ML29452

Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest

Steinbacher Hohl 2-26, Frankfurt, Germany, 60488

Dr. Claudia Pauligk, Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, petrarca@ikf-khnw.de

Dr. Claudia Pauligk, Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, petrarca@ikf-khnw.de

No

No

No

Final

26 Nov 2021

Yes

17 Jan 2020

Yes

17 Jul 2020

No

The aim of this trial was to evaluate the efficacy and safety of the perioperative treatment of patients with HER-2 expressing adenocarcinoma of the stomach and gastroesophageal junctions with the anti-Her-2 antibody pertuzumab (Perjeta®) in addition to the anti-Her-2 antibody trastuzumab (Herceptin®) plus FLOT chemotherapy versus patients treated with FLOT alone (Phase II). The primary efficacy objective was the rate of patholocigal complete responses. Secondary efficacy endpoints were disease-free survival, overall survival and R0 resection rate.

This clinical study was designed and shall be implemented and reported in accordance with the protocol, the AMG (Arzneimittelgesetz), the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki. The trial was authorized/approved by the competent authority (Paul-Ehrlich-Institut, PEI) and the competent ethics committee responsible for the trial (“federführende Ethikkommission”). Before recruitment into the clinical trial, each patient was informed that participation in the study is completely voluntary, and that he or she may withdraw his or her participation in the trial at any time without any declaration of reasons, which will not lead to any disadvantage for the respective patient. The eligibility of a new patient was determined by the local investigator during regular clinical visits. The examinations for the study and the inclusion of the patient were done after detailed written and oral education about aims, methods, anticipated benefits and potential hazards of the study by use of the informed consent forms and after given written consent of the patient. Safety of FLOT/Herceptin/Perjeta was monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported. An independent data safety and monitoring board (DSMB) was responsible for assessment of reports summarizing safety data or study results and gave recommendations for planned protocol.

30 Jun 2016

No

No

Germany: 81

81

81

0

0

0

0

0

0

53

28

0

Overall trial (overall period)

Randomised - controlled

Yes

Docetaxel

Concentrate and solvent for solution for injection/infusion, Concentrate for solution for infusion

Infusion , Intravenous use

Administration 50 mg/m², iv over 1 h d1, d15, d29, d43 pre- and post-operative

Oxaliplatin

Concentrate for solution for infusion

Infusion , Intravenous use

85 mg/m², iv over 2-6 h; d1, d15, d29, d43 pre- and post-operative

Leucovorin

folinic acid

Solution for injection/infusion, Powder for solution for injection/infusion

Infusion , Injection , Intramuscular and intravenous use

200 mg/m², iv, d1, d15, d29, d43 pre- and post-operative

5-Fluorouracil

5-FU

Solution for injection/infusion, Concentrate for solution for infusion

Infusion , Injection , Intravenous use

2600 mg/m², iv over 24 h, on d1, d15, d29, d43 pre- and post-operative

Trastuzumab

RO0452317

Herceptin

Powder for concentrate for solution for infusion

Infusion , Intravenous use

Herceptin was administered with a „loading dose“ of 8 mg/kg for the initial dose (d1 preoperative and d1 postoperative), followed by doses of 6 mg/kg, three-weekly cylces. Herceptin was given followed by a 30-60 minute post-infusion observation period

Pertuzumab

RO4368451

Perjeta

Concentrate for solution for infusion

Infusion , Intravenous use

Perjeta was administered intravenoeus at a flat dose of 840 mg every 3 weeks Perjeta was given followed by a 30-60 minute post infusion oberservation period

Docetaxel

Concentrate and solvent for solution for injection/infusion, Concentrate for solution for infusion

Infusion , Intravenous use

Administration 50 mg/m², iv over 1 h d1, d15, d29, d43 pre- and post-operative

Oxaliplatin

Concentrate for solution for infusion

Infusion , Intravenous use

85 mg/m², iv over 2-6 h; d1, d15, d29, d43 pre- and post-operative

Leucovorin

folinic acid

Powder for solution for injection/infusion, Solution for injection/infusion

Infusion , Injection , Intramuscular and intravenous use

200 mg/m², iv, d1, d15, d29, d43 pre- and post-operative

5-Fluorouracil

5-FU

Concentrate for solution for infusion, Solution for injection/infusion

Infusion , Injection , Intravenous use

2600 mg/m², iv over 24 h, on d1, d15, d29, d43 pre- and post-operative

FLOT

FLOT/Herceptin/Perjeta

FLOT

FLOT/Herceptin/Perjeta

The pathological complete response (pCR) rate was chosen as primary endpoint for the phase II part of the trial and was defined as the proportion of patients with pCR as evaluated blinded, separately by two central pathologist referring to the total number of patients of the ITT population (missing data were considered as failure) as denominator in the primary analysis. The relevant time point for the primary study endpoint was reached upon completion of surgery. Patients with a pCR at this timepoint added to the rate of the primary endpoint.

Primary

The relevant time point for the primary study endpoint was reached upon completion of surgery. Patients with a pCR at this timepoint added to the rate of the primary endpoint.

The pCR rate was evaluated and reported in an explorative or descriptive manner. Analysis of the primary endpoint was additionally carried out using Fisher´s exact test

FLOT/Herceptin/Perjeta v FLOT

81

Pre-specified

The subgroup of patients with IHC 3+ consisted of 66 patients, 34 in arm A, and 32 in arm B. Within this subgroup, two patients did not undergo surgery because of early progression and premature EOT (patient lost). Thus, information on pathological response is documented and analysed as missing value. Pathological responses were assessed by central pathology according to the Becker criteria.

