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About
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.
Full 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).
Enrollment
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Inclusion criteria
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
Signed informed consent before start of specific protocol procedure
Histologically or cytologically documented diagnosis of adenocarcinoma of the colon or rectum
Presence of at least one measurable site of disease following RECIST 1.1 criteria
ECOG (Eastern Cooperative Oncology Group) performance 0-1
Known RAS and BRAF V600E mutational status
Life expectancy of at least 3 months
Adequate hematological, hepatic and renal function parameters:
Patient able and willing to provide written informed consent and to comply with the study protocol
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
Known hypersensitivity against ramucirumab or TAS102
Other known contraindications against ramucirumab, TAS102, or other anti-angiogenic therapies
Prior therapy with TAS102
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
Any antineoplastic treatment including irradiation within 14 days (42 days for mitomycin c) prior to start of therapy.
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.
Symptomatic brain metastasis
Clinically significant cardiovascular disease
Active clinically serious infections (> grade 2 NCI-CTC version 4.0)
Chronic inflammatory bowel disease
History of uncontrolled HIV infection or chronic hepatitis B or C
Patients with evidence of bleeding diathesis
Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy
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 gastrointestinal perforation or fistulae in past 6 months or risk factors for perforation
Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy
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
Any condition that could jeopardize the safety of the patient and their compliance of the study
Medical, psychological or social conditions that may interfere with the participation in the study
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
On-treatment participation in another clinical study or received investigational drug therapy 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
Primary purpose
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Interventional model
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430 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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