Synopsis Ergebnisbericht

Report-ID: FLOT65+ Ergebnisbericht 05.11.13 (revised 05.02.2019)

1. Name of Sponsor/Company Krankenhaus Nordwest GmbH, Steinbacher Hohl 2-26, 60488 Frankfurt/M

2. Name of Finished Product Eloxatin Taxotere Further components not applicable; 4 components with marketing authorization in Germany (partially for other entities), partially available as generics, were combined for therapy optimization.

3. Name of Active Substance Oxaliplatin Docetaxel Folinic acid (Calciumfolinate) 5-Fluorouracil

4. Individual Study Table: Referring to Part of the Dossier Not applicable

5. Title of Study Multizentrische randomisierte Phase II Studie zur Therapie des fortgeschrittenen Magenkarzinoms oder Adenokarzinoms des Ösophagogastralen Überganges bei Patienten über 65 Jahre unter besonderer Beachtung der Lebensqualität und des pharmakogenetischen Risikoprofils (A multicenter, randomised phase II trial on the therapy of advanced gastric cancer or adenocarcinoma of the esophagogastric junction in patients older than 65 years with special regard on quality of life and the pharmacogenetic risk profile - FLOT65+) First valid protocol: Version 1 01.03.07 Amendments: Version 2 12.09.07: inclusion of patients >60 years but with biological age of >65, addition of two more questionnaires for assessment of quality of life; Approval of IRB: 31.10.2007, approval of BfArM: 30.10.2007. Version 3 16.06.08: no. of enrolled patients increased, inclusion criterion for patients >60 years further differentiated (estimation of biological age by IADL form); Approval of IRB: 14.07.2008, approval of BfArM: 18.07.2008.

6. Investigators (principal investigators, alphabetical) 7. Study centre(s)

Dr. med. Wolfgang Blau Dr. med. Arne Brecht Klinikum Offenbach GmbH Klinikum Darmstadt Medizinische Klinik II Med. Klinik V Starkenburgring 66 Hämatologie und Onkologie 63069 Offenbach Grafenstr. 9 64283 Darmstadt Prof. Dr. Carsten Bokemeyer Abteilung für Hämatologie / Onkologie Prof. Dr. Karel Caca Universitätskrankenhaus Eppendorf Klinikum Ludwigsburg Martinistr. 52 Med. Klinik I 20246 Hamburg Posilipostr. 4 71640 Ludwigsburg

page 1 of 8 Prof. Dr. Michael Clemens Prof. Dr. Volker Heinemann Innere Medizin I Medizinische Klinik und Poliklinik III Klinikum Mutterhaus d. Borromäerinnen Klinikum Großhadern Feldstr. 16 Marchioninistr. 15 54290 Trier 81377 München

Dr. Beate Dargel Prof. Dr. Heinz-Gert Höffkes Harz-Klinikum Wernigerode GmbH Tumorklinik Abt. Hämatologie-Onkologie Klinikum Fulda gAG Ilsenburger Str. 15 Pacelliallee 4 38855 Wernigerode 36043 Fulda

Prof. Dr. med. Hans Günter Derigs Dr. Ralf Hofheinz Städtische Kliniken Höchst Uniklinik Mannheim III. Medizinische Klinik Onkologisches Zentrum Hämatologie und Onkologie 3. Medizinische Klinik Gotenstr. 6-8 Theodor Kutzer Ufer 1-3 65929 Frankfurt am Main 68167 Mannheim

Dr. med. Ludwig Fischer von Weikersthal Prof. Dr. med. Stephan Hollerbach Hämatologie/ Internistische Onkologie Allgemeines Krankenhaus Celle MVZ Gesundheitszentrum St. Marien GmbH Klinik für Gastroenterologie Mariahilfbergweg 7 Siemensplatz 4 92224 Amberg 29223 Celle

Dr. med. Markus Fritz PD Dr. med. Nils Homann Krankenhaus Bad Cannstatt Universitätsklinikum Schleswig-Holstein Prießnitzweg 24 Campus Lübeck 70374 Stuttgart Med. Klinik I Ratzeburger Allee 160 Dr. Stefan Fuxius 23538 Lübeck Gemeinschaftspraxis Dr. Karcher/Dr. Fuxius Kurfürsten Anlage 34 Dr. Jutta Hübner 69115 Heidelberg Gemeinschaftspraxis am Rhönplatz Standort onkologische Therapie PD Dr. Martin Görner Wigandstr. 1 Städtische Kliniken Bielefeld 34131 Kassel Klinik für Hämatologie und Onkologie Teutoburger Str. 50 Dr. Gerald Illerhaus 33604 Bielefeld Innere Medizin, Hämatologie/Onkologie Universitätsklinikum Freiburg PD Dr. Johannes Grossmann Hugstetter Str. 55 Ev. Krankenhaus Bethesda 79106 Freiburg Ludwig Weber Str. 15 41061 Mönchengladbach Prof. Dr. Elke Jäger Dr. Salah-Eddin Al-Batran (LKP nach AMG) Prof. Dr. Jörg T. Hartmann Krankenhaus Nordwest Internistische Onkologie II. Medizinische Klinik Universitätsklinikum der Eberhard-Karls- Steinbacher Hohl 2-26 Universität 60488 Frankfurt am Main Medizinische Klinik II Otfried-Müller-Str. 10 Dr. Andreas Köhler 72076 Tübingen Praxis für Hämatologie und Onkologie Fachärztezentrum an der Asklepios Klinik Röntgenstr. 6 63225 Langen

page 2 of 8 Prof. Dr. Frank Kullmann Klinikum Weiden Dr. Georg C. Schliesser Med. Klinik I Praxis für Hämatologie / Onkologie Söllnerstr. 16 Wingertshecke 6 92637 Weiden 35392 Giessen

Prof. Dr. Uwe Martens PD Dr. med. Gernot Seipelt Medizinische Klinik III Gemeinschaftspraxis für Hämatologie und SLK-Kliniken GmbH Internistische Onkologie Am Gesundbrunnen 20-26 Kronberger Straße 38 74078 Heilbronn 65812 Bad Soden

PD Dr. Markus Möhler Dr. Jan Stöhlmacher I. Med. Klinik und Poliklinik Universitätsklinik Dresden Johannes-Gutenberg Universität Mainz Fetscherstr. 74 Langenbeckstr.1 01307 Dresden 55101 Mainz Dr. Frank Strohbach Prof. Dr. Andreas Neubauer Medizinisches Versorgungszentrum Dr. Jorge Riera Ärzteforum Seestraße Zentrum für Innere Medizin Seestraße 64 Hämatologie / Onkologie 13347 Berlin Baldingerstraße 35043 Marburg PD Dr. med. Jörg Trojan Med. Klinik I PD Dr. Thomas Neuhaus Klinikum der Johann-Wolfgang-Goethe St. Vincenz-Krankenhaus Limburg Universität Abteilung Hämatologie und internistische Theodor-Stern-Kai 7 Onkologie 60590 Frankfurt Auf dem Schafsberg 65549 Limburg Dr. Manfred Welslau Gemeinschaftspraxis Dr. Klausmann/ Dr. Dr. Christoph Plöger Welslau Mannheimer Onkologie Praxis Elisenstraße 28 Dres. Brust/Plöger/Hensel/Schuster 63739 Aschaffenburg Q 5, 14 – 22 68161 Mannheim

Dr. Volker Rethwisch Klinik für Hämatologie/Onkologie Kath. Krankenhaus Hagen Betriebsstätte St. Marienhospital Bergstr. 56 58095 Hagen

8. Publication (reference) Al-Batran S-E, Pauligk C, Homann N, Hartmann JT, Moehler M, Probst S, Rethwisch V, Stoehlmacher-Williams J, Prasnikar N, Hollerbach S, Bokemeyer C, Mahlberg R, Hofheinz RD, Luley K, Kullmann F, Jäger E. The Feasibility of Triple-Drug Chemotherapy Combination in Older Adult Patients with Esophagogastric Cancer: a Randomized Trial of the Arbeitsgemeinschaft Internistische Onkologie (FLOT65+). Eur J Cancer. 2013 Mar;49(4):835-42

page 3 of 8 9. Studied period (years): date of first enrolment, date of last completed 2007-2010

10. Phase of development Phase II

11. Objectives

Primary Responserate Secondary - validation of a pharmacogenetic risk-profile for patients with advanced gastric cancer in platin/docetaxel-containing first-line therapy - evaluation of life quality - safety and tolerability - time to treatment failure - time to progression - overall survival

