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History of Changes for Study: NCT03520946
RAMucirumab in Combination Wth TAS102 vs. TAS102 Alone in Chemotherapy Refractory Metastatic Colorectal Cancer Patients (RAMTAS)
Latest version (submitted February 15, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 April 27, 2018 None (earliest Version on record)
2 June 28, 2018 Study Status
3 July 4, 2018 Eligibility and Study Status
4 December 20, 2018 Recruitment Status, Study Status, IPDSharing, Contacts/Locations and Oversight
5 January 8, 2019 Contacts/Locations and Study Status
6 January 24, 2019 Study Status
7 August 8, 2019 Contacts/Locations and Study Status
8 April 20, 2020 Contacts/Locations and Study Status
9 July 21, 2020 Study Status
10 November 13, 2020 Outcome Measures, Study Status, Contacts/Locations, Study Design, Eligibility and Study Identification
11 February 15, 2022 Study Status
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Study NCT03520946
Submitted Date:  April 27, 2018 (v1)

Open or close this module Study Identification
Unique Protocol ID: RAMTAS
Brief Title: RAMucirumab in Combination Wth TAS102 vs. TAS102 Alone in Chemotherapy Refractory Metastatic Colorectal Cancer Patients (RAMTAS)
Official Title: A Phase IIb Study of RAMucirumab in Combination With TAS102 vs. TAS102 Monotherapy in Chemotherapy Refractory Metastatic Colorectal Cancer Patients
Secondary IDs: 2017-004162-99 [EudraCT Number]
Open or close this module Study Status
Record Verification: April 2018
Overall Status: Not yet recruiting
Study Start: June 1, 2018
Primary Completion: June 1, 2020 [Anticipated]
Study Completion: June 1, 2021 [Anticipated]
First Submitted: April 17, 2018
First Submitted that
Met QC Criteria:
April 27, 2018
First Posted: May 11, 2018 [Actual]
Last Update Submitted that
Met QC Criteria:
April 27, 2018
Last Update Posted: May 11, 2018 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Responsible Party: Sponsor
Collaborators: Eli Lilly and Company
Trium Analysis Online GmbH
Open or close this module Oversight
U.S. FDA-regulated Drug: No
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary: Interventional, prospective, randomized (1:1), controlled, open label, multicenter phase IIb study in patients with advanced metastatic colorectal cancer. The scope of the trial is to evaluate overall survival of either regimen (TAS102 +/- Ramucirumab) and evaluate safety and tolerability.
Detailed Description:

This is an interventional, prospective, randomized (1:1), controlled, open label, multicenter phase IIb study in patients with advanced metastatic colorectal cancer. The scope of the trial is to evaluate overall survival of either regimen and evaluate safety and tolerability.

Patients with advanced metastatic and inoperable, colorectal cancer who have progressed on/after or did not tolerate: fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic therapies (bevacizumab, aflibercept, regorafenib or ramucirumab) and when indicated anti-EGFR (epidermal growth factor receptor) antibodies (cetuximab or panitumumab) will be included in this trial.

Patients will be stratified by the duration of previous anti-angiogenic therapy ≥ or <12 months in total, BRAF V600E mutation status (mutation vs. wildtype), RAS mutation status (mutation vs. wildtype), and randomized 1:1 to receive either ramucirumab/TAS102 (arm A) or TAS102 (arm B). Concurrent use of other chemotherapy is not allowed.

Two interim safety analyses will be conducted when 10 and 40 patients are fully documented in arm A after receiving 2 cycles (one 4-week cycle comprises ramucirumab 8mg/kg administered at d1 and d15 and TAS102 35mg/m2 p.o. twice daily administered on d1-5 and d8-12). The analysis will be reviewed by the lead coordinating investigator (Prof. Dr. Kasper) and members of the steering committee and then by the data safety monitoring board. It is not planned to discontinue recruitment for the interim safety analyses.

