1. No category

Supplementary appendix
This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6
inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line
treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer
(PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2014; published online
Dec 16. http://dx.doi.org/10.1016/S1470-2045(14)71159-3.
Site
St. Vincent’s University Hospital Medical
Oncology, Dublin, Ireland
Orszagos Onkolagiai Intezet, Budapest,
Hungary
Szent Margit Korhaz Onkologia, Budapest,
Hungary
University of California Los Angeles, Los
Angeles, CA, USA
Dnipropetrovsk Medical Academy, City
Multiple-Discipline Clinical Hospital #4,
Dnipropetrovsk, Ukraine
Municipal Treatment and Prophylactic
Institution, Donetsk, Ukraine
Technical University of Munich, Munich,
Germany
Comprehensive Blood and Cancer Center,
Bakersfield, CA, USA
Petz Aladar Megyei Oktato Korhaz, Gyor,
Hungary
University Hospital Mainz, Mainz,
Germany
Lviv State Oncologic Regional Treatment
and Diagnostic Center, Lviv, Ukraine
Comprehensive Cancer Centers of Nevada,
Las Vegas, NV, USA
Kyiv City Clinical Oncologic Center, Kyiv,
Ukraine
Frauenklinik von Roten Kreuz, Munich,
Germany
ICO-Hospitalet Servicio de Oncologia
Medica, Barcelona, Spain
Pyatigorsk Oncology Center, Pyatigorsk,
Russian Federation
National Cancer Center, South Korea
Cancer Care Associates Medical Group,
Redondo Beach, CA, USA
Central Hematology Oncology Medical
Group Inc., Alhambra, CA, USA
Gwinnett Hospital System, Lawrenceville,
GA, USA
Divisione Oncologia Medica Istituto
Scientifico Romagnolo, Meldola, Italy
Mater Misericordiae University Hospital,
Principal investigator
John Crown
Number of patients
randomly assigned
13
Istvan Lang
9
Katalin Boer
8
Richard Finn
7
Igor Bondarenko
7
Sergey Kulyk
7
Johannes Ettl
6
Ravindranath Patel
5
Tamas Pinter
5
Marcus Schmidt
5
Yaroslav Shparyk
5
Anu Thummala
5
Nataliya Voytko
5
Claus Hanusch
4
Juan Miguel Gil Gil
4
Vladimir Vladimirov
4
Jungsil Ro
David Chan
4
3
Eddie Hu
3
Aldemar Montero
3
Dino Amadori
3
John McCaffrey
3
1
Dublin, Ireland
BC Cancer Agency, Vancouver, Canada
Mutterhaus der Borromaeerinnen, Trier,
Germany
Hospital Universitario Virgen Del Rocio
Servicio de Oncologia, Sevilla, Spain
Centro Oncologico de Galicia Oncologia
Medica, La Coruna, Spain
Hospital Universitario, Madrid, Spain
Republican Clinical Oncology Dispensary
of the Ministry of Health of Bashkortostan,
Ufa, Russian Federation
CSSS Champlain – Charles Le Moyne,
Greenfield Park, Canada
Central Coast Medical Oncology
Corporation, Santa Maria, CA, USA
Frauenaerzte Pruener Gang Abts & Partner,
Kiel, Germany
Universitaetsklinik und Poliklinik fuer
Gynaekologie, Halle, Germany
Onkolog Gemeinschaftspraxis, Munich,
Germany
State Healthcare Institution, Samara,
Russian Federation
Hospital General Universitario, Barcelona,
Spain
St. Jude Heritage Healthcare Virginia K.
