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RAMucirumab in Combination Wth TAS102 vs. TAS102 Alone in Chemotherapy Refractory Metastatic Colorectal Cancer Patients (RAMTAS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03520946
Recruitment Status : Recruiting
First Posted : May 11, 2018
Last Update Posted : February 16, 2022
Sponsor:
Collaborators:
Eli Lilly and Company
Trium Analysis Online GmbH
Information provided by (Responsible Party):
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Tracking Information
First Submitted Date  ICMJE April 17, 2018
First Posted Date  ICMJE May 11, 2018
Last Update Posted Date February 16, 2022
Actual Study Start Date  ICMJE January 24, 2019
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 13, 2020)
Overall survival [ Time Frame: Up to 4 years ]
Overall survival according to Kaplan-Meier
Original Primary Outcome Measures  ICMJE
 (submitted: April 27, 2018)
Overall survival [ Time Frame: Up to 3 years ]
Overall survival according to Kaplan-Meier
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 13, 2020)
  • Overall response rate (ORR) [ Time Frame: Up to 4 years ]
    ORR defined as the proportion of patients with complete or partial remission according to RECIST 1.1
  • Disease control rate (DCR) [ Time Frame: Up to 4 years ]
    DCR defined as the proportion of patients with complete or partial remission and stable disease according to RECIST 1.1
  • Progression-free survival (PFS) [ Time Frame: Up to 4 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
  • Overall survival (OS) rate 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
  • Efficacy (ORR) subgroup [ Time Frame: Up to 4 years ]
    Efficacy (ORR) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1
  • Efficacy (PFS) subgroup [ Time Frame: Up to 4 years ]
    Efficacy (PFS) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1
  • Efficacy (OS) subgroup [ Time Frame: Up to 4 years ]
    Efficacy (OS) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1
  • 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).
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 27, 2018)
  • 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
  • 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
  • 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
  • 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
  • Efficacy (ORR) [ Time Frame: Up to 3 years ]
    Efficacy (ORR) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1
  • Efficacy (PFS) [ Time Frame: Up to 3 years ]
    Efficacy (PFS) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1
  • Efficacy (OS) [ Time Frame: Up to 3 years ]
    Efficacy (OS) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1
  • 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).
  • 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.
Current Other Pre-specified Outcome Measures
 (submitted: November 13, 2020)
  • Explorative: Overall response rate (ORR) [ Time Frame: Up to 4 years ]
    ORR according to gene expression, mutational profiles, plasma biomarkers and radiologic analysis
  • Explorative: Overall survival (OS) [ Time Frame: Up to 4 years ]
    OS according to gene expression, mutational profiles, plasma biomarkers and radiologic analysis
  • Explorative: Progression-free survival (PFS) [ Time Frame: Up to 4 years ]
    PFS according to gene expression, mutational profiles, plasma biomarkers and radiologic analysis
Original Other Pre-specified Outcome Measures
 (submitted: April 27, 2018)
  • Explorative: Overall response rate (ORR) [ Time Frame: Up to 3 years ]
    ORR according to gene expression, mutational profiles and plasma biomarkers
  • Explorative: Overall survival (OS) [ Time Frame: Up to 3 years ]
    OS according to gene expression, mutational profiles and plasma biomarkers
  • Explorative: Progression-free survival (PFS) [ Time Frame: Up to 3 years ]
    PFS according to gene expression, mutational profiles and plasma biomarkers
 
Descriptive Information
Brief Title  ICMJE RAMucirumab in Combination Wth TAS102 vs. TAS102 Alone in Chemotherapy Refractory Metastatic Colorectal Cancer Patients
Official Title  ICMJE A Phase III Study of RAMucirumab in Combination With TAS102 vs. TAS102 Monotherapy in Chemotherapy Refractory Metastatic Colorectal Cancer Patients
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Colorectal Cancer
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Ramucirumab
    • Drug: TAS 102
  • 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.
    Intervention: Drug: TAS 102
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 13, 2020)
426
Original Estimated Enrollment  ICMJE
 (submitted: April 27, 2018)
144
Estimated Study Completion Date  ICMJE June 2024
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Metastatic and inoperable, colorectal cancer who has progressed on/after, or did not tolerate, refuse or have contraindications to: fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic therapies (bevacizumab, aflibercept, regorafenib or ramucirumab) and if indicated anti-EGFR antibodies (cetuximab or panitumumab).

    Intolerance is defined as a permanent discontinuation of the respective treatment resulting from toxicity

  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 or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute (that is, if serum creatinine is >1.5 times the ULN, a 24-hour urine collection to calculate creatinine clearance must be performed)
    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. 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) or hormonal contraception (implantable, patch, oral). Women who use a hormonal contraception method should use an additional barrier method like 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. Any antineoplastic treatment including irradiation within 14 days (42 days for mitomycin c) prior to start of therapy.
  6. 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. The patient has elective or planned major surgery to be performed during the course of the clinical trial.
  7. Symptomatic brain metastasis
  8. 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), symptomatic 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
  9. Active clinically serious infections (> grade 2 NCI-CTC version 4.0)
  10. Chronic inflammatory bowel disease
  11. History of uncontrolled HIV infection or chronic hepatitis B or C
  12. Patients with evidence of bleeding diathesis
  13. Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy
  14. 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
  15. History of gastrointestinal perforation or fistulae in past 6 months or risk factors for perforation
  16. Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy
  17. 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
  18. Any condition that could jeopardize the safety of the patient and their compliance of the study
  19. Medical, psychological or social conditions that may interfere with the participation in the study
  20. 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

  21. On-treatment participation in another clinical study or received investigational drug therapy in the period 30 days prior to inclusion and during the study
  22. Subject pregnant or breast feeding, or planning to become pregnant within 7 months after the end of treatment
  23. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
  24. Any other concurrent antineoplastic treatment including irradiation
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Stefan Kasper-Virchow, Prof. Dr. +49201723 ext 3449 stefan.kasper@uk-essen.de
Contact: Claudia Pauligk, Dr. +49697601 ext 3906 ramtas@ikf-khnw.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03520946
Other Study ID Numbers  ICMJE RAMTAS
2017-004162-99 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: No IPD will be shared
Current Responsible Party Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Eli Lilly and Company
  • Trium Analysis Online GmbH
Investigators  ICMJE
Study Chair: Salah-Eddin Al-Batran, Prof. Dr. Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
PRS Account Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Verification Date February 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP