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Stomach CancerPhase 2/3RAMSES/FLOT7NCT02661971

FLOT vs. FLOT/Ramucirumab for Perioperative Therapy of Gastric or GEJ Cancer (RAMSES)

A Phase 2/3 study testing Docetaxel, Oxaliplatin and Calciumfolinat in people with Stomach Cancer and Gastroesophageal Junction Cancer, run by Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest at 2 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Previous studies provide a strong theoretical rationale for the conduct of a randomized study evaluating the efficacy and safety of ramucirumab in combination with FLOT in the perioperative treatment of resectable adenocarcinoma of the stomach or GEJ. Read more about this study

Who is it for?
Ages 18 to 70 years
What is being tested?
Docetaxel, Oxaliplatin and Calciumfolinat
Could I receive a placebo?
No, everyone receives an active treatment
How many people
180 participants
Where
2 sitesin 2 countries
Study dates
Jun 2016to 20 Jun 2022
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologically confirmed, resectable adenocarcinoma of the gastroesophageal junction (AEG/GEJ-type II-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, according to the techniques described in Chapter 12 Surgical Therapy that are subtotal, total or transhiatal extended gastrectomy (patients planned to receive transthoracic esophagectomy are not eligible for the study)
  • Participating sites in PETRARCA study: Negative HER-2 detection (score IHC HER-2 0 or IHC HER-2 1+ ); IHC HER-2 2+ and negative by FISH, SISH or CISH1
  • No preceding cytotoxic or targeted therapy
  • No prior partial or complete tumor resection
  • Female and male patients ≥ 18 and ≤ 70 years. Patients in reproductive age must be willing to use adequate contraception during the study and for 7 months after the end of ramucirumab 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.
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  • ECOG ≤ 1
  • Exclusion of distant metastasis by CT or MRI of abdomen, pelvis, and thorax, bone scan or MRI (if bone metastases are suspected due to clinical signs). Exclusion of the infiltration of any adjacent organs or structures by CT or MRI.
  • Laparoscopic exclusion of peritoneal carcinomatosis, in case of ascites, peritoneal masses, or if otherwise suspected clinically
  • Adequate hematological, hepatic and renal function parameters:
  • Leukocytes ≥ 3000/mm³, platelets ≥ 100,000/mm³, neutrophil count (ANC) ≥1000/µL, hemoglobin ≥9 g/dL (5.58 mmol/L),
  • Adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to randomization.
  • Serum creatinine ≤ 1.5 x upper limit of normal
  • Urinary protein ≤1+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must demonstrate <1000 mg of protein in 24 hours to allow participation in this protocol).
  • Bilirubin ≤ 1.5 x upper limit of normal, AST and ALT ≤ 3.0 x upper limit of normal, alkaline phosphatase ≤ 6 x upper limit of normal
  • Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures

Who cannot join

  • Known hypersensitivity against ramucirumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
  • Other known contraindications against ramucirumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
  • Patients with esophageal cancer and those with adenocarcinoma of GEJ type I and all patients who are planned to have transthoracic esophagectomy.
  • Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, peripheral artery occlusive disease (PAOD, German pAVK), or any history of aortic aneurysm
  • Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina.
  • Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management.
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  • Clinically significant valvular defect
  • 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
  • Criteria of unresectability, e.g.:
  • Radiologically documented evidence of major blood vessel invasion or encasement by cancer.
  • Patients with involved retroperitoneal (e.g. para-aortal, paracaval or interaortocaval lymph nodes) or mesenterial lymph nodes (distant metastases!)
  • Known brain metastases
  • Other severe internal disease or acute infection
  • Peripheral polyneuropathy ≥ NCI Grade II
  • Chronic inflammatory bowel disease
  • Grade 3-4 GI bleeding within 3 months prior to enrollment.
  • History of gastric perforation or fistulae in past 6 months
  • Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to enrollment.
  • The patient has undergone major surgery within 28 days prior to enrollment except staging laparoscopy.
  • Receiving chronic antiplatelet therapy, including aspirin (Once-daily aspirin use (maximum dose 325 mg/day) is permitted), nonsteroidal anti-inflammatory drugs (including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents.
  • History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to randomization.
  • Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites.
  • 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 7 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
  • Current chronic alcohol, nicotine or drug abuse or history of chronic alcohol abuse during last 12 months. Nicotine abuse is defined as ≥ 25 pack-years (Willigendael et al., 2004).