Crosson Cancer Center, Fullerton, CA, USA
Szabolcs-Szatmar-Bereg Megyei Korhazak
es Egyetemi Oktatokorhaz Onkoradiologia,
Nyiregyhaza, Hungary
Centre Paul Papin, CRLCC, France
Markusovszky Egyetemi Oktatokorhaz,
Szombathely, Hungary
CHD Vendee Service de Medecine Interne
Onco-Hematologie, La Roche-sur-Yon,
France
St. James’s Hospital, Dublin, Ireland
Bon Secours Hospital, Cork, Ireland
Virginia Cancer Specialists, Fairfax, VA,
USA
Borsod-Abauj-Zemplen Megyei Korhaz es
Egyetemi Oktato Korhaz, Miskolc, Hungary
Fovarosi Onkormanyzat Uzsoki Utcai
Korhaz, Budapest, Hungary
Gemeinschaftspraxis, Onkologischer
Howard Lim
Michael Clemens
3
3
Manuel Ruiz Borrego
3
Manuel Ramos Vazquez
3
Eva Maria Ciruelos Gil
Oleg Lipatov
3
3
Pierre Desjardins
2
Robert Dichmann
2
Volker Schulz
2
Christoph Thomssen
2
Wolfgang Abenhardt
2
Mikhail Kopp
2
Meritxell Bellet Ezquerra
2
William Lawler
1
Jozsef Erfan
1
Patrick Soulie
Miklos Wenczl
1
1
Frank Priou
1
Michael Kennedy
Conleth Murphy
Nicholas Robert
1
1
1
Agnes Weber
1
Laszlo Landherr
1
Andreas Kirsch
1
2
Schwerpunkt, Berlin, Germany
Eastleigh Breast Care Centre, Pretoria,
South Africa
Russian Oncological Research Center,
Moscow, Russian Federation
Seoul National University, Seoul, South
Korea
Texas Oncology-Baylor Charles A.
Sammons Cancer Center, Dallas, TX, USA
Maria Coccia-Portugal
1
Sergei Tjulandin
1
Seock-Ah Im
1
Joanne Blum
1
3
Recommended dose reductions for palbociclib (PD 0332991) are detailed in supplementary table
1. Doses may be held as needed for toxic effect resolution during a cycle. Doses omitted for
toxic effects are not replaced or restored within the same cycle. Patients should instead resume
palbociclib at the next planned treatment cycle.
Supplementary table 1: Recommended palbociclib (PD 0332991) dose modifications based
on worst treatment-related toxic effect in the previous cycle
New cycle
Grade 4 neutropenia
↓ 1 dose level
Grade 4 thrombocytopenia
↓ 1 dose level
Grade 3 neutropenia associated with a documented infection or
fever ≥38.5°C
Grade ≥3 non-haematological toxic effect (includes nausea,
vomiting, diarrhea, and hypertension only if persisting despite
maximal medical treatment)
Delay by >1 week in receiving the next scheduled dose of either
study treatment due to persisting treatment-related toxicities
(platelet count <50,000/µL; ANC <1,000/µL; nonhaematological toxic effects of grade ≥3 severity) (phase 1 only)
Inability to deliver at least 80% of the planned palbociclib (PD
0332991) or letrozole doses during cycle 2 due to adverse
events possibly related to study treatment (phase 1 only)
↓ 1 dose level
↓ 1 dose level
If recovery occurs within a maximum of
2 weeks, continue and ↓ 1 dose level
↓ 1 dose level
Supplementary table 2: Dose levels
Dose level
1
-1
-2
Palbociclib for 3 out of 4 weeks
(3/1 schedule)
125 mg/d
100 mg/d
75 mg/d*
Letrozole on a continuous
regimen
2.5 mg/d
2.5 mg/d
2.5 mg/d
* Palbociclib dose de-escalation below 75 mg/d is not allowed.
Retreatment criteria
A new cycle of treatment with palbociclib may begin only if:
•
ANC ≥1,000/µL.
•
Platelets count ≥50,000/µL.
•
Non-haematological toxic effects have returned to baseline or grade ≤1 severity (or, at the
investigator discretion, grade ≤2 if not considered a safety risk for the patient).
4
If these conditions are not met, letrozole treatment may be continued but treatment with
palbociclib must be delayed by 1 week. If, after a 1-week delay, all toxic effects have recovered
within the limits described above, treatment with palbociclib can be resumed.
If the patient has not recovered after 2 weeks (including the scheduled 1-week off treatment
period within a cycle), treatment with palbociclib may be permanently discontinued if the toxic
effect is considered treatment-related after discussion with the funder.
Letrozole is administered in a continuous regimen and therefore no retreatment criteria apply.
5