Arm A (ramucirumab/TAS102) Patients randomized to arm A will receive ramucirumab 8 mg/kg iv over 60 min on d1+15, q4w and TAS102 35mg/m2 p.o. twice daily (BID) d1-5 and 8-12, q4w until progression or intolerance or completion of 6 cycles.

Arm B (TAS102) Patients randomized to arm B will receive TAS102 35mg/m2 p.o. twice daily (BID) d1-5 and 8-12, q4w until progression, intolerance or completion of 6 cycles.

In both arms, tumor assessments (CT or MRI) are performed before enrollment/randomization and then every 8 weeks (every 2nd cycle) during therapy and every 12 weeks during follow-up 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) will be performed prior to every treatment dose of ramucirumab or every two weeks in arm B or if ramucirumab was discontinued in arm A. Safety of TAS102 +/- ramucirumab will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported. Every 4 weeks during therapy Quality of life (QoL) will be assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC-QLQ-C30) and the EuroQol 5 dimensions 5-level version (EQ-5D-5L).

Open or close this module Conditions
Conditions: Colorectal Cancer
Keywords: colorectal cancer
ramucirumab
tas102
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: None (Open Label)
Allocation: Randomized
Enrollment: 144 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: Arm A (ramucirumab + TAS102)
Patients randomized to arm A will receive ramucirumab 8 mg/kg iv over 60 min on d1+15, q4w and TAS102 35mg/m2 p.o. twice daily (BID) d1-5 and 8-12, q4w until progression or intolerance or completion of 6 cycles.
Drug: Ramucirumab
8 mg/kg iv over 60 min on d1+15, q4w
Drug: TAS 102
35mg/m2 p.o. twice daily (BID) d1-5 and d8-12, q4w
Active Comparator: Arm B (TAS102 only)
Patients randomized to arm B will receive TAS102 35mg/m2 p.o. twice daily (BID) d1-5 and 8-12, q4w until progression, intolerance or completion of 6 cycles.
Drug: TAS 102
35mg/m2 p.o. twice daily (BID) d1-5 and d8-12, q4w
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Overall survival
[ Time Frame: Up to 3 years ]

Overall survival according to Kaplan-Meier
Secondary Outcome Measures:
1. Overall response rate (ORR)
[ Time Frame: Up to 3 years ]

ORR defined as the proportion of patients with complete or partial remission according to RECIST 1.1
2. Disease control rate (DCR)
[ Time Frame: Up to 3 years ]

DCR defined as the proportion of patients with complete or partial remission and stable disease according to RECIST 1.1
3. Progression-free survival (PFS)
[ Time Frame: Up to 3 years ]

PFS, defined as the time from enrollment/randomization to the first occurrence of progression, as determined by the investigator using CT criteria, or death from any cause
4. Overall survival (OS) at different time points
[ Time Frame: 6 months and 1 year ]

OS rate at 6 and 12 months, defined as patients who are alive after at 6 and 12 months, respectively
5. Efficacy (ORR)
[ Time Frame: Up to 3 years ]

Efficacy (ORR) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1
6. Efficacy (PFS)
[ Time Frame: Up to 3 years ]

Efficacy (PFS) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1
7. Efficacy (OS)
[ Time Frame: Up to 3 years ]

Efficacy (OS) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1
8. Quality of life I (QoL)
[ Time Frame: Up to 1 year ]

Quality of life (QoL) as measured by EORTC-QLQ-C30 at d1 of each cycle and on EOT (end of treatment).
9. Quality of life II (QoL)
[ Time Frame: Up to 1 year ]

Quality of life (QoL) as measured by EQ-5D-5L at d1 of each cycle and on EOT.
Other Outcome Measures:
1. Explorative: Overall response rate (ORR)
[ Time Frame: Up to 3 years ]

ORR according to gene expression, mutational profiles and plasma biomarkers
2. Explorative: Overall survival (OS)
[ Time Frame: Up to 3 years ]

