FLOT vs. FLOT/Herceptin/Pertuzumab for Perioperative Therapy of HER-2 Expressing Gastric or GEJ Cancer (PETRARCA)
Primary Purpose
Stomach Cancer, Gastroesophageal Junction Cancer
Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
FLOT alone
FLOT + Herceptin/Pertuzumab
Sponsored by
About this trial
This is an interventional treatment trial for Stomach Cancer
Eligibility Criteria
Inclusion Criteria:
Histologically confirmed adenocarcinoma of the GEJ (type I-III) or the stomach (uT2, uT3, uT4, any N category, M0), or any T N+ M0 patient, with the following specifications:
- Medical and technical operability
- Centralized detection of either an adenocarcinoma with HER-2 3+ (IHC) or HER-2 2+ (IHC) with amplification proven by FISH, SISH or CISH
- No preceding cytotoxic or targeted therapy
- No prior partial or complete tumor resection
- Exclusion of the infiltration of any adjacent organs or structures by CT or MRI
- Exclusion of distant metastasis by CT or MRI of thorax and abdomen, and bone scan (if osseous lesions are suspected due to clinical signs)
- Female and male patients ≥ 18 years. Patients in reproductive age must be willing to use adequate contraception during the study and for 7 months after the end of pertuzumab and Herceptin treatment (Appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap)). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start.
- ECOG ≤ 2
- Laparoscopic exclusion of peritoneal carcinomatosis, if suspected clinically
Adequate haematological, hepatic and renal function parameters:
- Leukocytes ≥ 3.000/mm³, platelets ≥ 100.000/mm3
- Serum creatinine ≤ 1.5 x upper limit of normal, or GFR > 40 ml/min
- Bilirubin ≤ 1.5 x upper limit of normal, AST and ALT ≤ 3.5 x upper limit of normal, alkaline phosphatase ≤ 6 x upper limit of normal
- LVEF value > 55 %, as assessed by echocardiography
- Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures
Exclusion Criteria:
- Patients with involved retroperitoneal (e.g. para-aortal, paracaval or interaortocaval lymph nodes) or mesenterial lymph nodes (distant metastasis!)
- Known hypersensitivity against Herceptin, pertuzumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
- Other known contraindications against Herceptin, pertuzumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
- Documented history of congestive heart failure of any NYHA, myocardial infarction within the past 6 months before the first dose of study treatment
- Clinically significant valvular defect , history of poorly controlled arterial hypertension (systolic blood pressure > 180 mmHG or diastolic blood pressure > 100 mmHg) or uncontrollable high-risk cardiac arrhythmia (i.e tachycardia with a heart rate > 100/min at rest), significant ventricular arrhythmia (ventricular tachycardia) or higher grade atrioventricular-block (second degree AV-block Type 2 (Mobitz2) or third degree AV-block)
- Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix
- Known brain metastases
- Other severe internal disease or acute infection
- Peripheral polyneuropathy ≥ NCI Grade II
- Chronic inflammatory bowel disease
- Clinically significant active GI bleeding
- On-treatment participation in another clinical study in the period 30 days prior to inclusion and during the study
- Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
- Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
- Any other concurrent antineoplastic treatment including irradiation
Sites / Locations
- Institute for Clinical Cancer Research Krankenhaus Nordwest
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
FLOT alone
FLOT + Herceptin/Pertuzumab
Arm Description
Pre-operative therapy with FLOT followed by surgical resection followed by post-operative therapy with FLOT
Pre-operative therapy with FLOT + Herceptin/Pertuzumab followed by surgical resection followed by post-operative therapy with FLOT + Herceptin/Pertuzumab
Outcomes
Primary Outcome Measures
PhaseII: Rate of pathological complete response
Phase III: Median Progression Free Survival
Secondary Outcome Measures
Phase II/III: R0 resection rate
Phase II: Median Progression Free Survival (PFS)
Phase II/III: Median Overall Survival
Phase II: PK Analysis
Phase II/III: Subgroup analyses: pathological response according to HER-2 status HER-2 IHC 3+ vs. other cases
Phase II/III: Subgroup analyses: PFS according to HER-2 status HER-2 IHC 3+ vs. other cases
Phase II/III: Subgroup analyses: OS according to HER-2 status HER-2 IHC 3+ vs. other cases
Phase III: Pathological Response Rates
Phase III: PFS rates
Phase III: OS rates
Phase III: Median OS
Full Information
NCT ID
NCT02581462
First Posted
October 19, 2015
Last Updated
August 10, 2020
Sponsor
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Collaborators
Trium Analysis Online GmbH
1. Study Identification
Unique Protocol Identification Number
NCT02581462
Brief Title
FLOT vs. FLOT/Herceptin/Pertuzumab for Perioperative Therapy of HER-2 Expressing Gastric or GEJ Cancer
Acronym
PETRARCA
Official Title
FLOT vs. FLOT/Herceptin/Pertuzumab for Perioperative Therapy of Adenocarcinoma of the Stomach and Gastroesophageal Junction Expressing HER-2. A Phase II/III Trial of the AIO.
Study Type
Interventional
2. Study Status
Record Verification Date
August 2020
Overall Recruitment Status
Completed
Study Start Date
June 2016 (Actual)
Primary Completion Date
July 17, 2020 (Actual)
Study Completion Date
July 17, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Collaborators
Trium Analysis Online GmbH
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Previous studies provide a strong theoretical rationale for the conduct of a randomized study evaluating the efficacy and safety of Herceptin and pertuzumab in combination with FLOT in the perioperative treatment of resectable HER-2 positive adenocarcinoma of the stomach or GEJ.
Detailed Description
This is a multicenter, randomized, controlled, open-label study including patients with locally advanced adenocarcinoma of the stomach and GEJ scheduled to receive perioperative chemotherapy. According to centrally assessed HER-2 status: Patients with HER-2 positive tumors will receive FLOT +/- Herceptin / pertuzumab.
The scope of the phase II portion of the trial is to evaluate pathological response rates of either regimen assessed by a centralized pathology and define safety and tolerability.
Patients with locally advanced esophagogastric adenocarcinoma (i.e. cT2 any N or any T N-positive) with exclusion of distant metastases will be included in this trial.
Patients will be stratified by age (18-69 vs. ≥ 70), tumor site (GEJ vs. gastric) and clinical stage (T1/2 vs. 3/4 and N- vs. N+) and randomized 1:1 to receive either FLOT (Arm A) or FLOT/Herceptin/pertuzumab (Arm B).
Arm A (control group) Patients randomized to Arm A will receive 4 pre-operative treatments of FLOT (Docetaxel 50 mg/m², iv over 2 h; Oxaliplatin 85 mg/m² in 500 ml G5%, iv over 2h; Leucovorin 200 mg/m² in 250 ml NaCl 0.9 %, iv over 1 h; 5-FU 2600 mg/m², iv over 24 h) on d1, d15, d29, d43 of the preoperative treatment phase. Surgery is recommended to occur 4 weeks after last FLOT (4 weeks after d43 = day 71). Patients will receive 4 additional post-operative treatments of FLOT on d1, d15, d29, and d43 of the post-operative treatment phase. Post-operative treatment should start 6 to 8 weeks, but at maximum 12 weeks after surgery.
Arm B (Herceptin/pertuzumab group) Patients randomized to Arm B will receive the FLOT regimen identical to Arm A as described above in conjunction with three-weekly Herceptin at 8mg/kg initial dose (Day 1, loading dose) followed by subsequent doses of Herceptin at 6mg/kg on d22 and d43 and pertuzumab at 840mg on d1, d22, and d43. Surgery is recommended to occur 4 weeks after last FLOT/Herceptin/pertuzumab dose (4 weeks after d43 = day 71). Patients will receive 3 additional doses of Herceptin and pertuzumab on d1, d22, and d43 of the post-operative treatment phase, together with the postoperative chemotherapy. Moreover, patients will receive 11 additional doses of Herceptin and pertuzumab after the end of post-operative FLOT.