Trial locations and contacts

2 sites in 2 countries.

2 sites in 2 countries

Germany1 site

  • Institute for Clinical Cancer Research Krankenhaus Nordwest

    Frankfurt, 60488

Other trials in Germany

Italy1 site

  • Università degli studi della Campania "Luigi Vanvitelli"

    Naples, Campania

Other trials in Italy

About this study

Official title: Perioperative RAMucirumab in Combination With FLOT Versus FLOT Alone for reSEctable eSophagogastric Adenocarcinoma - RAMSES - a Phase II/III Trial of the AIO

Previous studies provide a strong theoretical rationale for the conduct of a randomized study evaluating the efficacy and safety of ramucirumab in combination with FLOT in the perioperative treatment of resectable adenocarcinoma of the stomach or GEJ.

Read the 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.

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 evaluate 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 centrally reviewed and then stratified by tumor site (GEJ vs. gastric), histological type (intestinal vs. diffuse/mixed or unknown) and clinical stage (T1/2 vs. T3/4 and/or N+) and randomized 1:1 to receive either FLOT (Arm A) or FLOT/ramucirumab (Arm B).

Arm A (FLOT) Patients randomized to Arm A will receive 4 pre-operative cycles (8 weeks) of biweekly FLOT (Docetaxel 50 mg/m² in 250 ml NaCl 0.9%, iv over 1 h; Oxaliplatin 85 mg/m² in 500 ml G5%, iv over 2h; Leucovorin 200 mg/m² in 250 ml NaCl 0.9%, iv over 30 min; 5-FU 2600 mg/m², iv over 24 h, q2wk) of the preoperative treatment phase. Surgery in Arm A is planned to occur 4 to 6 weeks after d1 of last FLOT. Patients will receive 4 additional post-operative cycles (8 weeks) of FLOT in the post-operative treatment phase. Post-operative treatment should start 6 to 8 weeks, but at maximum 12 weeks after surgery.

Arm B (FLOT/ramucirumab) Patients randomized to Arm B will receive ramucirumab 8mg/kg i.v. over 60 min in combination with the FLOT regimen, which is administered identical to Arm A as described above. Surgery in Arm B is planned to occur 4 to 6 weeks after d1 of last FLOT/ramucirumab dose (but never earlier than 4 weeks after d1 of last FLOT/ramucirumab dose). Patients will receive 4 additional post-operative cycles (8 weeks) of FLOT/ramucirumab in the post-operative treatment phase followed by a total of 16 cycles of ramucirumab as a monotherapy (q2wk), starting 2 weeks after d1 of the last cycle of FLOT/ramucirumab.

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. A change from CT into MRI in the follow up period is possible at any time.

During treatment, clinical visits (blood cell counts, detection of toxicity) occur prior to every treatment dose. Safety of FLOT/ramucirumab will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported.

Being tested
Docetaxel, Oxaliplatin, Calciumfolinat, 5-Fluorouracil, Ramucirumab
Medical subject headings
Stomach Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DocetaxelDrug

    Also called TAXOTERE®

    Docetaxel 50 mg/m², d1

  • OxaliplatinDrug

    Also called ELOXATIN®

    Oxaliplatin 85 mg/m², d1

  • CalciumfolinatDrug

    Also called Leucovorin

    Leucovorin 200 mg/m², d1

  • 5-FluorouracilDrug

    Also called 5-FU

    5-FU 2600 mg/m², d1

  • RamucirumabBiological

    Ramucirumab 8mg/kg, d1

Study groups in NCT02661971
Study groupRoleWhat they receive
FLOT aloneActive comparatorPre-operative therapy with FLOT followed by surgical resection followed by post-operative therapy with FLOT * Docetaxel 50 mg/m², d1 * Oxaliplatin 85 mg/m², d1 * Calciumfolinat 200 mg/m², d1 * 5-Fluorouracil 2600 mg/m², d1
Receives: Drug: Docetaxel; Drug: Oxaliplatin; Drug: Calciumfolinat; Drug: 5-Fluorouracil
FLOT + RamucirumabExperimentalPre-operative therapy with FLOT + ramucirumab followed by surgical resection followed by post-operative therapy with FLOT + ramucirumab * Ramucirumab 8mg/kg, d1 * Docetaxel 50 mg/m², d1 * Oxaliplatin 85 mg/m², d1 * Calciumfolinat 200 mg/m², d1 * 5-Fluorouracil 2600 mg/m², d1
Receives: Drug: Docetaxel; Drug: Oxaliplatin; Drug: Calciumfolinat; Drug: 5-Fluorouracil; Biological: Ramucirumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Phase II: Rate of pathological complete or subtotal responses (pCR/pSR): assessed according to Becker remission criteria

    Measured: 3 years

  2. Phase III: Overall Survival (OS): time from randomization to death of any cause

    Survival rates for the different time points will be determined using the Kaplan-Meier analysis of OS.

    Measured: 3 years

Secondary outcomes (9)

  1. Phase II/III: R0 resection rate: reported descriptively

    Measured: 75 days

  2. Phase II/III: Progression Free Survival (PFS): time from randomization until disease progression, disease recurrence after surgery or death of any cause

    Survival rates for the different time points will be determined using the Kaplan-Meier analysis of PFS

    Measured: 3 years

  3. Phase II: Overall Survival (OS): time from randomization to death of any cause

    Measured: 3 years

  4. Phase III: Pathological response rates: assessed according to Becker remission criteria (Becker et al., 2003)

    Measured: 75 days

  5. Phase III: Progression Free Survival (PFS): time from randomization until disease progression, disease recurrence after surgery or death of any cause

    Measured: 3/5 years

  6. Phase III: Overall Survival (OS): time from randomization to death of any cause

    Measured: 3/5 years

  7. Phase II/III: Subgroup analyses: pCR/pSR according to subgroup (intestinal vs. diffuse/mixed or unknown and GEJ vs. gastric)

    Measured: 3/5 years

  8. Phase II/III: Subgroup analyses: OS (medians and rates) according to subgroup (intestinal vs. diffuse/mixed or unknown and GEJ vs. gastric)

    Measured: 3/5 years

  9. Phase II/III: Subgroup analyses: PFS (medians and rates) according to subgroup (intestinal vs. diffuse/mixed or unknown and GEJ vs. gastric)

    Measured: 3/5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Jan 2016 (estimated)
  2. Study startJun 2016
  3. Primary completionDec 2021
  4. Study completion20 Jun 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
180 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02661971
Sponsor's protocol ID
RAMSES/FLOT7
Acronym
RAMSES/FLOT7
Status last verified
Jul 2022
First submitted
19 Jan 2016
Last updated
11 Jul 2022
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No: No IPD will be shared.

Publications

  • Goetze TO, Hofheinz RD, Gaiser T, Schmalenberg H, Strumberg D, Goekkurt E, Angermeier S, Zander T, Kopp HG, Pink D, Siegler G, Schenk M, de Vita F, Galizia G, Maiello E, Bechstein WO, Elshafei M, Loose M, Sookthai D, Brulin T, Pauligk C, Homann N, Al-Batran SE. Perioperative FLOT plus ramucirumab for resectable esophagogastric adenocarcinoma: A randomized phase II/III trial of the German AIO and Italian GOIM. Int J Cancer. 2023 Jul 1;153(1):153-163. doi: 10.1002/ijc.34495. Epub 2023 Mar 23.

    PubMed 36883420

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Docetaxel, Oxaliplatin and Calciumfolinat in people with Stomach Cancer and Gastroesophageal Junction Cancer, run by Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest at 2 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Germany, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase II: Rate of pathological complete or subtotal responses (pCR/pSR): assessed according to Becker remission criteria (time frame: 3 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02661971, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jul 2022.

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