OS according to gene expression, mutational profiles and plasma biomarkers
3. Explorative: Progression-free survival (PFS)
[ Time Frame: Up to 3 years ]

PFS according to gene expression, mutational profiles and plasma biomarkers
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age: 70 Years
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  1. Metastatic and inoperable, colorectal cancer who has progressed on/after or did not tolerate: fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic therapies (bevacizumab, aflibercept, regorafenib or ramucirumab) and if indicated anti-EGFR antibodies (cetuximab or panitumumab)
  2. Signed informed consent before start of specific protocol procedure
  3. Histologically or cytologically documented diagnosis of adenocarcinoma of the colon or rectum
  4. Presence of at least one measurable site of disease following RECIST 1.1 criteria
  5. ECOG (Eastern Cooperative Oncology Group) performance 0-1
  6. Known RAS and BRAF V600E mutational status
  7. Life expectancy of at least 3 months
  8. Adequate hematological, hepatic and renal function parameters:
    1. Leukocytes ≥3000/mm³, platelets ≥100,000/mm³, neutrophil count (ANC) ≥1500/μL, hemoglobin ≥9 g/dL (5.58 mmol/L)
    2. Adequate coagulation function as defined by International Normalized Ratio (INR) ≤1.5, and a partial thromboplastin time (PTT) ≤5 seconds above the ULN (upper limit of normal) (unless receiving anticoagulation therapy). Patients receiving warfarin/phenprocoumon must be switched to low molecular weight heparin and have achieved a stable coagulation profile prior to first dose of protocol therapy
    3. Serum creatinine ≤1.5 x upper limit of normal
    4. 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)
    5. Bilirubin ≤1.5 x upper limit of normal, AST and ALT ≤3.0 x upper limit of normal, ≤5xULN if liver metastasis present, alkaline phosphatase ≤6 x upper limit of normal
  9. Patient able and willing to provide written informed consent and to comply with the study protocol
  10. 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 (There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.)

Exclusion Criteria:

  1. Known hypersensitivity against ramucirumab or TAS102
  2. Other known contraindications against ramucirumab, TAS102, or other anti-angiogenic therapies
  3. Prior therapy with TAS102
  4. Drug-related severe adverse events upon pretreatment with antiangiogenic drugs that would require permanent discontinuation and not allow re-challenge with the same class of drug (i.e. ramucirumab) such as noncontrollable severe hypertension or thromboembolic events
  5. Major surgery within 4 weeks of starting therapy within this study, or minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy
  6. Symptomatic brain metastasis
  7. Clinically significant cardiovascular disease
    • NYHA>II°, myocardial infarction within 6 months prior study entry
    • Known clinically significant valvular defect
    • Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or >100 mmHg diastolic for >4 weeks) despite standard medical management
    • Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy
    • History of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy
  8. Active clinically serious infections (> grade 2 NCI-CTC version 4.0)
  9. Chronic inflammatory bowel disease
  10. History of uncontrolled HIV infection or chronic hepatitis B or C
  11. Patients with evidence of bleeding diathesis
  12. Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy
  13. 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
  14. History of gastrointestinal perforation or fistulae in past 6 months or risk factors for perforation
  15. Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy
  16. 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 or bladder, or low/intermediate risk prostate cancer (Gleason score ≤7) with normal PSA levels
  17. Any condition that could jeopardize the safety of the patient and their compliance of the study
  18. Medical, psychological or social conditions that may interfere with the participation in the study
  19. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites.

    Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis

  20. On-treatment participation in another clinical study or received investigational drug therapy in the period 30 days prior to inclusion and during the study
  21. Subject pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment
  22. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
  23. Any other concurrent antineoplastic treatment including irradiation
Open or close this module Contacts/Locations
Central Contact Person: Salah-Eddin Al-Batran, Prof. Dr.
Telephone: +49697601 Ext. 4420
Email: albatran@ikf-khnw.de
Central Contact Backup: Gerrit zur Hausen, Dr.
Telephone: +49697601 Ext. 4518
Email: zurhausen.gerrit@ikf-khnw.de
Study Officials: Stefan Kasper, Prof. Dr.
Principal Investigator
West German Cancer Center - University Hospital Essen, University Duisburg-Essen
Locations: Germany
Klinikum Altenburger Land GmbH
Altenburg, Germany, 04600
Contact:Contact: Armin Schulz-Abelius, Dr.
MVZ Gesundheitszentrum St. Marien GmbH
Amberg, Germany, 922241
Contact:Contact: Ludwig Fischer von Weikersthal, Dr.
HELIOS Klinikum Bad Saarow
Bad Saarow, Germany, 15526
Contact:Contact: Daniel Pink, Dr.
Charité - Universitätsmedizin Berlin Campus Mitte
Berlin, Germany, 10115
Contact:Contact: Susen Burock, Dr.
MVZ Seestrasse
Berlin, Germany, 13347
Contact:Contact: Alexander Schmittel, Dr.
St.-Johannes-Hospital
Dortmund, Germany, 44137
Contact:Contact: Volker Hagen, Dr.
Universitätsklinikum Düsseldorf
Düsseldorf, Germany, 40225
Contact:Contact: Dirk Graf, Prof. Dr.
Universitätsklinikum Essen
Essen, Germany, 45147
Contact:Contact: Stefan Kasper, Prof. Dr.
Krankenhaus Nordwest GmbH
Frankfurt, Germany, 60488
Contact:Contact: Thorsten O Goetze, PD Dr.
Universitätsklinikum Hamburg-Eppendorf
Hamburg, Germany, 20246
Contact:Contact: Alexander Stein, Prof. Dr.
Medizinische Hochschule Hannover
Hannover, Germany, 30625
Contact:Contact: Arndt Vogel, Prof. Dr.
Vincentius-Diakonissen-Kliniken gAG
Karlsruhe, Germany, 76137
Contact:Contact: Alexander Kolov, Dr.
Universitätsklinikum Leipzig
Leipzig, Germany, 04103
Contact:Contact: Albrecht Hoffmeister, Prof. Dr.
Klinikum Ludwigsburg
Ludwigsburg, Germany, 71640
Contact:Contact: Stefan Angermeier, Dr.
Tagestherapiezentrum am ITM Universitätsmedizin Mannheim
Mannheim, Germany, 68167
Contact:Contact: Ralf D Hofheinz, Prof. Dr.
Johannes Weslin Klinikum Minden
Minden, Germany, 32429
Contact:Contact: Hans J Tischler, Dr.
Kliniken Maria Hilf GmbH
Mönchengladbach, Germany, 41063
Contact:Contact: Ullrich Graeven, Prof. Dr.
Klinikum der Universität München-Großhadern
München, Germany, 81377
Contact:Contact: Volker Heinemann, Prof. Dr.
Klinikum Nürnberg
Nürnberg, Germany, 90419
Contact:Contact: Gabriele Siegler, Dr.
Studienzentrum Onkologie Ravensburg
Ravensburg, Germany, 88212
Contact:Contact: Tobias Dechow, Prof. Dr.
Leopoldina Krankenhaus
Schweinfurt, Germany, 97422
Contact:Contact: Stephan Kanzler, Prof. Dr.
MVZ Klinik Dr. Hancken GmbH
Stade, Germany, 21680
Contact:Contact: Johannes Meiler, Dr.
Klinikum Wilhelmshaven
Wilhelmshaven, Germany, 26389
Contact:Contact: Tanja Trarbach, Dr.
Hämatologisch-Onkologische Praxis
Würselen, Germany, 52146
Contact:Contact: Christoph Maintz, Dr.
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Citations:
Links:
Available IPD/Information:

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