In both of the arms, tumor assessments (CT or MRI) are performed before randomization and prior to surgery and then every 3 months thereafter until progression/relapse, death or end of follow-up.
During treatment, clinical visits (blood cell counts, detection of toxicity) occur prior to every treatment dose. Safety of FLOT/Herceptin/pertuzumab will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stomach Cancer, Gastroesophageal Junction Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
81 (Actual)
8. Arms, Groups, and Interventions
Arm Title
FLOT alone
Arm Type
Experimental
Arm Description
Pre-operative therapy with FLOT followed by surgical resection followed by post-operative therapy with FLOT
Arm Title
FLOT + Herceptin/Pertuzumab
Arm Type
Experimental
Arm Description
Pre-operative therapy with FLOT + Herceptin/Pertuzumab followed by surgical resection followed by post-operative therapy with FLOT + Herceptin/Pertuzumab
Intervention Type
Drug
Intervention Name(s)
FLOT alone
Intervention Description
Pre-operative therapy:
Docetaxel 50 mg/m², d1, d15, d29, d43
Oxaliplatin 85 mg/m², d1, d15, d29, d43
Leucovorin 200 mg/m², d1, d15, d29, d43 (can be replaced by sodium folinate according to local guidelines)
5-FU 2600 mg/m², d1, d15, d29, d43
Surgery is recommended to be scheduled 4 weeks after d43.
Post-operative therapy (start 6 to 8 weeks after surgery):
Docetaxel 50 mg/m², d1, d15, d29, d43
Oxaliplatin 85 mg/m², d1, d15, d29, d43
Leucovorin 200 mg/m², d1, d15, d29, d43 (can be replaced by sodium folinate according to local guidelines)
5-FU 2600 mg/m², d1, d15, d29, d43
Intervention Type
Biological
Intervention Name(s)
FLOT + Herceptin/Pertuzumab
Intervention Description
Pre-operative therapy:
Herceptin 8/6 mg/kg, d1, d22, d43
Pertuzumab 840 mg, d1, d22, d43
Docetaxel 50 mg/m², d1, d15, d29, d43
Oxaliplatin 85 mg/m², d1, d15, d29, d43
Leucovorin 200 mg/m², d1, d15, d29, d43 (can be replaced by sodium folinate according to local guidelines)
5-FU 2600 mg/m², d1, d15, d29, d43
Surgery is recommended to be scheduled 4 weeks after d43.
Post-operative therapy (start 6 to 8 weeks after surgery):
Herceptin 8/6 mg/kg, d1, d22, d43
Pertuzumab 840 mg, d1, d22, d43
Docetaxel 50 mg/m², d1, d15, d29, d43
Oxaliplatin 85 mg/m², d1, d15, d29, d43
Leucovorin 200 mg/m², d1, d15, d29, d43 (can be replaced by sodium folinate according to local guidelines)
5-FU 2600 mg/m², d1, d15, d29, d43.
Primary Outcome Measure Information:
Title
PhaseII: Rate of pathological complete response
Time Frame
3 years
Title
Phase III: Median Progression Free Survival
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Phase II/III: R0 resection rate
Time Frame
75 days
Title
Phase II: Median Progression Free Survival (PFS)
Time Frame
3 years
Title
Phase II/III: Median Overall Survival
Time Frame
3/5 years
Title
Phase II: PK Analysis
Time Frame
3 years
Title
Phase II/III: Subgroup analyses: pathological response according to HER-2 status HER-2 IHC 3+ vs. other cases
Time Frame
3/5 years
Title
Phase II/III: Subgroup analyses: PFS according to HER-2 status HER-2 IHC 3+ vs. other cases
Time Frame
3/5 years
Title
Phase II/III: Subgroup analyses: OS according to HER-2 status HER-2 IHC 3+ vs. other cases
Time Frame
3/5 years
Title
Phase III: Pathological Response Rates
Time Frame
5 years
Title
Phase III: PFS rates
Time Frame
3 and 5 years
Title
Phase III: OS rates
Time Frame
3 and 5 years
Title
Phase III: Median OS
Time Frame
5 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histologically confirmed adenocarcinoma of the GEJ (type I-III) or the stomach (uT2, uT3, uT4, any N category, M0), or any T N+ M0 patient, with the following specifications:
Medical and technical operability
Centralized detection of either an adenocarcinoma with HER-2 3+ (IHC) or HER-2 2+ (IHC) with amplification proven by FISH, SISH or CISH
No preceding cytotoxic or targeted therapy
No prior partial or complete tumor resection
Exclusion of the infiltration of any adjacent organs or structures by CT or MRI
Exclusion of distant metastasis by CT or MRI of thorax and abdomen, and bone scan (if osseous lesions are suspected due to clinical signs)
Female and male patients ≥ 18 years. Patients in reproductive age must be willing to use adequate contraception during the study and for 7 months after the end of pertuzumab and Herceptin treatment (Appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap)). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start.
