Regorafenib in Combination With TAS-102 in Subjects With Metastatic Colorectal Cancer Who Have Progressed After Standard Therapy: A Multicenter Phase I Study
Regorafenib in Combination With TAS-102 in Subjects With Metastatic Colorectal Cancer Who Have Progressed After Standard Therapy: A Multicenter Phase I Study
0116-ASG REMETY is a multicenter, open-label, non-randomized, dose-escalation Phase I study evaluating the safety and anti-tumor activity of TAS-102 administered in combination with Regorafenib in patients with metastatic colorectal cancer.
The primary objective is to determine safety, feasibility and the recommended phase II dose (RP2D) of a combination treatment consisting of TAS-102 and Regorafenib in subjects with mCRC who have progressed after standard therapy.
Inclusion Criteria:
Written informed consent and any locally-required authorization (EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
Age ≥ 18 years at time of study entry
Histological or cytological documentation of adenocarcinoma of the colorectal region (CRC)
Metastatic disease not amenable to surgical resection with curative intent
Study treatment must constitute 3rd-line treatment for metastatic disease. Prior treatment lines must encompass at least one fluoropyrimidine-based chemotherapy, an anti-VEGF and, in case of RAS wildtype tumors, an anti-EGFR treatment.
Patients treated with oxaliplatin in an adjuvant setting need to have progressed during or within 6 months of completion of adjuvant therapy to be counted as prior treatment line. Note: Neoadjuvant, perioperative or adjuvant regimens with progression more than 6 months after completion are not considered as prior treatment line for metastatic disease.
Measurable disease, defined as at least one unidimensional measurable lesion on a CT scan as defined by RECIST 1.1
Eastern Cooperative Oncology Group (ECOG) performance status <2 and life expectancy of at least 3 months
Adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days prior to study treatment initiation:
Women of childbearing potential and male subjects must agree to use adequate contraception for the duration of study participation and up to 6 months following completion of therapy. Females of childbearing potential who are sexually active with a non-sterilized male partner must use 2 methods of effective contraception from screening, and must agree to continue using such precautions for 6 months after the final dose of investigational product.
Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a pregnancy test performed at a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.
In the assessment of the investigator, patient is able to comply with study requirements.
Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
Exclusion Criteria:
Prior treatment with Regorafenib, or any other tyrosine kinase inhibitor for the treatment of malignancy
Prior treatment with TAS-102
Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to study inclusion EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (Non invasive tumor), Tis (Carcinoma in situ) and T1 (Tumor invades lamina propria)].
Known history of/or concomitant malignancy other than mCRC likely to affect life expectancy in the judgment of the investigator
History of Gilbert's syndrome
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days and last chemotherapy <21 days prior to first dose of treatment
Radiotherapy within 4 weeks prior to first dose of treatment
Active cardiac disease including any of the following:
Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before start of treatment
Known history of human immunodeficiency virus (HIV) infection
Chronic hepatitis B or C infection (If hepatitis status can not be obtained from medical records re-testing is required.)
Patients with seizure disorder requiring medication
Symptomatic metastatic brain or meningeal tumors unless the patient is >6 months from definitive therapy, has a negative imaging study within 4 weeks prior to treatment initiation, and is clinically stable with respect to the tumor at the time of study entry. Also, the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable, provided that the dose is stable for one month prior to and following screening radiographic studies).
History of organ allograft
Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ Grade 3 (CTCAE v. 4.0) within 4 weeks prior to the start of study treatment.
Non-healing wound, ulcer or bone fracture
Renal failure requiring hemo- or peritoneal dialysis
Dehydration according to CTCAE v. 4.03 Grade >1
Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products
Known dihydropyrimidine dehydrogenase (DPD) deficiency or treatment with DPD inhibitors, including sorivudine or its chemically related analogues such as brivudine within 4 weeks prior to the start of study treatment.
Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
Inability to swallow oral medications
Any malabsorption condition
Unresolved toxicity higher than Grade 1 CTCAE v. 4.03 attributed to any prior therapy/procedure excluding alopecia, anemia and oxaliplatin-induced neurotoxicity (which must be ≤Grade 2) or ongoing infection >Grade 2.
Patients unable or unwilling to discontinue (and substitute if necessary) use of prohibited drugs for at least 2 weeks prior to Day 1 of treatment initiation.
Female subjects who are pregnant, breast-feeding or intent to become pregnant
Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
Participation in another clinical study with an investigational product during the last 30 days before inclusion
Previous enrollment in the present study (does not include screening failure).
Involvement in the planning and/or conduct of the study (applies to Bayer staff and/or staff of sponsor and/or staff of the CRO and study site)
Patient who might be interconnected with or dependent on the sponsor, site or the investigator Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.