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Fachinformation
JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT03520946

Studienbeginn:
Januar 2019

Letztes Update:
17.11.2020

Wirkstoff:
Ramucirumab, TAS 102

Indikation (Clinical Trials):
Colorectal Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Collaborator:
Eli Lilly and Company, Trium Analysis Online GmbH,

Studienleiter

Salah-Eddin Al-Batran, Prof. Dr.
Study Chair
Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Kontakt

Stefan Kasper-Virchow, Prof. Dr.
Kontakt:
Phone: +49201723
Phone (ext.): 3449
E-Mail: stefan.kasper@uk-essen.de» Kontaktdaten anzeigen

Studienlocations (3 von 29)

Klinikum Altenburger Land GmbH
04600 Altenburg
(Thüringen)
GermanyZurückgezogen» Google-Maps
Gynäkologisches Krebszentrum der Ruhruniversität Bochum am Marien Hospital Herne
Hölkeskampring 40
44625 Herne
DeutschlandRekrutierend» Google-Maps
Ansprechpartner:
Dirk Strumberg, Prof. Dr.» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

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).

Ein-/Ausschlusskriterien

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

Studien-Rationale

Primary outcome:

1. Overall survival (Time Frame - Up to 4 years):
Overall survival according to Kaplan-Meier



Secondary outcome:

1. 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

2. 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

3. 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

4. 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

5. Efficacy (ORR) subgroup (Time Frame - Up to 4 years):
Efficacy (ORR) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1

6. Efficacy (PFS) subgroup (Time Frame - Up to 4 years):
Efficacy (PFS) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1

7. Efficacy (OS) subgroup (Time Frame - Up to 4 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.

Studien-Arme

  • 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.
  • 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.

Geprüfte Regime

  • Ramucirumab:
    8 mg/kg iv over 60 min on d1+15, q4w
  • TAS 102:
    35mg/m2 p.o. twice daily (BID) d1-5 and d8-12, q4w

Quelle: ClinicalTrials.gov


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