ECOG ≤ 2
Laparoscopic exclusion of peritoneal carcinomatosis, if suspected clinically
Adequate haematological, hepatic and renal function parameters:
Leukocytes ≥ 3.000/mm³, platelets ≥ 100.000/mm3
Serum creatinine ≤ 1.5 x upper limit of normal, or GFR > 40 ml/min
Bilirubin ≤ 1.5 x upper limit of normal, AST and ALT ≤ 3.5 x upper limit of normal, alkaline phosphatase ≤ 6 x upper limit of normal
LVEF value > 55 %, as assessed by echocardiography
Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures
Exclusion Criteria:
Patients with involved retroperitoneal (e.g. para-aortal, paracaval or interaortocaval lymph nodes) or mesenterial lymph nodes (distant metastasis!)
Known hypersensitivity against Herceptin, pertuzumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
Other known contraindications against Herceptin, pertuzumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
Documented history of congestive heart failure of any NYHA, myocardial infarction within the past 6 months before the first dose of study treatment
Clinically significant valvular defect , history of poorly controlled arterial hypertension (systolic blood pressure > 180 mmHG or diastolic blood pressure > 100 mmHg) or uncontrollable high-risk cardiac arrhythmia (i.e tachycardia with a heart rate > 100/min at rest), significant ventricular arrhythmia (ventricular tachycardia) or higher grade atrioventricular-block (second degree AV-block Type 2 (Mobitz2) or third degree AV-block)
Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix
Known brain metastases
Other severe internal disease or acute infection
Peripheral polyneuropathy ≥ NCI Grade II
Chronic inflammatory bowel disease
Clinically significant active GI bleeding
On-treatment participation in another clinical study in the period 30 days prior to inclusion and during the study
Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
Any other concurrent antineoplastic treatment including irradiation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Salah-Eddin Al-Batran, Prof. Dr.
Organizational Affiliation
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Official's Role
Study Chair
Facility Information:
Facility Name
Institute for Clinical Cancer Research Krankenhaus Nordwest
City
Frankfurt
ZIP/Postal Code
60488
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
No IPD will be shared.
Citations:
PubMed Identifier
35709415
Citation
Hofheinz RD, Merx K, Haag GM, Springfeld C, Ettrich T, Borchert K, Kretzschmar A, Teschendorf C, Siegler G, Ebert MP, Goekkurt E, Mahlberg R, Homann N, Pink D, Bechstein W, Reichardt P, Flach H, Gaiser T, Battmann A, Oduncu FS, Loose M, Sookthai D, Pauligk C, Goetze TO, Al-Batran SE. FLOT Versus FLOT/Trastuzumab/Pertuzumab Perioperative Therapy of Human Epidermal Growth Factor Receptor 2-Positive Resectable Esophagogastric Adenocarcinoma: A Randomized Phase II Trial of the AIO EGA Study Group. J Clin Oncol. 2022 Nov 10;40(32):3750-3761. doi: 10.1200/JCO.22.00380. Epub 2022 Jun 16.
Results Reference
derived
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FLOT vs. FLOT/Herceptin/Pertuzumab for Perioperative Therapy of HER-2 Expressing Gastric or GEJ Cancer
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