Secondary

The relevant time point was reached upon completion of surgery.

The subgroup of patients with other cases than IHC 3+ consisted of 15 patients, 7 in arm A, and 8 in arm B.

Secondary

The relevant time point was reached upon completion of surgery

R0 resection rate was defined as the percentage of patients achieving a R0 (margin-free) resection referring to the total number of patients randomized into the respective treatment arm. Classification of residual tumor as R0, R1 or other was evaluated according to documentation in the reports of the local pathologists. Reports were centrally reviewed by medical experts of the sponsor. Patients with no R0 resection either were those who had no resection at all, for whom no data for residual tumor was documented (both shown as missing), or those who were not resected margin-free and had R1 resection. No R2 resection was documented

Secondary

The relevant time point was reached upon completion of surgery

Disease-free survival (DFS) was defined as the time from randomization to the first occurrence of disease progression or disease recurrence after surgery, as determined by the investigator using CT criteria, or death from any cause. Patients without event were censored at the date of their last tumor assessment. In arm A, the median DFS was 26 months, in arm B the median was not yet reached at database closure.

Secondary

Tumors were assessed before randomization & prior to surgery and then every 3 months thereafter until progression/relapse, death or end of follow-up (was set at 1 year after last patient in ,but did not end earlier than 3 months after last dose)

Event related data like disease-free and overall survival were estimated by the product limit method providing the numbers of events and censored cases and compared using the log-rank test. Additional hazard ratios (HR) and 95% confidence intervals (CI) were estimated using a Cox regression model. Patients without any documentation of events, lost to follow-up or with early drop-out were censored at last observation i.e., the date of last tumor assessment for disease-free survival.

FLOT v FLOT/Herceptin/Perjeta

81

Pre-specified

Median DFS was 26 months in arm A within this subgroup and was not yet reached in arm B until the end of follow-up period

Secondary

Tumors were assessed before randomization & prior to surgery and then every 3 months thereafter until progression/relapse, death or end of follow-up (was set at 1 year after last patient in ,but did not end earlier than 3 months after last dose)

FLOT/Herceptin/Perjeta v FLOT

66

Pre-specified

Median DFS was 31 months in arm A within this subgroup and was not yet reached in arm B until the end of follow-up period.

Secondary

Tumors were assessed before randomization & prior to surgery and then every 3 months thereafter until progression/relapse, death or end of follow-up (was set at 1 year after last patient in ,but did not end earlier than 3 months after last dose)

The follow-up time at the final analysis was a median of 21 months in arm A and 25 months in arm B. The maximum observation period was 42 months. One patient in arm B was lost to follow-up immediately after randomization. At the time of analysis, 11 deaths were observed in arm A (i.e. 27% of the patients) and 7 in arm B (18%) within the ITT population. The rest of the patients was censored at indicated time points. The median OS was not reached in both treatment arms at the time of the final analysis.

Secondary

Overall survival (OS) was defined as the time from randomization to death from any cause. Patients without the respective event being observed at the time of maximum follow-up are censored at this time point.

Event related data like disease-free and overall survival were estimated by the product limit method providing the numbers of events and censored cases and compared using the log-rank test. Additional hazard ratios (HR) and 95% confidence intervals (CI) were estimated using a Cox regression model. Patients without any documentation of events, lost to follow-up or with early drop-out were censored at last observation i.e., the last known alive date for overall survival

FLOT v FLOT/Herceptin/Perjeta

81

Pre-specified

At the time of analysis, 10 deaths (29% of the patients) were observed in arm A versus 6 deaths (19%) in arm B. Median OS was not yet reached in arm A and arm B until the end of follow-up period

Secondary

Overall survival (OS) was defined as the time from randomization to death from any cause. Patients without the respective event being observed at the time of maximum follow-up are censored at this time point

FLOT v FLOT/Herceptin/Perjeta

66

Pre-specified

Median OS was was not yet reached in arm A and arm B until the end of follow-up period. At the time of analysis, 1 patient (14%) in arm A died versus 1 patient (13%) in arm B.

Secondary

Overall survival (OS) was defined as the time from randomization to death from any cause. Patients without the respective event being observed at the time of maximum follow-up are censored at this time point

Secondary

up to 60 days after surgery

Secondary

up to 60 days after surgery

The ITT population includes all patients who were randomized. Treatment assignment is based on the randomized treatment (primary population). The ITT population is the primary population for the description of the patient and treatment characteristics and is used for the primary efficacy analysis.

Other pre-specified

The relevant time point for the pathological response was reached upon completion of surgery

The Per-Protocol Analysis Set (PP) contains all eligible patients, who fulfilled all inclusion/exclusion criteria, and who underwent surgery and experienced no other major protocol violations such as wrong treatment received. Treatment assignment is based on the treatment received. This set is used in efficacy evaluation for comparison to the full analysis set.

Other pre-specified

The relevant time point for the pathological response was reached upon completion of surgery

Patients were assessed for adverse events at each visit during the study. Adverse event monitoring continued for at least 30 days (FLOT) and 90 days (monoclonal antibodies) following the last dose of study treatment

Toxicity was assessed by non-directive questioning of patients as well as physical examination and laboratory tests of patients at each visit during the study. Toxic effects were graded according to NCI-CTCAE v4.0. A relationship of an AE to the study treatment was determined by the Investigator.

4

FLOT

FLOT/Herceptin/Perjeta