12. Methodology Patients aged 65 years or older with locally advanced, potentially operable or metastatic adenocarcinoma of the stomach or esophagogastric junction were stratified for site, metastatic or locally advanced disease, liver metastases (yes vs no), ECOG (0 or 1 vs 2) and pharmacogenetical risk profile (high vs low risk) and randomized to infusional 5-FU, leucovorin, and oxaliplatin without (FLO) or with docetaxel 50 mg/m2 (FLOT) every 2 weeks. Change of the chemotherapy schema before progression of the disease was not allowed. Patients were seen for clinical visits at baseline/screening and then every two weeks for safety assessment and therapy application until disease progression or discontinuation of trial therapy for other reasons. Patients were assessed for adverse events by non-directive questioning at each visit during the study. Adverse events also were detected when they were volunteered by the patient during or between visits or through physical examination, laboratory test, or other assessments. Adverse events were documented according to the CTC AE version 3. Additionally, relationship of an adverse event to the investigational agent was determined by the Investigator. Radiological tumor assessment (CT, MRI) and evaluation of quality of life (via questionnaires EORTC-Q30-, EORTC STO22- and LQMN1) was performed at baseline and then every 2 months until progression of the disease. Post- study follow-up was completed after 6 months for survival and tumor assessment. 2ml EDTA blood was analysed initially for pharmacogenetics risk profile (stratification parameter). Patients in the FLO- Arm who had progressive disease were recommended to continue with monotherapy of weekly docetaxel (30-35mg/m2 weekly for 4 weeks, followed by 2 weeks without therapy, qw6) if general condition was acceptable.

13. Number of patients (planned and analysed) Planned: 70 patients per Arm, 140 total. Analysed: 143 patients.

14. Diagnosis and main criteria for inclusion - metastatic, locally advanced or refractory gastric cancer or adenocarcinoma of the esophagogastric junction - no previous chemotherapy in metastatic state - patients (male and female) older than 65 years - ECOG 0, 1 or 2 - Leucocytes > 3000/µl - Thrombocytes >100000/µl - Creatinine serum level < 1,5x ULN or Creatinine clearance > 40 ml/min - signed informed consent

page 4 of 8 15. Test product, dose and mode of administration, batch number Patients received oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and docetaxel 50 mg/m2, each as an I.V. infusion followed by 5-FU 2600 mg/m2 as a 24-h continuous infusion (FLOT) or the same regimen without docetaxel (FLO). Treatment was administered on day one of two weekly cycles. Batch number: not applicable (market approved substances/generics)

16. Duration of treatment Patients received 8 cycles of FLOT or FLO, which could be extended to a maximum of 12 cycles upon investigator’s decision. Treatment in both arms was continued until disease progression, unacceptable toxicity, patient’s refusal, physician’s decision, or until 8 cycles (or 12 cycles upon investigator’s decision) were completed.

17. Reference therapy, dose and mode of administration, batch number Not applicable

18. Criteria for evaluation: Efficacy, Safety For the assessment of toxicity, patients were interviewed during regular clinical visits and were evaluated by physical examination and laboratory tests, including differential blood count, blood chemistry, and urine analysis, every two weeks. Toxic effects were graded according to NCI-CTC version 3.0. Peripheral sensitive neuropathy was graded according to an oxaliplatin-specific scale. Safety analyses were done in the population of all patients who received at least one dose of combination therapy.

Response rates were analysed within the intent-to-treat population. Tumor responses were classified according to the World Health Organization (WHO) criteria to ensure comparability to previous studies. For patients whose response can be evaluated only by endoscopy, specific remission criteria defined in the protocol were used: complete response: disappearance of all tumor lesions; partial response: estimated reduction oft he tumor >50%; no change: no change which complies with the other criteria; progressive disease: estimated increase of tumor by ≥ 25% and/or new lesions. Computed tomography scans of the reference lesions were carried out within 3 weeks before the start of treatment and were repeated every eight weeks. Patients who discontinued the study without progression were evaluated every 2 months. Patients were followed for at least 6 months after end of treatment.

19. Statistical methods Tolerability and feasibility were defined as per group differences in toxic effects, serious adverse events, treatment durations, treatment withdrawals or discontinuations for toxicity or patient’s request, and the proportions of patients with a ≥ 10-point change of QoL global health status at eight weeks compared to baseline.

Based on historical response rates observed for FLO (32%) and FLOT (58%), we assumed response rates of 30% and 50% with FLO and FLOT, respectively. The resulting sample size was 140 patients, using an 80% power at one-sided significance level of 0.05. Further endpoints were Progression-free survival (PFS) and Overall survival (OS). PFS was measured from the date of randomization until disease progression or death of any cause. OS was measured from date of randomization until death of any cause.

20. Summary – Conclusions: Efficacy Results, Safety Results, Conclusion 143 (FLO, 71; FLOT, 72) patients with a median age of 70 years were enrolled. The triple combination was associated with more treatment-related NCI-CTC grade 3/4 adverse events (FLOT, 81.9%; FLO, 38.6%; P<.001) and more patients experiencing a ≥10-points deterioration of EORTC QoL global health status scores (FLOT, 47.5%; FLO 20.5%; p=.011). The triple combination was associated with more alopecia (P<.001), neutropenia (P<.001), leukopenia (P<.001), diarrhea (P=.006), and nausea (P=.029).

page 5 of 8 Table 1: Main Toxicities According to the National Cancer Institute Common Toxicity Criteria Version 3.0* Grade 1 or 2 Grade 3 or 4 FLOT (n=72) FLO (n=70) FLOT (n=72) FLO (n=70) Toxicity No. % No. % No. % No. % P-value§ Hematologic toxicity Anemia 60 83.3 60 85.7 8 11.1 3 4.3 0.210 Thrombopenia 31 43.1 28 40.0 2 2.8 2 2.9 1.000 Leukopenia 32 44.4 25 35.7 21 29.2 4 5.7 <0.001 Neutropenia 10 13.9 18 25.7 38 52.8 9 12.9 <0.001 Fever 15 20.8 16 22.9 1 1.4 0 0.0 1.000 Infection 12 16.7 13 18.6 13 18.1 7 10.0 0.229 Neurosensory toxicity Sensorium 38 52.8 47 67.1 8 11.6 14 19.4 0.248 Gastrointestinal toxicity Nausea 44 61.1 43 61.4 15 20.8 5 7.3 0.029 Diarrheaǂ 43 59.7 31 44.3 6 8.3 1 1.5 0.116 Vomiting 32 44.4 18 25.7 3 4.2 2 2.9 0.100 Mucositis 23 31.9 22 31.4 7 9.7 2 2.9 0.166 Constipation 22 30.6 22 31.4 0 0.0 2 2.9 0.238 Lab abnormalities ALP 24 33.3 27 38.6 1 1.4 2 2.9 0.617 Creatinine 15 20.8 21 30.0 0 0.0 0 0.0 0.427 ALT 23 31.9 20 28.6 0 0.0 0 0.0 0.888 AST 32 44.4 17 24.3 0 0.0 1 1.5 0.486 Other toxicities Fatigue 47 65.3 47 67.1 8 11.1 5 7.3 0.563 Pain 32 44.4 30 42.9 8 11.1 8 11.6 1.000 Alopecia 54 75.0 15 21.4 NA NA NA NA <0.001 Fluid retention 17 23.6 10 14.3 1 1.4 3 4.4 0.362 Allergy 5 6.9 5 7.1 1 1.4 1 1.5 1.000 *Data for events (maximum grade per patient) with suspected relation to the study drugs. §Fisher’s exact test was used. With the exception of alopecia, p-values are related to the groupings grade 0-2 vs. grade 3-4 for FLOT vs. FLO. ǂP-value for the comparison of all grade diarrhea with FLOT vs. FLO is P=.006 Abbreviations: FLOT, 5-FU, leucovorin, oxaliplatin, docetaxel; FLO, 5-FU, leucovorin, oxaliplatin; NA, not applicable; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST aspartate aminotransferase

Reasons for treatment discontinuation were comparable in the FLOT and FLO arms, and were disease progression (21.1% vs. 26.0%), death (9.8% vs 8.6%, all but one due to disease progression), toxicity or patient´s request (23.8 vs. 20.1%), and other reasons (11.2% vs. 11.5%). No differences were observed in treatment duration and discontinuation due to toxicity, cumulative doses or toxic deaths between arms. However, in the subgroup of patients aged ≥ 70 years, more patients discontinued treatment for toxicity in the FLOT arm (FLOT, 20.6%; FLO, 7.5%).

