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

NCT ID: NCT03520946

Last Updated: 2024-08-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 430 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-24
• Study Completion Date: 2024-07-30

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).

Conditions

Colorectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Ramucirumab

Intervention Type: DRUG

8 mg/kg iv over 60 min on d1+15, q4w

TAS 102

Intervention Type: DRUG

35mg/m2 p.o. twice daily (BID) d1-5 and d8-12, q4w

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.

Group Type: ACTIVE_COMPARATOR

TAS 102

Intervention Type: DRUG

35mg/m2 p.o. twice daily (BID) d1-5 and d8-12, q4w

Interventions

Ramucirumab

8 mg/kg iv over 60 min on d1+15, q4w

Intervention Type: DRUG

TAS 102

35mg/m2 p.o. twice daily (BID) d1-5 and d8-12, q4w

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eli Lilly and Company

INDUSTRY

Sponsor Role: collaborator

Trium Analysis Online GmbH

INDUSTRY

Sponsor Role: collaborator

Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Salah-Eddin Al-Batran, Prof. Dr.

Role: STUDY_CHAIR

Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Locations

MVZ Gesundheitszentrum St. Marien GmbH

Amberg, , Germany

HELIOS Klinikum Bad Saarow

Bad Saarow, , Germany

Charité - Universitätsmedizin Berlin Campus Mitte

Berlin, , Germany

MVZ Seestrasse

Berlin, , Germany

St.-Johannes-Hospital

Dortmund, , Germany

Universitätsklinikum Düsseldorf

Düsseldorf, , Germany

Universitätsklinikum Essen

Essen, , Germany

Krankenhaus Nordwest GmbH

Frankfurt, , Germany

Universitätsklinikum Hamburg-Eppendorf

Hamburg, , Germany

Asklepios Klinik Hamburg Barmbek

Hamburg, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Marien Hospital Herne

Herne, , Germany

Vincentius-Diakonissen-Kliniken gAG

Karlsruhe, , Germany

Universitätsklinikum Leipzig

Leipzig, , Germany

Klinikum Ludwigsburg

Ludwigsburg, , Germany

Tagestherapiezentrum am ITM Universitätsmedizin Mannheim

Mannheim, , Germany

Johannes Wesling Klinikum Minden

Minden, , Germany

Kliniken Maria Hilf GmbH

Mönchengladbach, , Germany

Klinikum der Universität München-Großhadern

München, , Germany

Unversitätsklinikum Münster

Münster, , Germany

Klinikum Nürnberg

Nuremberg, , Germany

Studienzentrum Onkologie Ravensburg

Ravensburg, , Germany

MedCenter Nordsachsen

Schkeuditz, , Germany

Leopoldina Krankenhaus

Schweinfurt, , Germany

MVZ Klinik Dr. Hancken GmbH

Stade, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

Klinikum Wilhelmshaven

Wilhelmshaven, , Germany

Hämatologisch-Onkologische Praxis

Würselen, , Germany

Countries

Germany

Other Identifiers

2017-004162-99

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

RAMTAS

Identifier Type: -

Identifier Source: org_study_id