The triple combination improved response rates and progression-free survival in the locally advanced subgroup and in the subgroup of patients aged between 65 and 70 years but not in the metastatic group or in patients aged 70 years and older. In the ITT population, there was a statistically significant improvement in RR in favor of FLOT (48.6%; 95% CI: 36.65% - 60.69%) vs. FLO (28.17%, 95% CI: 18.13% - 40.1%; 2-sided P=.016). In the FLOT arm, 4 patients (5.6%) had a CR and 31 patients (43%) had a PR. In the FLO arm, no patients had a CR and 20 patients (28.17%) had PR. Stable disease was achieved in 27 (37.5%) and 36 patients (50.7%), respectively, and progressive disease in 6 patients in each arm (8.5% and 8.3%,

page 6 of 8 respectively). Four (5.6%) and 9 (12.7%) patients were not evaluable for response in the FLOT and FLO arm, respectively. In the subgroup analyses, FLOT was associated with improved RR in patients aged <70 years (FLOT, 63.2%, 95% CI: 45.99% - 78.19%; FLO, 23.3%, 95% CI: 9.93% - 42.28%; p=.001) or patients with locally advanced disease (FLOT, 59.1%, 95% CI: 36.35% - 79.29%; FLO, 18.2%, 95% CI: 5.19% - 40.28%; p=.012), while no difference regarding RR between arms was found in patients aged ≥70 years (FLOT, 32.4%; FLO, 31.7; p=1.0) or patients with metastatic disease (FLOT, 44%; FLO, 32.7%; p=.303). Patients treated with FLOT showed a trend towards longer median PFS (9.0 months, 95% CI 7.3 to 11.8) compared to patients in the FLO group (7.1 months, 95% CI, 5.2 to 10.1; P=.079) (Figure 1a), and there was no significant difference in median OS between the two groups (FLOT, 17.3 months; 95% CI, 12.7 to undetermined; FLO, 14.5 months; 95% CI, 11.7 to 21.1 months; P=.39; Figure 1b). Similar to the RR, FLOT was associated with longer median PFS in patients with locally advanced disease (p=.019; Figure 1c) and in patients aged <70 years (p=.05; Figure 1e), while no between group differences in PFS were observed in patients with metastatic disease (p=.43; Figure 1d) or in patients aged ≥70 years (p=.65; Figure 1f).

page 7 of 8 1.0

FLO 1.0 FLO Median: 7.1 months Median: 14.5 months

FLOT FLOT 0.8 Median: 9.0 months 0.8 Median: 17.3 months

P=0.0786 P=0.39

0.6

0.4

Probability

0.2 0.2

A B

0.0 0.0 0 6 12 18 24 0 6 12 18 24

Months Months 1.0 1.0 FLO FLO Median: 10.3 months Median: 6.0 months FLOT

FLOT 0.8 0.8 Median: 24.2 months P=0.019 Median: 7.3 months

P=0.43

0.6

0.4

Probability

0.2 0.2

C D

0.0 0.0 0 6 12 18 24 0 6 12 18 24 Months Months

FLO FLO

1.0 1.0 Median: 7.1 months Median: 7.5 months

FLOT FLOT 0.8 Median: 10.6 months 0.8 Median: 7.6 months

P=0.050 P=0.65

0.6

0.4

Probability

0.2 0.2

E F

0.0 0.0 0 6 12 18 24 0 6 12 18 24 Months Months

Figure 1: Kaplan-Meier analysis of (A) progression-free survival and (B) overall survival in the ITT population (n=143), and of progression-free survival in patients with locally advanced disease, n=44 (C) versus metastatic disease, n=99 (D) and patients aged <70 years, n=68 (E) versus ≥ 70 years, n=75 (F).

Summary: The triple-drug chemotherapy was feasible in elderly patients with esophagogastric cancer. However, toxicity was significantly increased and QoL deteriorated in a relevant proportion of patients.

21. Date of report 05.11.2013 (revised 05.02.2019)

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